(Former name, former address and former fiscal year, if changed since last report)

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of ‘‘large accelerated filer,’’ ‘‘accelerated filer,’’ ‘‘smaller reporting company,’’ and ‘‘emerging growth company’’ in Rule 12b–2 of the Exchange Act.

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

Number of registrant’s ordinary shares, nominal value $0.0001, outstanding as of October 28, ~~2020: 220,710,086.~~

	As of			As of			As of			As of
	September 30,			December 31,			September 30,			December 31,
	2020			2019			2021			2020
ASSETS
CURRENT ASSETS:
Cash and cash equivalents	$	1,725,403		$	1,076,287		$	1,068,547		$	2,079,906
Restricted cash		3,573			3,752			3,839			3,573
Accounts receivable, net		705,898			408,685			775,371			659,701
Inventories, net		77,104			53,802			237,434			75,283
Prepaid expenses and other current assets		220,341			143,577			328,730			251,945
Total current assets		2,732,319			1,686,103			2,413,921			3,070,408
Property and equipment, net		156,287			30,159
Property, plant and equipment, net								285,837			189,037
Developed technology and other intangible assets, net		1,847,880			1,702,628			3,051,135			1,782,962
In-process research and development								880,000			—
Goodwill		413,669			413,669			1,069,031			413,669
Deferred tax assets, net		566,605			555,165			782,852			560,841
Other assets		50,115			48,310			125,912			55,699
Total assets	$	5,766,875		$	4,436,034		$	8,608,688		$	6,072,616
LIABILITIES AND SHAREHOLDERS’ EQUITY
CURRENT LIABILITIES:
Accounts payable	$	38,978		$	21,514		$	50,724		$	37,710
Accrued expenses		421,827			235,234
Accrued expenses and other current liabilities								483,833			485,567
Accrued trade discounts and rebates		322,798			466,421			303,486			352,463
Long-term debt—current portion								16,000			—
Total current liabilities		783,603			723,169			854,043			875,740
LONG-TERM LIABILITIES:
Exchangeable Senior Notes, net		—			351,533
Long-term debt, net		1,002,846			1,001,308			2,557,864			1,003,379
Deferred tax liabilities, net		97,647			94,247			591,552			66,474
Other long-term liabilities		85,968			80,328			155,015			101,672
Total long-term liabilities		1,186,461			1,527,416			3,304,431			1,171,525
COMMITMENTS AND CONTINGENCIES
SHAREHOLDERS’ EQUITY:
Ordinary shares, $0.0001 nominal value; 600,000,000 shares authorized at September 30, 2020 and December 31, 2019; 220,995,108 and 188,402,040 shares issued at September 30, 2020 and December 31, 2019, respectively, and 220,610,742 and 188,017,674 shares outstanding at September 30, 2020 and December 31, 2019, respectively		22			19
Treasury stock, 384,366 ordinary shares at September 30, 2020 and December 31, 2019		(4,585	)		(4,585	)
Ordinary shares, $0.0001 nominal value; 600,000,000 shares authorized at September 30, 2021 and December 31, 2020; 227,026,047 and 221,721,674 shares issued at September 30, 2021 and December 31, 2020, respectively, and 226,641,681 and 221,337,308 shares outstanding at September 30, 2021 and December 31, 2020, respectively								22			22
Treasury stock, 384,366 ordinary shares at September 30, 2021 and December 31, 2020								(4,585	)		(4,585	)
Additional paid-in capital		4,208,845			2,797,602			4,310,886			4,245,945
Accumulated other comprehensive loss		(1,028	)		(1,905	)		(1,532	)		(145	)
Accumulated deficit		(406,443	)		(605,682	)
Retained earnings (accumulated deficit)								145,423			(215,886	)
Total shareholders’ equity		3,796,811			2,185,449			4,450,214			4,025,351
Total liabilities and shareholders' equity	$	5,766,875		$	4,436,034		$	8,608,688		$	6,072,616

The accompanying notes are an integral part of these condensed consolidated financial statements.

	For the Three Months Ended September 30,						For the Nine Months Ended September 30,						For the Three Months Ended September 30,						For the Nine Months Ended September 30,
	2020			2019			2020			2019			2021			2020			2021			2020
Net sales	$	636,427		$	335,466		$	1,455,115		$	936,484		$	1,036,992		$	636,427		$	2,211,946		$	1,455,115
Cost of goods sold		151,475			89,949			370,406			267,254			251,640			151,475			553,003			370,406
Gross profit		484,952			245,517			1,084,709			669,230			785,352			484,952			1,658,943			1,084,709
OPERATING EXPENSES:
Research and development		30,206			24,572			138,483			74,611			93,549			30,206			291,076			138,483
Selling, general and administrative		226,164			172,326			696,271			511,720			360,260			226,164			1,047,456			696,271
Loss on sale of assets		—			—			—			10,963
Impairment of long-lived asset														—			—			12,371			—
Gain on sale of asset														—			—			(2,000	)		—
Total operating expenses		256,370			196,898			834,754			597,294			453,809			256,370			1,348,903			834,754
Operating income		228,582			48,619			249,955			71,936			331,543			228,582			310,040			249,955
OTHER EXPENSE, NET:
Loss on debt extinguishment		(14,602	)		(41,371	)		(31,856	)		(58,835	)
Interest expense, net		(12,185	)		(20,428	)		(48,100	)		(69,991	)		(22,977	)		(12,185	)		(59,018	)		(48,100	)
Foreign exchange (loss) gain		(753	)		(40	)		306			(25	)		(476	)		(753	)		(1,363	)		306
Other income (expense), net		717			890			1,791			(193	)
Loss on debt extinguishment														—			(14,602	)		—			(31,856	)
Other (expense) income, net														(849	)		717			2,113			1,791
Total other expense, net		(26,823	)		(60,949	)		(77,859	)		(129,044	)		(24,302	)		(26,823	)		(58,268	)		(77,859	)
Income (loss) before benefit for income taxes		201,759			(12,330	)		172,096			(57,108	)
Income before benefit for income taxes														307,241			201,759			251,772			172,096
Benefit for income taxes		(91,081	)		(30,564	)		(27,143	)		(37,359	)		(19,302	)		(91,081	)		(109,537	)		(27,143	)
Net income (loss)	$	292,840		$	18,234		$	199,239		$	(19,749	)
Net income (loss) per ordinary share—basic	$	1.38		$	0.10		$	1.00		$	(0.11	)
Net income													$	326,543		$	292,840		$	361,309		$	199,239
Net income per ordinary share—basic													$	1.44		$	1.38		$	1.61		$	1.00
Weighted average ordinary shares outstanding—basic		212,320,219			186,470,141			198,413,779			181,949,838			226,096,747			212,320,219			225,053,704			198,413,779
Net income (loss) per ordinary share—diluted	$	1.31		$	0.09		$	0.95		$	(0.11	)
Net income per ordinary share—diluted													$	1.38		$	1.31		$	1.54		$	0.95
Weighted average ordinary shares outstanding—diluted		223,743,903			194,171,967			208,678,460			181,949,838			236,198,789			223,743,903			235,256,424			208,678,460
OTHER COMPREHENSIVE INCOME (LOSS), NET OF TAX
OTHER COMPREHENSIVE (LOSS) INCOME, NET OF TAX
Foreign currency translation adjustments	$	858		$	(809	)	$	877		$	(952	)	$	(514	)	$	858		$	(1,100	)	$	877
Other comprehensive income (loss)		858			(809	)		877			(952	)
Comprehensive income (loss)	$	293,698		$	17,425		$	200,116		$	(20,701	)
Pension remeasurements														—			—			(287	)		—
Other comprehensive (loss) income														(514	)		858			(1,387	)		877
Comprehensive income													$	326,029		$	293,698		$	359,922		$	200,116

The accompanying notes are an integral part of these condensed consolidated financial statements.

										Additional			Accumulated Other						Total												Additional			Accumulated Other			Retained Earnings			Total
	Ordinary Shares				Treasury Stock					Paid-in			Comprehensive			Accumulated			Shareholders’			Ordinary Shares				Treasury Stock					Paid-in			Comprehensive			(Accumulated			Shareholders’
	Shares		Amount		Shares		Amount			Capital			Loss			Deficit			Equity			Shares		Amount		Shares		Amount			Capital			Loss			Deficit)			Equity
Balances at December 31, 2019		188,402,040	$	19		384,366	$	(4,585	)	$	2,797,602		$	(1,905	)	$	(605,682	)	$	2,185,449
Balances at December 31, 2020																							221,721,674	$	22		384,366	$	(4,585	)	$	4,245,945		$	(145	)	$	(215,886	)	$	4,025,351
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units		2,560,573		—		—		—			7,049			—			—			7,049			3,305,947		—		—		—			19,843			—			—			19,843
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(46,664	)		—			—			(46,664	)		—		—		—		—			(128,261	)		—			—			(128,261	)
Share-based compensation		—		—		—		—			56,421			—			—			56,421			—		—		—		—			62,296			—			—			62,296
Currency translation adjustment		—		—		—		—			—			(325	)		—			(325	)		—		—		—		—			—			(821	)		—			(821	)
Pension remeasurements																							—		—		—		—			—			(287	)		—			(287	)
Net loss		—		—		—		—			—			—			(13,591	)		(13,591	)		—		—		—		—			—			—			(123,351	)		(123,351	)
Balances at March 31, 2020		190,962,613	$	19		384,366	$	(4,585	)	$	2,814,408		$	(2,230	)	$	(619,273	)	$	2,188,339
Balances at March 31, 2021																							225,027,621	$	22		384,366	$	(4,585	)	$	4,199,823		$	(1,253	)	$	(339,237	)	$	3,854,770
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units		1,427,108		—		—		—			18,838			—			—			18,838			597,169		—		—		—			7,996			—			—			7,996
Issuance of ordinary shares in conjunction with ESPP program		376,718		—		—		—			7,979			—			—			7,979
Issuance of ordinary shares in conjunction with Exchangeable Senior Notes		7,225,368		1		—		—			205,649			—			—			205,650
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(6,345	)		—			—			(6,345	)
Share-based compensation		—		—		—		—			27,057			—			—			27,057
Currency translation adjustment		—		—		—		—			—			344			—			344
Net loss		—		—		—		—			—			—			(80,010	)		(80,010	)
Balances at June 30, 2020		199,991,807	$	20		384,366	$	(4,585	)	$	3,067,586		$	(1,886	)	$	(699,283	)	$	2,361,852
Issuance of ordinary shares - public offering		13,570,000		1		—		—			919,513			—			—			919,514
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units		760,255		—		—		—			8,111			—			—			8,111
Issuance of ordinary shares in conjunction with Exchangeable Senior Notes		6,673,046		1		—		—			190,022			—			—			190,023
Issuance of ordinary shares in conjunction with Employee Share Purchase Plan																							474,997		—		—		—			11,482			—			—			11,482
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(6,743	)		—			—			(6,743	)		—		—		—		—			(13,388	)		—			—			(13,388	)
Share-based compensation		—		—		—		—			30,356			—			—			30,356			—		—		—		—			54,424			—			—			54,424
Currency translation adjustment		—		—		—		—			—			858			—			858			—		—		—		—			—			235			—			235
Net income		—		—		—		—			—			—			292,840			292,840			—		—		—		—			—			—			158,117			158,117
Balances at September 30, 2020		220,995,108	$	22		384,366	$	(4,585	)	$	4,208,845		$	(1,028	)	$	(406,443	)	$	3,796,811
Balances at June 30, 2021																							226,099,787	$	22		384,366	$	(4,585	)	$	4,260,337		$	(1,018	)	$	(181,120	)	$	4,073,636
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units																							926,260		—		—		—			12,173			—			—			12,173
Ordinary shares withheld for payment of employees’ withholding tax liability																							—		—		—		—			(16,428	)		—			—			(16,428	)
Share-based compensation																							—		—		—		—			54,804			—			—			54,804
Currency translation adjustment																							—		—		—		—			—			(514	)		—			(514	)
Net income																							—		—		—		—			—			—			326,543			326,543
Balances at September 30, 2021																							227,026,047	$	22		384,366	$	(4,585	)	$	4,310,886		$	(1,532	)	$	145,423		$	4,450,214

The accompanying notes are an integral part of these condensed consolidated financial statements.

										Additional			Accumulated Other						Total												Additional			Accumulated Other						Total
	Ordinary Shares				Treasury Stock					Paid-in			Comprehensive			Accumulated			Shareholders’			Ordinary Shares				Treasury Stock					Paid-in			Comprehensive			Accumulated			Shareholders’
	Shares		Amount		Shares		Amount			Capital			Loss			Deficit			Equity			Shares		Amount		Shares		Amount			Capital			Loss			Deficit			Equity
Balances at December 31, 2018		169,244,520	$	17		384,366	$	(4,585	)	$	2,374,966		$	(1,523	)	$	(1,178,769	)	$	1,190,106
Cumulative effect adjustments from adoption of ASU No. 2016-02, Leases (Topic 842)		—		—		—		—			—			—			64			64
Issuance of ordinary shares - public offering		14,081,632		1		—		—			326,848			—			—			326,849
Issuance of ordinary shares in conjunction with vesting of restricted stock units and stock option exercises		1,804,196		—		—		—			10,042			—			—			10,042
Balances at December 31, 2019																							188,402,040	$	19		384,366	$	(4,585	)	$	2,797,602		$	(1,905	)	$	(605,682	)	$	2,185,449
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units																							2,560,573		—		—		—			7,049			—			—			7,049
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(17,171	)		—			—			(17,171	)		—		—		—		—			(46,664	)		—			—			(46,664	)
Share-based compensation		—		—		—		—			27,548			—			—			27,548			—		—		—		—			56,421			—			—			56,421
Currency translation adjustment		—		—		—		—			—			(487	)		—			(487	)		—		—		—		—			—			(325	)		—			(325	)
Net loss		—		—		—		—			—			—			(32,863	)		(32,863	)		—		—		—		—			—			—			(13,591	)		(13,591	)
Balances at March 31, 2019		185,130,348	$	18		384,366	$	(4,585	)	$	2,722,233		$	(2,010	)	$	(1,211,568	)	$	1,504,088
Issuance of ordinary shares - public offering		—		—		—		—			(55	)		—			—			(55	)
Issuance of ordinary shares in conjunction with vesting of restricted stock units and stock option exercises		781,026		1		—		—			1,986			—			—			1,987
Balances at March 31, 2020																							190,962,613	$	19		384,366	$	(4,585	)	$	2,814,408		$	(2,230	)	$	(619,273	)	$	2,188,339
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units																							1,427,108		—		—		—			18,838			—			—			18,838
Issuance of ordinary shares in conjunction with Employee Share Purchase Plan																							376,718		—		—		—			7,979			—			—			7,979
Issuance of ordinary shares in conjunction with 2.5% Exchangeable Senior Notes due 2022																							7,225,368		1		—		—			205,649			—			—			205,650
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(7,203	)		—			—			(7,203	)		—		—		—		—			(6,345	)		—			—			(6,345	)
Issuance of ordinary shares in conjunction with ESPP program		558,856		—		—		—			5,465			—			—			5,465
Share-based compensation		—		—		—		—			21,367			—			—			21,367			—		—		—		—			27,057			—			—			27,057
Currency translation adjustment		—		—		—		—			—			344			—			344			—		—		—		—			—			344			—			344
Net loss		—		—		—		—			—			—			(5,120	)		(5,120	)		—		—		—		—			—			—			(80,010	)		(80,010	)
Balances at June 30, 2019		186,470,230	$	19		384,366	$	(4,585	)	$	2,743,793		$	(1,666	)	$	(1,216,688	)	$	1,520,873
Issuance of ordinary shares in conjunction with vesting of restricted stock units and stock option exercises		704,189		—		—		—			4,207			—			—			4,207
Balances at June 30, 2020																							199,991,807	$	20		384,366	$	(4,585	)	$	3,067,586		$	(1,886	)	$	(699,283	)	$	2,361,852
Issuance of ordinary shares - public offering																							13,570,000		1		—		—			919,513			—			—			919,514
Issuance of ordinary shares in conjunction with the exercise of stock options and the vesting of restricted stock and performance stock units																							760,255		—		—		—			8,111			—			—			8,111
Issuance of ordinary shares in conjunction with 2.5% Exchangeable Senior Notes due 2022																							6,673,046		1		—		—			190,022			—			—			190,023
Ordinary shares withheld for payment of employees’ withholding tax liability		—		—		—		—			(5,086	)		—			—			(5,086	)		—		—		—		—			(6,743	)		—			—			(6,743	)
Issuance of ordinary shares in conjunction with ESPP program		376		—		—		—			3			—			—			3
Share-based compensation		—		—		—		—			18,151			—			—			18,151			—		—		—		—			30,356			—			—			30,356
Currency translation adjustment		—		—		—		—			—			(809	)		—			(809	)		—		—		—		—			—			858			—			858
Net income		—		—		—		—			—			—			18,234			18,234			—		—		—		—			—			—			292,840			292,840
Balances at September 30, 2019		187,174,795	$	19		384,366	$	(4,585	)	$	2,761,068		$	(2,475	)	$	1,198,454		$	1,555,573
Balances at September 30, 2020																							220,995,108	$	22		384,366	$	(4,585	)	$	4,208,845		$	(1,028	)	$	(406,443	)	$	3,796,811

The accompanying notes are an integral part of these condensed consolidated financial statements.

	For the Nine Months Ended September 30,						For the Nine Months Ended September 30,
	2020			2019			2021			2020
CASH FLOWS FROM OPERATING ACTIVITIES:
Net income (loss)	$	199,239		$	(19,749	)
Adjustments to reconcile net income (loss) to net cash provided by operating activities:
Net income							$	361,309		$	199,239
Adjustments to reconcile net income to net cash provided by operating activities:
Depreciation and amortization expense		209,906			177,336			257,216			209,906
Equity-settled share-based compensation		113,834			67,066			170,394			113,834
Acquired in-process research and development expense		47,517			—			46,500			47,517
Impairment of long-lived asset								12,371			—
Amortization of debt discount and deferred financing costs								3,740			12,025
Loss on debt extinguishment		31,856			58,835			—			31,856
Amortization of debt discount and deferred financing costs		12,025			17,069
Loss on sale of assets		—			10,963
Gain on sale of asset								(2,000	)		—
Deferred income taxes		(8,041	)		8,302			(147,934	)		(8,041	)
Foreign exchange and other adjustments		1,084			572			(1,494	)		1,084
Changes in operating assets and liabilities:
Accounts receivable		(297,392	)		68,162			(107,776	)		(297,392	)
Inventories		(23,329	)		(8,004	)		(10,494	)		(23,329	)
Prepaid expenses and other current assets		(83,226	)		(72,055	)		(60,790	)		(83,226	)
Accounts payable		17,709			(3,338	)		7,640			17,709
Accrued trade discounts and rebates		(143,551	)		(53,241	)		(50,838	)		(143,551	)
Accrued expenses		56,830			(10,591	)
Deferred revenues		—			(4,901	)
Accrued expenses and other current liabilities								34,380			56,830
Other non-current assets and liabilities		11,410			(1,474	)		(15,510	)		11,410
Net cash provided by operating activities		145,871			234,952			496,714			145,871
CASH FLOWS FROM INVESTING ACTIVITIES:
Payments for acquisitions		(262,305	)		—
Purchases of property and equipment		(133,399	)		(11,325	)
Payments for long-term investments		(8,937	)		—
Payments for acquisitions, net of cash acquired								(2,843,275	)		(262,305	)
Purchases of property, plant and equipment								(59,695	)		(133,399	)
Payments related to license agreements								(46,500	)		—
Payments for long-term investments, net								(9,797	)		(8,937	)
Proceeds from sale of asset								2,000			—
Change in escrow deposit for property purchase		6,000			—			—			6,000
Proceeds from sale of assets		—			6,000
Net cash used in investing activities		(398,641	)		(5,325	)		(2,957,267	)		(398,641	)
CASH FLOWS FROM FINANCING ACTIVITIES:
Net proceeds from the issuance of ordinary shares		919,995			326,793			—			919,995
Net proceeds from the issuance of senior notes		—			590,057
Repayment of senior notes		(1,739	)		(814,420	)
Net proceeds from term loans		—			517,378			1,574,993			—
Repayment of term loans		—			(918,181	)		(8,000	)		—
Contingent consideration proceeds from divestiture		—			3,297
Proceeds from the issuance of ordinary shares in conjunction with ESPP program		7,979			5,468
Repayment of senior notes								—			(1,739	)
Proceeds from the issuance of ordinary shares in conjunction with Employee Share Purchase Plan								11,482			7,979
Proceeds from the issuance of ordinary shares in connection with stock option exercises		33,999			16,236			40,013			33,999
Payment of employee withholding taxes relating to share-based awards		(59,752	)		(29,460	)		(158,077	)		(59,752	)
Net cash provided by (used in) financing activities		900,482			(302,832	)
Net cash provided by financing activities								1,460,411			900,482
Effect of foreign exchange rate changes on cash, cash equivalents and restricted cash		1,225			(1,202	)		(10,951	)		1,225
Net increase (decrease) in cash, cash equivalents and restricted cash		648,937			(74,407	)
Net (decrease) increase in cash, cash equivalents and restricted cash								(1,011,093	)		648,937
Cash, cash equivalents and restricted cash, beginning of the period		1,080,039			962,117			2,083,479			1,080,039
Cash, cash equivalents and restricted cash, end of the period	$	1,728,976		$	887,710		$	1,072,386		$	1,728,976

The accompanying notes are an integral part of these condensed consolidated financial statements.

	For the Nine Months Ended September 30,				For the Nine Months Ended September 30,
	2020		2019		2021		2020
SUPPLEMENTAL CASH FLOW INFORMATION:
Cash paid for interest	$	49,275	$	71,867	$	61,998	$	49,275
Cash paid for income taxes, net of refunds received		3,461		9,034		57,178		3,461
Cash paid for amounts included in the measurement of lease liabilities		5,802		4,525
Cash paid for amounts included in the measurement of operating lease liabilities						7,289		5,802
SUPPLEMENTAL NON-CASH FLOW INFORMATION:
Principal amount of Exchangeable Senior Notes converted into ordinary shares	$	398,261	$	—
Milestone payments for TEPEZZA intangible asset included in accrued expenses		121,232		—
Purchases of property and equipment included in accounts payable and accrued expenses		12,126		526
Lease liabilities arising from obtaining right-of-use assets					$	62,156	$	—
Purchases of property, plant and equipment included in accounts payable and accrued expenses and other current liabilities as of September 30, 2021 and 2020, respectively						14,297		12,126
Principal amount of 2.5% Exchangeable Senior Notes due 2022 converted into ordinary shares						—		398,261
Milestone payments for TEPEZZA intangible asset included in accrued expenses and other current liabilities as of September 30, 2021 and 2020, respectively						—		121,232

The accompanying notes are an integral part of these condensed consolidated financial statements.

Unless otherwise indicated or the context otherwise requires, references to “Horizon”, the “Company”, “we”, “us” and “our” refer to Horizon Therapeutics plc and its consolidated subsidiaries.

On March 15, 2021, the Company completed its acquisition of Viela Bio, Inc. (“Viela”) and acquired all of the issued and outstanding shares of Viela’s common stock for $53.00 per share. The total consideration for the acquisition was approximately $3.0 billion, including cash acquired of $342.3 million. Following the completion of the acquisition, Viela became a wholly-owned subsidiary of the Company. The unaudited condensed consolidated financial statements presented herein include the results of operations of the acquired business from the date of acquisition.

The unaudited condensed consolidated financial statements presented herein have been prepared in accordance with accounting principles generally accepted in the United States (“GAAP”) for interim financial information and in accordance with the instructions to Form 10-Q and Article 10 of Regulation S-X. Accordingly, the financial statements do not include all of the information and notes required by GAAP for complete financial statements. In the opinion of management, all adjustments, including normal recurring adjustments, considered necessary for a fair statement of the financial statements have been included. Operating results for the three and nine months ended September 30, ~~2020~~2021 are not necessarily indicative of the results that may be expected for the year ending December 31, ~~2020.~~2021. The December 31, ~~2019~~2020 condensed consolidated balance sheet was derived from audited financial statements, but does not include all disclosures required by GAAP.

During the nine months ended September 30, 2020, the Company recorded out of period adjustments that decreased income tax benefit by $3.2 million and increased share-based compensation expense by $1.9 million to correct for expenses that should have been recorded in the year ended December 31, 2019. In addition, the Company recorded an out of period adjustment that increased employee benefit plan expense by $2.3 million to correct for expenses that should have been recorded in the years ended 2017, 2018 and 2019. The Company evaluated the materiality of the adjustments to prior-period financial statements and the current period, and concluded the effect of the adjustments were immaterial to both the current and prior-period financial statements.

Horizon is focused on ~~researching, developing~~the discovery, development and ~~commercializing~~commercialization of medicines that address critical needs for people impacted by rare, autoimmune and ~~rheumatic~~severe inflammatory diseases. The Company’s pipeline is purposeful: it applies scientific expertise and courage to bring clinically meaningful therapies to patients. Horizon believes science and compassion must work together to transform lives. The Company has 2 reportable segments, the orphan segment and the inflammation segment, and its commercial portfolio is currently composed of ~~eleven~~12 medicines in the areas of rare diseases, gout, ophthalmology and inflammation.

~~Effective in the first quarter of 2020, the Company (i) reorganized its commercial operations and moved responsibility for and reporting of RAYOS~~® to the inflammation segment and (ii) renamed the orphan and rheumatology segment the orphan segment. Net sales generated by TEPEZZA®, which was approved by the U.S. Food and Drug Administration (“FDA”) on January 21, 2020, are reported as part of the renamed orphan segment.

As of September 30, ~~2020,~~2021, the Company’s ~~medicine~~commercial portfolio consisted of the ~~following:~~following medicines:

From time to time, the Company adopts new accounting pronouncements issued by the Financial Accounting Standards Board (“FASB”) or other standard-setting bodies.

In ~~June 2016, the FASB issued Accounting Standards Update No. 2016-13,~~ ~~Financial Instruments – Credit Losses (Topic 326): Measurement of Credit Losses on Financial Instruments~~ (“ASU 2016-13”), which modifies the measurement of expected credit losses on certain financial instruments and became effective for the Company as of January 1, 2020. The adoption of ASU 2016-13 did not have a material impact on the Company’s condensed consolidated financial statements and related disclosures.

In December 2019, the FASB issued Accounting Standards Update No. 2019-12, Income Taxes (Topic 740): Simplification and reduce the cost of accounting for income taxes (“ASU 2019-12”), which iswas effective for the Company as of January 1, 2021. The ~~Company does not expect the~~ adoption of ASU 2019-12 todid not have a material impact on the Company’s condensed consolidated financial statements and related disclosures.

Other recent authoritative guidance issued by the FASB (including technical corrections to the Accounting Standards Codification (“ASC”)), the American Institute of Certified Public Accountants and the Securities and Exchange Commission (“SEC”) did not, or are not expected to, have a material impact on the Company’s condensed consolidated financial statements and related disclosures.

The ~~Company's~~Company’s significant accounting policies have not changed from those previously described in the ~~Company's~~Company’s Annual Report on Form 10-K for the year ended December 31, ~~2019,~~2020. The following accounting policy relating to intangible assets is disclosed in connection with the ~~exception of the change to the accounting policy related to property and equipment due to the purchase of land and buildings as described below.~~Viela acquisition.

Indefinite-lived intangible assets consist of capitalized in-process research and ~~Equipment~~

~~Land~~development (“IPR&D”). IPR&D assets represent capitalized incomplete research projects that the Company acquired through business combinations. Such assets are initially measured at their acquisition date fair values and are tested for impairment, until completion or abandonment of research and development efforts associated with the projects. An IPR&D asset is ~~stated at cost. Property~~considered abandoned when research and ~~equipment, other than land,~~development efforts associated with the asset have ceased, and there are ~~stated at cost less accumulated depreciation. Depreciation is recognized using~~no plans to sell or license the ~~straight-line method over the estimated useful lives of the related assets for financial reporting purposes and an accelerated method for income tax reporting purposes. Upon retirement~~asset or ~~sale of an asset, the cost and related accumulated depreciation and amortization are removed~~derive value from the ~~balance sheet~~asset. At that point, the asset is considered to be impaired and is written off. Upon successful completion of each project, the ~~resulting gain or loss is reflected in operations. Repair and maintenance costs are charged to expenses as incurred and improvements are capitalized.~~

~~Leasehold improvements are amortized on~~Company will make a ~~straight-line basis over~~determination about the ~~term of the applicable lease, or the~~then remaining useful life of the ~~assets, whichever is shorter.~~

~~Depreciation~~intangible asset and ~~amortization periods for the Company’s property and equipment are as follows:~~

begin amortization. The Company ~~capitalizes software development costs associated with internal use software,~~tests its indefinite-lived intangibles, including ~~external direct costs of materials and services and payroll costs~~IPR&D assets, for ~~employees devoting time to a software project. Costs incurred~~impairment annually during the ~~preliminary project stage, as well as costs for maintenance~~fourth quarter and ~~training, are expensed as incurred.~~

~~Software includes internal-use software acquired and modified to meet~~more frequently if events or changes in circumstances indicate that it is more likely than not that the ~~Company’s internal requirements. Amortization commences when the software~~asset is ~~ready for its intended use.~~impaired.

The following table presents basic and diluted net income ~~(loss)~~ per share for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except share and per share data):

Basic net income ~~(loss)~~ per share is computed by dividing net income ~~(loss)~~ by the weighted-average number of ordinary shares outstanding during the period. Diluted net income ~~(loss)~~ per share reflects the potential dilution that could occur if securities or other contracts to issue ordinary shares were exercised, converted into ordinary shares or resulted in the issuance of ordinary shares that would have shared in the Company’s earnings.

During the three and nine months ended September 30, 2021 and 2020, the difference between the basic and diluted weighted average ordinary shares outstanding represents the effect of incremental shares from the Company’s share-based compensation programs.

The computation of diluted net income ~~(loss)~~per share excluded 0.8 million and 3.0 million shares subject to equity awards for the three and nine months ended September 30, 2021, respectively, because their inclusion would have had an anti-dilutive effect on diluted net income per share.

The computation of diluted net income per share excluded 0.2 million and 3.4 million shares subject to equity awards for the three and nine months ended September 30, 2020, respectively, and 1.5 million and 9.2 million shares (based on the if-converted method) related to the Company’s 2.5% Exchangeable Senior Notes due 2022 (the “Exchangeable Senior Notes”) for the three and nine months ended September 30, 2020, respectively, because their inclusion would have had an anti-dilutive effect on diluted net income ~~(loss)~~ per share.

The computation of diluted net income (loss) per share excluded 0.3 million and 8.8 million shares subject to equity awards for each of the three and nine months ended September 30, 2019, respectively, because their inclusion would have had an anti-dilutive effect on diluted net income (loss) per share.

During the three and nine months ended September 30, 2019, the potentially dilutive impact of the Exchangeable Senior Notes was determined using a method similar to the treasury stock method. Under this method, no numerator or denominator adjustments arose from the principal and interest components of the Exchangeable Senior Notes because the Company had the intent, at that time, and ability to settle the Exchangeable Senior Notes’ principal and interest in cash. Instead, the Company was required to increase the diluted net income (loss) per share denominator by the variable number of shares that would be issued upon conversion if it settled the conversion spread obligation with shares. For diluted net income (loss) per share purposes, the conversion spread obligation was calculated based on whether the average market price of the Company’s ordinary shares over the reporting period was in excess of the exchange price of the Exchangeable Senior Notes. There was no calculated spread added to the denominator for the three and nine months ended September 30, 2019. Beginning in the fourth quarter of 2019, with the ordinary share price significantly above the $28.66 exchange price, the Company decided that it no longer had the intent to settle the notes for cash and, as a result, began to prospectively apply the if-converted method to the Exchangeable Senior Notes when determining the diluted net income (loss) per share. ByOn August 3, 2020, the Exchangeable Senior Notes were fully extinguished through exchanges for ordinary shares or cash redemption. ~~Refer to Note 13 for further detail.~~

In July 2021, the Company completed the purchase of a drug product manufacturing facility from EirGen Pharma Limited (“EirGen”), a subsidiary of OPKO Health, Inc. in Waterford, Ireland for $67.9 million, which included an upfront cash payment of $64.8 million and $3.1 million of additional transaction costs, legal fees and liabilities assumed.The facility, which is located in an Industrial Development Agency Ireland (“IDA Ireland”) business park, includes a filling line and lyophilizer, or freeze dryer, that can be used for both the Company’s commercial medicines, including its rare disease biologics TEPEZZA, KRYSTEXXA and UPLIZNA, and certain of its medicine candidates in development, following build-out, validation and regulatory approval processes. In addition, there is adjacent IDA Ireland land available for further manufacturing and development expansion. The Company accounted for the transaction as an asset acquisition.

The following table summarizes fair values of assets acquired as of the acquisition date (in thousands):

On March 15, 2021, the Company completed its acquisition of Viela and acquired all of the issued and outstanding shares of Viela’s common stock for $53.00 per share. The acquisition added an additional rare disease medicine, UPLIZNA, to the Company’s commercial medicine portfolio. The Viela acquisition provides multiple opportunities to drive long-term growth and solidify the Company’s future as an innovation-driven biotech company. Viela’s mid-stage biologics pipeline, research and development (“R&D”) team and on-market medicine UPLIZNA, made it a complementary strategic fit with the Company’s pipeline, commercial portfolio and therapeutic areas of focus. Following completion of the acquisition, Viela became a wholly-owned subsidiary of the Company. The Company financed the transaction through cash on hand and $1.6 billion of aggregate principal amount of term loans pursuant to Company’s existing credit agreement, as described in Note 13.

The total consideration for the acquisition was approximately $3.0 billion, including cash acquired of $342.3 million, and was composed of the following (in thousands):

During the nine months ended September 30, 2021, the Company incurred $28.6 million in Viela transaction costs, including advisory, legal, accounting, valuation and otherprofessional and consulting fees, which were accounted for as “Selling, General and Administrative Expenses” in the condensed consolidated statement of comprehensive income.

Pursuant to ASC 805, Business Combinations (“ASC 805”), the Company accounted for the Viela acquisition as a business combination using the acquisition method of accounting. Identifiable assets and liabilities of Viela, including identifiable intangible assets, were recorded based on their estimated fair values as of the date of the closing of the acquisition. The excess of the purchase price over the fair value of the net assets acquired was recorded as goodwill. The valuation of assets acquired and liabilities assumed has not yet been finalized as of September 30, 2021. While all amounts remain subject to adjustments, the areas subject to the most significant potential adjustments are inventory, intangible assets, IPR&D and deferred income taxes. As a result, the Company recorded preliminary estimates for the fair value of assets acquired and liabilities assumed as of the acquisition date. Such preliminary valuation required estimates and assumptions including, but not limited to, estimating future cash flows and direct costs in addition to developing the appropriate discount rates and current market profit margins. Accordingly, the purchase price adjustments are preliminary and are subject to further adjustments as additional information becomes available and as additional analyses are performed, and such further adjustments may be material. The Company’s management believes the fair values recognized for the assets acquired and the liabilities assumed are based on reasonable estimates and assumptions.

During the nine months ended September 30, 2021, the Company recorded measurement period adjustments related to deferred tax liabilities, accrued expenses and other current liabilities, accrued trade discounts and rebates, accounts receivable, prepaid expenses and other current assets and inventory, which resulted in a net reduction in goodwill of $7.4 million.

The following table summarizes the preliminary fair values assigned to the assets acquired and the liabilities assumed by the Company along with the resulting goodwill before and after the measurement period adjustments (in thousands):

Inventories acquired included raw materials, work in process and finished goods for UPLIZNA. Inventories were recorded at their preliminary estimated fair values. The fair value of finished goods has been determined based on the estimated selling price, net of selling costs and a margin on the selling activities. The fair value of work in process has been determined based on estimated selling price, net of selling costs and costs to complete the manufacturing, and a margin on the selling and manufacturing activities. The fair value of raw materials was estimated to equal the replacement cost. A step-up in the value of inventory of $149.3 million was originally recorded in connection with the acquisition, which was composed of $10.1 million for raw materials, $119.0 million for work-in-process and $20.2 million for finished goods. During the nine months ended September 30, 2021, the step-up in the value of inventory was increased to $151.6 million following the recording of $2.3 million in measurement period adjustments which was composed of $1.9 million for work-in-process and $0.4 million for finished goods. During the three and nine months ended September 30, 2021, the Company recorded inventory step-up expense of $8.9 million and $16.9 million, respectively, related to UPLIZNA based on the acquired units sold during the period.

Other tangible assets and liabilities were valued at their respective carrying amounts as management believes that these amounts approximated their acquisition-date fair values.

Developed technology is an intangible asset that reflects the estimated fair value of the rights to UPLIZNA in the United States. The preliminary estimated fair values of the developed technology represent preliminary valuations performed with the assistance of an independent appraisal firm based on management’s estimates, forecasted financial information and reasonable and supportable assumptions. The preliminary fair value of developed technology was determined using an income approach. The income approach explicitly recognizes that the fair value of an asset is premised upon the expected receipt of future economic benefits such as earnings and cash inflows based on current sales projections and estimated direct costs for UPLIZNA. Indications of value were developed by discounting these benefits to their acquisition-date fair value at a discount rate of 11.5% that reflects the return requirements of the market. Some of the most significant assumptions inherent in the development of the asset valuation include the estimated net cash flows for each year (including net sales, cost of goods sold, sales and marketing costs and R&D costs) and the discount rate. The fair value of the UPLIZNA developed technology was capitalized as of the Viela acquisition date and is subsequently being amortized over approximately 14 years.

Each IPR&D asset is considered separable from the business as each project could be sold to a third party. The fair value of each IPR&D asset was determined using an income approach. The income approach explicitly recognizes that the fair value of an asset is premised upon the expected receipt of future economic benefits such as earnings and cash inflows based on sales projections and estimated direct costs. Indications of value are developed by discounting these benefits to their present value at a discount rate of 12.5% that reflects the return requirements of the market. Some of the most significant assumptions inherent in the development of the asset valuations include the estimated net cash flows for each year (including net sales, cost of goods sold, sales and marketing costs and R&D costs), the discount rate, the assessment of each asset’s life cycle and the potential regulatory and commercial success risk. The fair value of the various IPR&D assets was recorded as an indefinite-lived intangible asset and will be tested for impairment until completion or abandonment of R&D efforts associated with the project. The Company reviews amounts capitalized as acquired IPR&D for impairment annually and whenever events or changes in circumstances indicate that the carrying value of the assets might not be recoverable.

Deferred tax assets and liabilities arise from acquisition accounting adjustments where book values of certain assets and liabilities differ from their tax bases. Deferred tax assets and liabilities are recorded at the currently enacted rates which will be in effect at the time when the temporary differences are expected to reverse in the country where the underlying assets and liabilities are located. The developed technology, IPR&D assets and inventory acquired through the Viela acquisition were located in the United States as of the acquisition date, where a U.S. tax rate of 23.8% is being utilized and a significant deferred tax liability of $451.1 million was recorded.

Goodwill represents the excess of the total consideration over the estimated fair value of net assets acquired and was recorded in the consolidated balance sheet as of the acquisition date. The goodwill was primarily attributable to the establishment of a deferred tax liability for the developed technology intangible asset and the IPR&D intangible assets. Viela’s mid-stage biologics pipeline, R&D team and on-market medicine UPLIZNA, made it a complementary strategic fit with the Company’s pipeline, commercial portfolio and therapeutic areas of focus. The Company does not expect any portion of this goodwill to be deductible for tax purposes.

The following table presents the pro forma combined results of the Company and Viela for the nine months ended September 30, 2021 and 2020 as if the acquisition of Viela had occurred on January 1, 2020 (in thousands):

The pro forma combined financial information was prepared using the acquisition method of accounting and was based on the historical financial information of the Company and Viela. In order to reflect the pro forma information as if the acquisition occurred on January 1, 2020 as required, the pro forma financial information includes adjustments to reflect incremental amortization expense to be incurred based on the current preliminary fair values of the identifiable intangible assets acquired; the incremental cost of products sold related to the fair value adjustments associated with acquisition date inventory; the additional interest expense associated with the issuance of debt to finance the acquisition; and the reclassification of transaction costs incurred during the nine months ended September 30, 2021 to the nine months ended September 30, 2020. Significant non-recurring pro forma adjustments include transaction costs of $86.6 million which were assumed to have been incurred on January 1, 2020 and were recognized as if incurred during the nine months ended September 30, 2020. The pro forma financial information is not necessarily indicative of what the consolidated results of operations would have been had the acquisition actually been completed on January 1, 2020. In addition, the pro forma financial information is not a projection of future results of operations of the combined company nor does it reflect the expected realization of any synergies or cost savings associated with the acquisition.

On April 1, 2020, the Company acquired Curzion Pharmaceuticals, Inc. (“Curzion”), a privately held development-stage biopharma company, and its development-stage oral selective lysophosphatidic acid 1 receptor (LPAR₁) antagonist, CZN001 (renamed HZN-825).

Under the terms of the acquisition agreement, the Company acquired Curzion for a $45.0 million upfront cash payment with additional payments contingent on the achievement of development and regulatory milestones. Pursuant to ASC 805 (as amended by ASU No. 2017-01, Business Combinations (Topic 805): Clarifying the Definition of a Business (“ASU No. 2017-01”)), the Company accounted for the Curzion acquisition as the purchase of an iIPR&D~~n-process research and development~~ asset and, pursuant to ASC Topic 730, Research and Development (“ASC 730”), recorded the purchase price as research and development expense during the nine months ended September 30, 2020. HZN-825 was originally discovered and developed by Sanofi-Aventis U.S. LLC, ~~(“Sanofi-Aventis U.S.”),~~ which is eligible to receive contingent payments upon the achievement of development and commercialization milestones and royalties based on revenue thresholds. A member of the Company’s board of directors was also a member of the board of directors of, and held a beneficial interest in, Curzion. This related party transaction was conducted in the normal course of business on an arm’s length basis.

On ~~June 28, 2019,~~October 27, 2020, the Company sold its rights to ~~MIGERGOT~~develop and commercialize RAVICTI and BUPHENYL in Japan to ~~Cosette Pharmaceuticals, Inc.,~~Medical Need Europe AB, part of the Immedica Group, for ~~$6.0~~$5.4 million and ~~total potential contingent consideration payments~~recorded a gain of ~~$4.0~~$4.9 million ~~(the “MIGERGOT transaction”).~~

~~Pursuant~~on the sale in the fourth quarter of 2020. The Company has retained the rights to ~~ASU No. 2017-01, the Company accounted for the MIGERGOT transaction as a sale of assets, specifically a sale of intellectual property rights,~~RAVICTI and ~~a sale of inventory.~~ BUPHENYL in North America.

~~The loss on sale of assets recorded to the consolidated statement of comprehensive income (loss) during the year ended December 31, 2019, was determined as follows (in thousands):~~

On May 8, 2017, the Company acquired 100% of the equity interests in River Vision Development Corp. (“River Vision”) for upfront cash payments totaling approximately $150.3 million, including cash acquired of $6.3 million, with additional potential future milestone and royalty payments contingent on the satisfaction of certain regulatory milestones and sales thresholds.Pursuant to ASU No. 2017-01, the Company accounted for the River Vision acquisition as the purchase of an i~~n-process research and development~~ IPR&D asset (teprotumumab, now known as TEPEZZA) and, pursuant to ASC 730, recorded the purchase price as research and development expense during the year ended December 31, 2017. Further, the Company recognized approximately $32.4 million of federal net operating losses, $2.2 million of state net operating losses and $9.5 million of federal tax credits. The acquired tax attributes were set up as deferred tax assets which were further netted within the net deferred tax liabilities of the U.S. group, offset by a deferred credit recorded in long-term liabilities.

Under the acquisition agreement for River Vision, the Company agreed to pay up to $325.0 million upon the attainment of various milestones, composed of $100.0 million related to ~~FDA~~U.S. Food and Drug Administration (“FDA”) approval and $225.0 million related to net sales thresholds for TEPEZZA. The agreement also includes a royalty payment of 3 percent of the portion of annual worldwide net sales exceeding $300.0 ~~million (if any).~~million. The Company made the milestone payment of $100.0 million related to FDA approval during the first quarter of 2020 which is now capitalized as a finite-lived intangible asset representing the developed technology for TEPEZZA.

Additionally, under the Company’s license agreement with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. (together referred to as “Roche”), the Company made a milestone payment of CHF5.0 million ($5.2 million when converted using a CHF-to-Dollar exchange rate at the date of payment of 1.0382), during the first quarter of 2020 which the Company also capitalized as a finite-lived intangible asset representing the developed technology for TEPEZZA.

In April 2020, a subsidiary of the Company entered into an agreement with S.R. One, Limited (“S.R. One”) and an agreement with Lundbeckfond Invest A/S (“Lundbeckfond”) pursuant to which the Company acquired all of S.R. One’s and Lundbeckfond’s beneficial rights to proceeds from certain contingent future TEPEZZA milestone and royalty payments in exchange for a one-time payment of $55.0 million to each of the respective parties. The total payments of $110.0 million were capitalized as a finite-lived intangible asset representing the developed technology for TEPEZZA during the second quarter of 2020.

~~During~~In addition, during the ~~second quarter of~~year ended December 31, 2020, the Company recorded ~~$98.7~~$120.8 million as a finite-lived intangible asset representing the developed technology for TEPEZZA, composed of $67.0 million in relation to the expected future attainment of various net sales milestones payable under the acquisition agreement for River Vision and ~~CHF30.0~~CHF50.0 million ($~~31.7~~53.8 million when converted using a CHF-to-Dollar exchange rate as of the date the intangible asset was recorded of 1.0556) in relation to the expected future attainment of various net sales milestones payable to Roche. During the third quarter of 2020, the Company recorded an additional $22.1 million as a finite-lived intangible asset representing the developed technology for TEPEZZA, composed of CHF20.0 million ($22.1 million when converted using a CHF-to-Dollar exchange rate as of the date the intangible asset was recorded of 1.1066)recorded) in relation to the expected future attainment of various net sales milestones payable to Roche. The liabilities relating to these TEPEZZA net sales milestones ~~have been~~were recorded in accrued expenses and other current liabilities on the ~~condensed~~ consolidated balance sheet as of December 31, 2020. The Company paid such TEPEZZA net sales milestones to Roche in February 2021 and to the former River Vision stockholders in April 2021 and, following such payments, there are no further TEPEZZA net sales milestone obligations remaining to Roche and the former River Vision stockholders. The Company’s remaining obligation to Roche relating to the attainment of various TEPEZZA development and regulatory milestones is CHF43.0 million ($46.2 million when converted using a CHF-to-Dollar exchange rate at September 30, ~~2020~~2021 of 1.0748).

On June 18, 2021, the Company entered into a global agreement with Arrowhead Pharmaceuticals, Inc. (“Arrowhead”) for ARO-XDH, a previously undisclosed discovery-stage investigational RNA interference (“RNAi”) therapeutic being developed by Arrowhead as a potential treatment for uncontrolled gout. Arrowhead granted the Company a worldwide exclusive license to develop, manufacture and commercialize products based on the ~~timing~~RNAi therapeutic. Arrowhead will conduct all research and preclinical development activities for the RNAi therapeutic products. The Company must use commercially reasonable efforts in, and will be responsible for, clinical development and commercialization of the RNAi therapeutic products. Under the terms of the agreement, the Company paid Arrowhead an upfront cash payment of $40.0 million in July 2021 and agreed to pay additional potential future milestone payments of up to $660.0 million contingent on the achievement of certain development, regulatory and commercial milestones, and low to mid-teens royalties on worldwide calendar year net sales of licensed products. The $40.0 million upfront payment was accounted for as the acquisition of an IPR&D asset and was recorded as a “research and development” expense in the condensed consolidated statement of comprehensive income during the nine months ended September 30, 2021.

On November 21, 2020, the Company entered into a global agreement with Halozyme Therapeutics, Inc. (“Halozyme”) that gives the Company exclusive access to Halozyme’s ENHANZE^® drug delivery technology for subcutaneous (“SC”) formulation of medicines targeting IGF-1R. The Company is ~~dependent~~using ENHANZE to develop a SC formulation of TEPEZZA, indicated for the treatment of thyroid eye disease, a serious, progressive and vision-threatening rare autoimmune disease, potentially shortening drug administration time, reducing healthcare practitioner time and offering additional flexibility and convenience for patients. Under the terms of the agreement, the Company paid Halozyme an upfront cash payment of $30.0 million in December 2020, with additional potential future milestone payments of up to $160.0 million contingent on ~~when~~ the ~~applicable milestone thresholds are attained.~~

~~Refer~~satisfaction of certain development and sales thresholds. Halozyme will also be entitled to ~~Note 15~~receive mid-single digit royalties on sales of commercialized medicines using the ENHANZE technology. The $30.0 million upfront payment was accounted for ~~further detail on TEPEZZA milestone payments.~~as the acquisition of an IPR&D asset and was recorded as a “research and development” expense in the consolidated statement of comprehensive income during the year ended December 31, 2020.

On January 3, 2019, the Company entered into ~~a collaboration~~an agreement with HemoShear Therapeutics, LLC (“HemoShear”), a biotechnology company, to discover novel therapeutic targets for gout. The ~~collaboration~~agreement provides the Company with an opportunity to address unmet treatment needs for people with gout by evaluating new targets for the control of serum uric acid levels. Under the terms of the agreement, the Company paid HemoShear an upfront cash payment of $2.0 million with additional potential future milestone payments upon commencement of new stages of development, contingent on the Company’s approval at each stage. In June ~~2019, a $4.0 million progress payment became due, which the Company subsequently paid in July 2019. In June~~ 2020, a $3.0 million progress payment became due, which the Company subsequently paid in July 2020. In February 2021, a $3.0 million progress payment became due and was paid during the first quarter of 2021. In July 2021, a $4.0 million progress payment became due and was paid during the third quarter of 2021.

Inventories are stated at the lower of cost or net realizable value. Inventories consist of raw materials, work-in-process and finished goods. The Company has entered into manufacturing and supply agreements for the manufacture of drug substance and finished goods inventories, and the purchase of raw materials and production supplies. The Company’s inventories include the direct purchase cost of materials and supplies and manufacturing overhead costs.

The components of inventories as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020		December 31, 2019		September 30, 2021		December 31, 2020
Raw materials	$	24,768	$	6,750	$	46,975	$	11,760
Work-in-process		22,398		22,465		96,761		33,167
Finished goods		29,938		24,587		93,698		30,356
Inventories, net	$	77,104	$	53,802	$	237,434	$	75,283

As part of the Viela acquisition, a step-up in the value of inventory of $149.3 million was originally recorded, which was composed of $10.1 million for raw materials, $119.0 million for work-in-process and $20.2 million for finished goods. During the nine months ended September 30, 2021, the step-up in the value of inventory was increased to $151.6 million following the recording of $2.3 million in measurement period adjustments which was composed of $1.9 million for work-in-process and $0.4 million for finished goods.The Company recorded $8.9 million and $16.9 million of UPLIZNA inventory step-up expense in cost of goods sold during the three and nine months ended September 30, 2021, respectively.

Because inventory step-up expense is related to an acquisition, will not continue indefinitely and has a significant effect on the Company’s gross profit, gross margin percentage and net loss for all affected periods, the Company discloses balance sheet and income statement amounts related to inventory step-up within the Notes to Unaudited Condensed Consolidated Financial Statements.

Prepaid expenses and other current assets as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020		December 31, 2019		September 30, 2021		December 31, 2020
Advance payments for inventory	$	74,978	$	31,203	$	168,847	$	137,680
Deferred charge for taxes on intra-company profit		50,934		46,388
Prepaid income taxes and income tax receivable		35,076		12,583
Deferred charge for taxes on intercompany profit						78,445		52,306
Rabbi trust assets		16,526		12,704		24,367		18,423
Other prepaid expenses and other current assets		42,827		40,699		57,071		43,536
Prepaid expenses and other current assets	$	220,341	$	143,577	$	328,730	$	251,945

Advance payments for inventory as of September 30, ~~2020~~2021 and December 31, ~~2019,~~2020, primarily represented payments made to the contract manufacturer of TEPEZZA drug substance.

Property, plant and equipment as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020			December 31, 2019			September 30, 2021			December 31, 2020
Buildings	$	80,341		$	—		$	171,906		$	80,341
Land		38,076			—
Construction in process								42,480			63,656
Land and land improvements								40,047			38,076
Furniture and fixtures								18,677			5,973
Machinery and equipment								17,135			4,695
Software								14,118			14,618
Leasehold improvements		26,300			25,985			9,847			26,323
Construction in process		26,025			265
Software		15,138			14,890
Machinery and equipment		4,508			5,217
Computer equipment		3,685			3,316
Other		6,262			6,334			9,035			3,146
		200,335			56,007			323,245			236,828
Less accumulated depreciation		(44,048	)		(25,848	)		(37,408	)		(47,791	)
Property and equipment, net	$	156,287		$	30,159
Property, plant and equipment, net							$	285,837		$	189,037

Depreciation expense was ~~$5.2~~$4.1 million and ~~$1.7~~$5.2 million for the three months ended September 30, ~~2020~~2021 and ~~2019,~~2020, respectively, and was ~~$19.2~~$12.0 million and ~~$4.6~~$19.2 million for the nine months ended September 30, 2021 and 2020, ~~and 2019,~~ respectively. ~~The increase in depreciation expense in both periods primarily relates~~

In July 2021, the Company completed the purchase of a drug product manufacturing facility from EirGen. Refer to ~~the reduction in the useful lives of leasehold improvements relating to the Company’s Lake Forest office.~~Note 4 for further details.

In February 2020, the Company purchased a 3-building campus in Deerfield, Illinois for total consideration and directly attributable transaction costs of $118.5 million. The Deerfield campus totals 70 acres and consists of approximately 650,000 square feet of office space.

~~Construction~~ The Company’s office employees previously located in Lake Forest, Illinois moved to the Deerfield campus in February 2021 and the Company is marketing its Lake Forest office space for sublease. The increase in amount classified as buildings and the decrease in amount classified as construction in process ~~as of September 30, 2020,~~is primarily ~~represents renovation costs of $25.2 million associated with~~due to the Deerfield ~~campus.~~campus becoming operational in February 2021. The decreases in leasehold improvements and accumulated depreciation amounts are primarily due to the Company vacating the Lake Forest office building in February 2021.

The gross carrying amount of goodwill as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 was $1,069.0 million and $413.7 ~~million.~~

Effective in the first quarter of 2020, the Company (i) reorganized its commercial operations and moved responsibility for and reporting of RAYOS to the inflammation segment and (ii) renamed the orphan and rheumatology segment the orphan segment. This resulted in a $3.2 million, increase in the Company’s allocation of goodwill to its inflammation segment and a corresponding decrease in the goodwill allocated to the orphan segment in the first quarter of 2020. The Company allocated goodwill to its new reporting units using a relative fair value approach. In addition, the Company completed ~~an assessment of any potential goodwill impairment for all reporting units immediately prior to the allocation and determined that no impairment existed.~~respectively.

The table below presents goodwill for the Company’s reportable segments as of September 30, ~~2020~~2021 (in thousands):

In March 2021, the Company recognized goodwill with a preliminary value of $662.7 million in connection with the Viela acquisition, which represented the excess of the purchase price over the fair value of the net assets acquired. During the nine months ended September 30, 2021, the Company recorded measurement period adjustments related to deferred tax liabilities, accounts receivable, prepaid expenses and other current assets, accrued expenses and other current liabilities and accrued trade discounts and rebates, which resulted in a net decrease in goodwill of $7.4 million, to $655.3 million. Refer to Note 4 for further details.

As of September 30, ~~2020,~~2021, there were 0no accumulated goodwill impairment losses.

At September 30, 2021, the Company determined that there was an indicator to trigger an interim impairment analysis of the inflammation reporting unit’s goodwill. The indicator was the August 2021 launch of a generic version of DUEXIS in the United States, resulting in a decrease in future expected net sales. As of September 30, 2021, the Company performed a quantitative assessment to determine if it was more likely than not that the fair value of the inflammation reporting unit exceeds its carrying value, including goodwill. The fair value of the inflammation reporting unit exceeds its carrying value by more than 30%,resulting in 0 impairment.

The Company determined the fair value of the inflammation reporting unit using accepted valuation methods, including the use of discounted cash flows that incorporate the use of projected financial information and a 7% discount rate developed using market participant-based assumptions. The cash-flow projections are based on a five-year financial forecast developed by management that includes net sales projections, which are updated annually and reviewed by management. The selected discount rate considers the risk and nature of the inflammation reporting unit’s cash flows and the rates of return market participants would require to invest their capital in the Company’s reporting unit.

The Company anticipates that an impairment of the inflammation reporting unit’s goodwill could occur in the next 12 to 18 months if the reporting unit does not achieve currently forecasted nets sales and profitability estimates.

As of September 30, ~~2020,~~2021, the Company’s finite-lived intangible assets consisted of developed technology related to ACTIMMUNE, BUPHENYL, KRYSTEXXA, ~~PENNSAID 2%,~~ PROCYSBI, RAVICTI, RAYOS, TEPEZZA and ~~TEPEZZA~~UPLIZNA as well as customer relationships for ACTIMMUNE. The intangible ~~asset~~assets related to PENNSAID 2% and VIMOVO developed technology ~~was~~were fully amortized as of December 31, ~~2019.~~2020.

In July 2021, in connection with the purchase of a drug product manufacturing facility from EirGen, the Company capitalized $21.8 million of intangible assets which are being amortized over a weighted-average estimated useful life of 16 years. Refer to Note 4 for further details.

On March 15, 2021, in connection with the acquisition of Viela, the Company capitalized $1,460.0 million of developed technology related to UPLIZNA. Refer to Note 4 for further details.

In connection with the acquisition of River Vision, the Company capitalized payments of $336.0 million related to TEPEZZA developed technology during the ~~nine months~~year ended ~~September 30,~~December 31, 2020. ~~See~~Refer to Note 4 for further details on the River Vision acquisition.

During the year ended December 31, 2019, in connection with the MIGERGOT transaction, the Company wrote off the remaining net book value of developed technology related to MIGERGOT of $17.0 million. See Note 4 for further details.

Intangible assets as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020							December 31, 2019							September 30, 2021							December 31, 2020
	Cost Basis		Accumulated Amortization			Net Book Value		Cost Basis		Accumulated Amortization			Net Book Value		Cost Basis		Accumulated Amortization			Net Book Value		Cost Basis		Accumulated Amortization			Net Book Value
Developed technology	$	3,094,331	$	(1,249,666	)	$	1,844,665	$	2,758,403	$	(1,059,595	)	$	1,698,808	$	4,585,524	$	(1,558,314	)	$	3,027,210	$	3,093,886	$	(1,313,934	)	$	1,779,952
Customer relationships		8,100		(4,885	)		3,215		8,100		(4,280	)		3,820
In-process research and development ⁽¹⁾																880,000		—			880,000		—		—			—
Customer relationships and other intangibles																29,894		(5,969	)		23,925		8,100		(5,090	)		3,010
Total intangible assets	$	3,102,431	$	(1,254,551	)	$	1,847,880	$	2,766,503	$	(1,063,875	)	$	1,702,628	$	5,495,418	$	(1,564,283	)	$	3,931,135	$	3,101,986	$	(1,319,024	)	$	1,782,962

Amortization expense for the three months ended September 30, 2021 and 2020 ~~and 2019~~ was ~~$65.4~~$90.4 million and ~~$57.7~~$65.4 million, respectively, and was ~~$190.7~~$245.3 million and ~~$172.8~~$190.7 million for the nine months ended September 30, ~~2020~~2021 and ~~2019,~~2020, respectively. As of September 30, ~~2020,~~2021, estimated future amortization expense was as follows (in thousands):

2020 (October to December)	$	64,289
2021		249,245
2021 (October to December)			$	89,838
2022		248,072		356,501
2023		247,455		355,987
2024		246,024		354,560
2025				352,311
Thereafter		792,795		1,541,938
Total	$	1,847,880	$	3,051,135

Accrued expenses and other current liabilities as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020		December 31, 2019		September 30, 2021		December 31, 2020
Accrued milestone payments	$	121,232	$	—
Payroll-related expenses		105,987		84,516	$	136,669	$	121,577
Accrued royalties		50,623		19,985		102,226		68,006
R&D and manufacturing programs						47,381		17,289
Allowances for returns						35,407		40,918
Advertising and marketing						27,595		12,428
Income taxes payable						21,829		13,583
Pricing review liability						20,532		16,046
Deferred revenues						20,349		—
Consulting and professional services		41,205		32,423		17,913		21,893
Allowances for returns		41,191		45,082
Pricing review liability		14,433		9,831
Accrued interest		6,033		18,709		7,019		14,207
Accrued upfront and milestone payments						—		123,442
Accrued other		41,123		24,688		46,913		36,178
Accrued expenses	$	421,827	$	235,234
Accrued expenses and other current liabilities					$	483,833	$	485,567

As of September 30, 2020, accrued milestone payments represented the expected attainment in 2020 of various TEPEZZA net sales milestones payable under the acquisition agreement for River Vision and license agreement with Roche. Refer to Note 4 for further detail.

Accrued trade discounts and rebates as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020		December 31, 2019		September 30, 2021		December 31, 2020
Accrued government rebates and chargebacks	$	162,170	$	164,508	$	205,816	$	172,893
Accrued commercial rebates and wholesaler fees		82,908		138,272		58,906		82,646
Accrued co-pay and other patient assistance		77,720		163,641		38,764		96,924
Accrued trade discounts and rebates	$	322,798	$	466,421	$	303,486	$	352,463
Invoiced commercial rebates and wholesaler fees, co-pay and other patient assistance costs, and government rebates and chargebacks in accounts payable		5,083		489		7,232		1,452
Total customer-related accruals and allowances	$	327,881	$	466,910	$	310,718	$	353,915

The following table summarizes changes in the Company’s customer-related accruals and allowances from December 31, ~~2019~~2020 to September 30, ~~2020~~2021 (in thousands):

The Company has 2 reportable segments, the orphan segment and the inflammation segment, and the Company reports net sales and segment operating income for each segment.

~~Effective in the first quarter of 2020,~~On March 15, 2021, the Company ~~(i) reorganized~~completed its acquisition of Viela. The acquisition expanded the Company’s commercial ~~operations and moved responsibility for and reporting of RAYOS~~medicine portfolio by adding an additional rare disease medicine, UPLIZNA, to ~~the inflammation segment and (ii) renamed the orphan and rheumatology segment the~~its orphan segment. ~~Net sales generated by TEPEZZA, which was approved in the first quarter of 2020, are reported as part of the renamed orphan segment.~~

The orphan segment includes the medicines TEPEZZA, KRYSTEXXA, RAVICTI, PROCYSBI, ACTIMMUNE, UPLIZNA, BUPHENYL and ~~QUINSAIR.~~QUINSAIR as well as the Company’s R&D programs. The inflammation segment includes the medicines PENNSAID 2%, DUEXIS, RAYOS and ~~VIMOVO and previously included MIGERGOT prior to the MIGERGOT transaction.~~VIMOVO.

The Company’s chief operating decision maker (“CODM”) evaluates the financial performance of the Company’s segments based upon segment operating income. Segment operating income is defined as ~~income (loss)~~loss before benefit for income taxes adjusted for the items set forth in the reconciliation below. Items below income from operations are not reported by segment, since they are excluded from the measure of segment profitability reviewed by the Company’s CODM. Additionally, certain expenses are not allocated to a segment. The Company does not report balance sheet information by segment as no balance sheet by segment is reviewed by the Company’s CODM.

The following table reflects net sales by medicine for the Company’s reportable segments for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands):

	Three Months Ended September 30				Nine Months Ended September 30				Three Months Ended September 30,				Nine Months Ended September 30,
	2020		2019		2020		2019		2021		2020		2021		2020
TEPEZZA	$	286,870	$	—	$	476,257	$	—	$	616,361	$	286,870	$	1,071,681	$	476,257
KRYSTEXXA		108,470		99,576		276,920		231,634		158,097		108,470		395,171		276,920
RAVICTI		64,648		59,954		191,386		160,299		76,323		64,648		217,566		191,386
PROCYSBI		43,112		40,397		122,812		121,142		49,346		43,112		142,484		122,812
ACTIMMUNE		28,312		27,861		83,152		78,883		30,063		28,312		86,603		83,152
UPLIZNA										18,677		—		35,025		—
BUPHENYL		3,229		3,036		8,389		8,173		1,868		3,229		5,790		8,389
QUINSAIR		163		211		499		550		302		163		733		499
Orphan segment net sales	$	534,804	$	231,035	$	1,159,415	$	600,681	$	951,037	$	534,804	$	1,955,053	$	1,159,415

PENNSAID 2%		50,314		42,091		126,925		143,751		47,963		50,314		142,721		126,925
DUEXIS		27,899		29,889		87,044		89,412		20,915		27,899		62,490		87,044
RAYOS		18,132		19,359		50,800		59,067		14,873		18,132		43,551		50,800
VIMOVO		5,278		13,092		30,931		41,751		2,204		5,278		8,131		30,931
MIGERGOT		—		—		—		1,822
Inflammation segment net sales	$	101,623	$	104,431	$	295,700	$	335,803	$	85,955	$	101,623	$	256,893	$	295,700

Total net sales	$	636,427	$	335,466	$	1,455,115	$	936,484	$	1,036,992	$	636,427	$	2,211,946	$	1,455,115

The table below provides reconciliations of the Company’s segment operating income to the Company’s total income ~~(loss)~~ before benefit for income taxes for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands):

	For the Three Months Ended September 30,						For the Nine Months Ended September 30,						For the Three Months Ended September 30,						For the Nine Months Ended September 30,
	2020			2019			2020			2019			2021			2020			2021			2020
Segment operating income:
Orphan	$	274,687		$	79,695		$	480,584		$	180,095		$	476,225		$	274,687		$	798,514		$	480,584
Inflammation		55,098			49,766			145,136			161,685			34,129			55,098			123,576			145,136
Reconciling items:
Amortization and step-up:
Intangible amortization expense		(65,353	)		(57,662	)		(190,677	)		(172,762	)		(90,368	)		(65,353	)		(245,260	)		(190,677	)
Inventory step-up expense		—			—			—			(90	)		(8,912	)		—			(16,914	)		—
Share-based compensation		(30,356	)		(18,151	)		(113,834	)		(67,066	)		(54,804	)		(30,356	)		(170,394	)		(113,834	)
Interest expense, net														(22,977	)		(12,185	)		(59,018	)		(48,100	)
Acquisition/divestiture-related costs														(9,224	)		(144	)		(89,241	)		(47,416	)
Litigation settlement														(5,000	)		—			(5,000	)		—
Depreciation														(4,111	)		(5,157	)		(11,955	)		(19,229	)
Upfront, progress and milestone payments related to license and collaboration agreements														(4,000	)		—			(53,500	)		(3,000	)
Manufacturing plant start-up costs														(1,712	)		—			(1,712	)		—
Restructuring and realignment costs														(680	)		—			(7,703	)		—
Foreign exchange (loss) gain														(476	)		(753	)		(1,363	)		306
Fees related to refinancing activities														—			—			—			(54	)
Loss on debt extinguishment		(14,602	)		(41,371	)		(31,856	)		(58,835	)		—			(14,602	)		—			(31,856	)
Interest expense, net		(12,185	)		(20,428	)		(48,100	)		(69,991	)
Depreciation		(5,157	)		(1,658	)		(19,229	)		(4,574	)
Foreign exchange (loss) gain		(753	)		(40	)		306			(25	)
Impairment of long-lived assets ⁽¹⁾														—			—			(12,371	)		(1,072	)
Drug substance harmonization costs		(193	)		(80	)		(483	)		(394	)		—			(193	)		—			(483	)
Acquisition/divestiture-related costs		(144	)		44			(47,416	)		(1,231	)
Upfront, progress and milestone payments related to license and collaboration agreements		—			(3,073	)		(3,000	)		(9,073	)
Fees related to refinancing activities		—			(262	)		(54	)		(1,437	)
Impairment of long-lived asset		—			—			(1,072	)		—
Loss on sale of assets		—			—			—			(10,963	)
Charges relating to discontinuation of Friedreich's ataxia program		—			—			—			(1,221	)
Litigation settlements		—			—			—			(1,000	)
Restructuring and realignment costs		—			—			—			(33	)
Other income (expense), net		717			890			1,791			(193	)
Income (loss) before benefit for income taxes	$	201,759		$	(12,330	)	$	172,096		$	(57,108	)
Gain on sale of asset														—			—			2,000			—
Other (expense) income, net														(849	)		717			2,113			1,791
Income before benefit for income taxes													$	307,241		$	201,759		$	251,772		$	172,096

The following table presents the amount and percentage of gross sales to customers that represented more than 10% of the Company’s gross sales included in its two reportable segments and all other customers as a group for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages):

	For the Three Months Ended September 30,
	2020					2019					For the Three Months Ended September 30,
	Amount		% of Gross			Amount		% of Gross			2021					2020
			Sales					Sales			Amount		% of Gross Sales			Amount		% of Gross Sales
Customer A	$	360,656		32	%	$	344,516		36	%	$	412,194		29	%	$	360,656		32	%
Customer B		262,362		24	%		202,410		21	%		387,705		27	%		262,362		24	%
Customer C		225,391		20	%		160,486		17	%		275,966		19	%		225,391		20	%
Customer D		148,098		13	%		88,256		9	%		274,106		19	%		148,098		13	%
Other Customers		118,386		11	%		157,742		17	%		94,393		6	%		118,386		11	%
Gross Sales	$	1,114,893		100	%	$	953,410		100	%	$	1,444,364		100	%	$	1,114,893		100	%

	For the Nine Months Ended September 30,
	2020					2019					For the Nine Months Ended September 30,
	Amount		% of Gross			Amount		% of Gross			2021					2020
			Sales					Sales			Amount		% of Gross Sales			Amount		% of Gross Sales
Customer A	$	921,719		33	%	$	1,056,439		36	%	$	1,071,370		30	%	$	921,719		33	%
Customer B		664,215		24	%		513,687		18	%		914,540		26	%		664,215		24	%
Customer C		520,080		18	%		497,413		17	%		634,293		18	%		520,080		18	%
Customer D		345,563		12	%		249,834		9	%		577,545		16	%		345,563		12	%
Other Customers		364,832		13	%		572,527		20	%		331,342		10	%		364,832		13	%
Gross Sales	$	2,816,409		100	%	$	2,889,900		100	%	$	3,529,090		100	%	$	2,816,409		100	%

Geographic revenues are determined based on the country in which the Company’s customers are located. The following table presents a summary of net sales attributed to geographic sources for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages):

	Three Months Ended September 30, 2020			Three Months Ended September 30, 2019			Three Months Ended September 30, 2021			Three Months Ended September 30, 2020
	Amount		% of Total Net Sales	Amount		% of Total Net Sales	Amount		% of Total Net Sales	Amount		% of Total Net Sales
United States	$	632,861	99%	$	333,011	99%	$	1,031,991	100%	$	632,861	99%
Rest of world		3,566	1%		2,455	1%		5,001	*		3,566	1%
Net sales	$	636,427		$	335,466		$	1,036,992		$	636,427

*Less than 1%

	Nine Months Ended September 30, 2020			Nine Months Ended September 30, 2019			Nine Months Ended September 30, 2021			Nine Months Ended September 30, 2020
	Amount		% of Total Net Sales	Amount		% of Total Net Sales	Amount		% of Total Net Sales	Amount		% of Total Net Sales
United States	$	1,447,704	99%	$	931,623	99%	$	2,202,506	100%	$	1,447,704	99%
Rest of world		7,411	1%		4,861	1%		9,440	*		7,411	1%
Net sales	$	1,455,115		$	936,484		$	2,211,946		$	1,455,115

*Less than 1%

The following tables and paragraphs set forth the Company’s financial instruments that are measured at fair value on a recurring basis within the fair value hierarchy. Assets and liabilities measured at fair value are classified in their entirety based on the lowest level of input that is significant to the fair value measurement. The Company’s assessment of the significance of a particular input to the fair value measurement in its entirety requires management to make judgments and consider factors specific to the asset or liability. The following describes three levels of inputs that may be used to measure fair value:

Level 1—Observable inputs such as quoted prices in active markets for identical assets or liabilities;

Level 2—Observable inputs other than Level 1 prices such as quoted prices for similar assets or liabilities, quoted prices in markets that are not active, or other inputs that are observable or can be corroborated by observable market data for substantially the full term of the assets or liabilities; and

Level 3—Unobservable inputs that are supported by little or no market activity and that are significant to the fair value of the assets or liabilities.

As of September 30, 2021, the Company’s cash and cash equivalents included bank time deposits which were measured at fair value using Level 2 inputs and their carrying values were approximately equal to their fair values. Level 2 inputs, obtained from various third-party data providers, represent quoted prices for similar assets in active markets, or these inputs were derived from observable market data, or if not directly observable, were derived from or corroborated by other observable market data.

The Company utilizes the market approach to measure fair value for its money market funds. The market approach uses prices and other relevant information generated by market transactions involving identical or comparable assets or liabilities.

Other current assets and other long-term liabilities recorded at fair value on a recurring basis are composed of investments held in a rabbi trust and the related deferred liability for deferred compensation arrangements. Quoted prices for this investment, primarily in mutual funds, are available in active markets. Thus, the Company’s investments related to deferred compensation arrangements and the related long-term liability are classified as Level 1 measurements in the fair value hierarchy.

The following tables set forth the Company’s financial assets and liabilities at fair value on a recurring basis as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 (in thousands):

	September 30, 2020										September 30, 2021
	Level 1			Level 2		Level 3		Total			Level 1			Level 2		Level 3		Total
Assets:
Bank time deposits											$	—		$	11,828	$	—	$	11,828
Money market funds	$	1,579,125		$	—	$	—	$	1,579,125			883,000			—		—		883,000
Other current assets		16,064			—		—		16,064			24,367			—		—		24,367
Total assets at fair value	$	1,595,189		$	—	$	—	$	1,595,189		$	907,367		$	11,828	$	—	$	919,195
Liabilities:
Other long-term liabilities		(16,064	)		—		—		(16,064	)		(24,367	)		—		—		(24,367	)
Total liabilities at fair value	$	(16,064	)	$	—	$	—	$	(16,064	)	$	(24,367	)	$	—	$	—	$	(24,367	)

	December 31, 2019										December 31, 2020
	Level 1			Level 2		Level 3		Total			Level 1			Level 2		Level 3		Total
Assets:
Money market funds	$	1,029,725			—		—	$	1,029,725		$	1,906,000			—		—	$	1,906,000
Other current assets		12,704			—		—		12,704			18,423			—		—		18,423
Total assets at fair value	$	1,042,429		$	—	$	—	$	1,042,429		$	1,924,423		$	—	$	—	$	1,924,423
Liabilities:
Other long-term liabilities		(12,704	)		—		—		(12,704	)		(18,423	)		—		—		(18,423	)
Total liabilities at fair value	$	(12,704	)	$	—	$	—	$	(12,704	)	$	(18,423	)	$	—	$	—	$	(18,423	)

The Company’s outstanding debt balances as of September 30, ~~2020~~2021 and December 31, ~~2019~~2020 consisted of the following (in thousands):

	September 30, 2020			December 31, 2019			September 30, 2021			December 31, 2020
Term Loan Facility due 2028							$	1,592,000			—
Term Loan Facility due 2026	$	418,026		$	418,026			418,026			418,026
Senior Notes due 2027		600,000			600,000			600,000			600,000
Exchangeable Senior Notes due 2022		—			400,000
Total face value		1,018,026			1,418,026			2,610,026			1,018,026
Debt discount		(10,420	)		(59,922	)		(12,663	)		(10,061	)
Deferred financing fees		(4,760	)		(5,263	)		(23,499	)		(4,586	)
Long-term debt and Exchangeable Senior Notes, net	$	1,002,846		$	1,352,841
Total long-term debt								2,573,864			1,003,379
Less: current maturities								16,000			—
Long-term debt, net of current maturities							$	2,557,864		$	1,003,379

On ~~December 18, 2019,~~March 15, 2021, Horizon Therapeutics USA, Inc. ~~(formerly known as Horizon Pharma USA, Inc.)~~ (the “Borrower” or “HTUSA”), a ~~wholly owned~~wholly-owned subsidiary of the Company, borrowed approximately ~~$418.0 million~~$1.6 billion aggregate principal amount of loans (the ~~“December 2019 Refinancing~~“2028 Term Loans”) pursuant to an amendment (the “March 2021 Amendment”) to the credit agreement, dated as of May 7, 2015, by and among the Borrower, the Company and certain of its subsidiaries as guarantors, the lenders party thereto from time to time and Citibank, N.A., as administrative agent and collateral agent, as amended by Amendment No. 1, dated as of October 25, 2016, Amendment No. 2, dated March 29, 2017, Amendment No. 3, dated October 23, 2017, Amendment No. 4, dated October 19, 2018, Amendment No. 5, dated March 11, 2019, ~~and~~ Amendment No. 6, dated May 22, 2019, Amendment No. 7, dated December 18, 2019 and the Incremental Amendment and Joinder Agreement, dated August 17, 2020 (the “Term Loan Facility”).

Pursuant to Amendment No. 7, the Borrower borrowed approximately $418.0 million aggregate principal amount of loans (the “2026 Term Loans”). Pursuant to Amendment No. 5, the Borrower received $200.0 million aggregate principal amount of revolving commitments, which was increased to $275.0 million aggregate amount of revolving commitments (the “Incremental Revolving Commitments”) pursuant to ~~an incremental amendment~~the Incremental Amendment and ~~joinder agreement entered into on August 17, 2020 (the “Incremental Amendment”).~~Joinder Agreement. The Incremental Revolving Commitments were established pursuant to an incremental facility (the “Revolving Credit Facility”) and includes a $50.0 million letter of credit sub-facility. The Incremental Revolving Commitments will terminate in March 2024. Borrowings under the Revolving Credit Facility are available for general corporate purposes. As of September 30, ~~2020,~~2021, the Revolving Credit Facility was undrawn. As used herein, all references to the “Credit Agreement” are references to the original credit agreement, dated as of May 7, 2015, as amended through the ~~Incremental~~March 2021 Amendment.

The ~~December 2019 Refinancing~~2028 Term Loans were incurred as a separate class of term loans under the Credit Agreement with substantially the same terms of the 2026 Term Loans. The Borrower used the proceeds of the 2028 Term Loans to fund a portion of the consideration payable in the acquisition of Viela. The 2028 Term Loans bear interest at a rate, at Borrower’s option, equal to the London Inter-Bank Offered Rate (“LIBOR”), plus 2.00% per annum (subject to a 0.50% LIBOR floor) or the adjusted base rate plus 1.00% per annum, with a step-down to LIBOR plus 1.75% per annum or the adjusted base rate plus 0.75% per annum at the time the Company’s leverage ratio is less than or equal to 2.00 to 1.00. The adjusted base rate is defined as the greatest of (a) LIBOR (using one-month interest period) plus 1.00%, (b) the prime rate, (c) the federal funds rate plus 0.50%, and (d) 1.00%.

The 2026 Term Loans were incurred as a separate new class of term loans under the Credit Agreement with substantially the same terms as the previously outstanding senior secured term loans incurred on May 22, 2019 (the “Refinanced Loans”) to effectuate a repricing of the Refinanced Loans. The Borrower used the proceeds of the ~~December 2019 Refinancing~~2026 Term Loans to repay the Refinanced Loans, which totaled approximately $418.0 million. The ~~December 2019 Refinancing~~2026 Term Loans bear interest at a rate, at the Borrower’s option, equal to ~~the London Inter-Bank Offered Rate (“LIBOR”),~~LIBOR plus 2.25% per annum (subject to a 0.00% LIBOR floor) or the adjusted base rate plus 1.25% per annum, with a step-down to LIBOR plus 2.00% per annum or the adjusted base rate plus 1.00% per annum at the time the Company’s leverage ratio is less than or equal to 2.00 to 1.00. ~~The adjusted base rate is defined as the greatest of (a) LIBOR (using one-month interest period) plus 1.00%, (b) the prime rate, (c) the federal funds rate plus 0.50%, and (d) 1.00%.~~

The loans under the Revolving Credit Facility bear interest, at the Borrower’s option, at a rate equal to either LIBOR plus an applicable margin of 2.25% per annum (subject to a LIBOR floor of 0.00%), or the adjusted base rate plus 1.25% per annum, with a step-down to LIBOR plus 2.00% per annum or the adjusted base rate plus 1.00% per annum at the time the Company’s leverage ratio is less than or equal to 2.00 to 1.00. The Credit Agreement provides for (i) the ~~December 2019 Refinancing~~2028 Term Loans, (ii) the 2026 Term Loans, (iii) the Revolving Credit Facility, ~~(iii)~~(iv) one or more uncommitted additional incremental loan facilities subject to the satisfaction of certain financial and other conditions, and ~~(iv)~~(v) one or more uncommitted refinancing loan facilities with respect to loans thereunder. The Credit Agreement allows for the Company and certain of its subsidiaries to become additional borrowers under incremental or refinancing facilities.

The obligations under the Credit Agreement (including obligations in respect of the ~~December 2019 Refinancing~~2028 Term Loans, 2026 Term Loans and the Revolving Credit Facility) and any swap obligations and cash management obligations owing to a lender (or an affiliate of a lender) are guaranteed by the Company and each of the Company’s existing and subsequently acquired or formed direct and indirect subsidiaries (other than certain immaterial subsidiaries, subsidiaries whose guarantee would result in material adverse tax consequences and subsidiaries whose guarantee is prohibited by applicable law). The obligations under the Credit Agreement (including obligations in respect of the ~~December 2019 Refinancing~~2028 Term Loans, 2026 Term Loans and the Revolving Credit Facility) and any related swap and cash management obligations are secured, subject to customary permitted liens and other agreed upon exceptions, by a perfected security interest in (i) all tangible and intangible assets of the Borrower and the guarantors, except for certain customary excluded assets, and (ii) all of the capital stock owned by the Borrower and guarantors thereunder (limited, in the case of the stock of certain non-U.S. subsidiaries of the Borrower, to 65% of the capital stock of such subsidiaries). The Borrower and the guarantors under the Credit Agreement are individually and collectively referred to herein as a “Loan Party” and the “Loan Parties,” as applicable.

The Company elected to exercise its reinvestment rights under the mandatory prepayment provisions of the Credit Agreement with respect to the net proceeds from the Company’s sale of its rights to PROCYSBI and QUINSAIR in the Europe, Middle East and Africa regions to Chiesi Farmaceutici S.p.A. To the extent the Company had not applied such net proceeds to permitted acquisitions (including the acquisition of rights to products and products lines) and/or the acquisition of capital assets within 365 days of the receipt thereof (or committed to so apply and then applied within 180 days after the end of such 365-day period), the Company was required to make a mandatory prepayment under the Credit Agreement in an amount equal to the unapplied net proceeds. In June 2018, the Company repaid $23.5 million under the mandatory prepayment provisions of the Credit Agreement.

On March 18, 2019, the Company completed the repayment of $300.0 million of the outstanding principal amount of term loans under the Credit Agreement following the closing of its underwritten public equity offering on March 11, 2019. ~~In July 2019, the Company repaid an additional $100.0 million of term loans under the Credit Agreement following the private placement of the Company’s 5.5% Senior Notes due 2027 (the “2027 Senior Notes”)~~. ~~Following these repayments, the outstanding principal balance of term loans under the Credit Agreement was $418.0 million.~~

Additionally, the Company elected to exercise its reinvestment rights under the mandatory prepayment provisions of the Credit Agreement with respect to the net proceeds from the Company’s sale of its ~~rights to RAVICTI and AMMONAPS (known as BUPHENYL in the United States) outside of North America and Japan to Medical Need Europe AB, part of the Immedica Group (the “Immedica transaction”).~~ To the extent the Company had not applied such net proceeds to permitted acquisitions (including the acquisition of rights to products and products lines) and/or the acquisition of capital assets within 365 days of the receipt of proceeds from the Immedica transaction (or commit to so apply and then apply within 180 days after the end of such 365-day period), the Company was required to make a mandatory prepayment under the Credit Agreement in an amount equal to the unapplied net proceeds. In March 2019, the Company repaid $35.0 million under the mandatory prepayment provisions of the Credit Agreement which was included in the $300.0 million repayment referred to above.

~~The~~ Borrower is permitted to make voluntary prepayments of the loans under the Credit Agreement at any time without payment of a ~~premium~~. premium. The Borrower is required to make mandatory prepayments of loans under the Credit Agreement (without payment of a premium) with (a) net cash proceeds from certain non-ordinary course asset sales (subject to reinvestment rights and other exceptions), (b) casualty proceeds and condemnation awards (subject to reinvestment rights and other exceptions), (c) net cash proceeds from issuances of debt (other than certain permitted debt), and (d) 50% of the Company’s excess cash flow (subject to decrease to 25% or 0% if the Company’s first lien leverage ratio is less than 2.25:1 or 1.75:1, respectively). The 2028 Term Loans will amortize in equal quarterly installments in an aggregate annual amount equal to 1% of the original principal amount thereof, with any remaining balance payable on March 15, 2028, the final maturity date of the 2028 Term Loans. The principal amount of the 2026 Term Loans~~December 2019 Refinancing Loans are~~ is due and payable on May 22, 2026, the final maturity date of the ~~December 2019 Refinancing~~2026 Term Loans.

The Credit Agreement contains customary representations and warranties and customary affirmative and negative covenants, including, among other things, restrictions on indebtedness, liens, investments, mergers, dispositions, prepayment of other indebtedness and dividends and other distributions. The Credit Agreement also contains a springing financial maintenance covenant, which requires that the Company maintain a specified leverage ratio at the end of each fiscal quarter. The covenant is tested if both the outstanding loans and letters of credit under the Revolving Credit Facility, subject to certain exceptions, exceed 25% of the total commitments under the Revolving Credit Facility as of the last day of any fiscal quarter. If the Company fails to meet this covenant, the commitments under the Revolving Credit Facility could be terminated and any outstanding borrowings, together with accrued interest, under the Revolving Credit Facility could be declared immediately due and payable.

Other events of default under the Credit Agreement include: (i) the failure by the Borrower to timely make payments due under the Credit Agreement; (ii) material misrepresentations or misstatements in any representation or warranty by any Loan Party when made; (iii) failure by any Loan Party to comply with the covenants under the Credit Agreement and other related agreements; (iv) certain defaults under a specified amount of other indebtedness of the Company or its subsidiaries; (v) insolvency or bankruptcy-related events with respect to the Company or any of its material subsidiaries; (vi) certain undischarged judgments against the Company or any of its restricted subsidiaries; (vii) certain ERISA-related events reasonably expected to have a material adverse effect on the Company and its restricted subsidiaries taken as a whole; (viii) certain security interests or liens under the loan documents ceasing to be, or being asserted by the Company or its restricted subsidiaries not to be, in full force and effect; (ix) any loan document or materialprovision thereof ceasing to be, or any challenge or assertion by any Loan Party that such loan document or material provision is not, in full force and effect; and (x) the occurrence of a change of control. If one or more events of default occurs and continues beyond any applicable cure period, the administrative agent may, with the consent of the lenders holding a majority of the loans and commitments under the facilities, or will, at the request of such lenders, terminate the commitments of the lenders to make further loans and declare all of the obligations of the Loan Parties under the Credit Agreement to be immediately due and payable.

The interest on the 2028 Term ~~Loan Facility~~Loans is variable and as of September 30, ~~2020~~2021, the interest rate on the 2028 Term ~~Loan Facility~~Loans was ~~2.19%~~2.50% and the effective interest rate was ~~2.48%~~2.75%.

The interest on the 2026 Term Loans is variable and as of September 30, 2021, the interest rate on the 2026 Term Loans was 2.38% and the effective interest rate was 2.67%.

As of September 30, ~~2020,~~2021, the fair value of the amounts outstanding under the 2028 Term ~~Loan Facility~~Loans and the 2026 Term Loans was approximately ~~$411.8~~$1,590.0 million and $415.9 million, respectively, categorized as a Level 2 instrument, as defined in Note 12.

On July 16, 2019, ~~Horizon Therapeutics USA, Inc. (formerly known as Horizon Pharma USA, Inc.), the Company’s wholly owned subsidiary (“HTUSA”),~~HTUSA completed a private placement of $600.0 million aggregate principal amount of ~~2027~~5.5% Senior Notes due 2027 (the “2027 Senior Notes”) to several investment banks acting as initial purchasers, who subsequently resold the 2027 Senior Notes to persons reasonably believed to be qualified institutional buyers.

The Company used the net proceeds from the offering of the 2027 Senior Notes, together with approximately $65.0 million in cash on hand, to redeem or prepay $625.0 million of its outstanding debt, consisting of (i) the outstanding $225.0 million principal amount of its 6.625% Senior Notes due 2023, (ii) the outstanding $300.0 million principal amount of its 8.750% Senior Notes due 2024 and (iii) $100.0 million of the outstanding principal amount of senior secured term loans under the Credit Agreement, as well as to pay the related premiums and fees and expenses, excluding accrued interest, associated with such redemption and prepayment.

The 2027 Senior Notes are HTUSA’s general unsecured senior obligations, rank equally in right of payment with all existing and future senior debt of HTUSA and rank senior in right of payment to any existing and future subordinated debt of HTUSA. The 2027 Senior Notes are effectively subordinate to all of the existing and future secured debt of HTUSA to the extent of the value of the collateral securing such debt.

The 2027 Senior Notes are unconditionally guaranteed on a senior basis by the Company and all of the Company’s restricted subsidiaries, other than HTUSA and certain immaterial subsidiaries, that guarantee the Credit Agreement. The guarantees are each guarantor’s senior unsecured obligations and rank equally in right of payment with such guarantor’s existing and future senior debt and senior in right of payment to any existing and future subordinated debt of such guarantor. The guarantees are effectively subordinated to all of the existing and future secured debt of each guarantor, including such guarantor’s guarantee under the Credit Agreement, to the extent of the value of the collateral securing such debt. The guarantees of a guarantor may be released under certain circumstances. The 2027 Senior Notes are structurally subordinated to all of the liabilities of the Company’s subsidiaries that do not guarantee the 2027 Senior Notes.

The 2027 Senior Notes accrue interest at an annual rate of 5.5% payable semiannually in arrears on February 1 and August 1 of each year, beginning on February 1, 2020. The 2027 Senior Notes will mature on August 1, 2027, unless earlier exchanged, repurchased or redeemed.

Except as described below, the 2027 Senior Notes may not be redeemed before August 1, 2022. Thereafter, some or all of the 2027 Senior Notes may be redeemed at any time at specified redemption prices, plus accrued and unpaid interest to the redemption date. At any time prior to August 1, 2022, some or all of the 2027 Senior Notes may be redeemed at a price equal to 100% of the aggregate principal amount thereof, plus a make-whole premium and accrued and unpaid interest to the redemption date. Also prior to August 1, 2022, up to 40% of the aggregate principal amount of the 2027 Senior Notes may be redeemed at a redemption price of 105.5% of the aggregate principal amount thereof, plus accrued and unpaid interest, with the net proceeds of certain equity offerings. In addition, the 2027 Senior Notes may be redeemed in whole but not in part at a redemption price equal to 100% of the principal amount plus accrued and unpaid interest and additional amounts, if any, to, but excluding, the redemption date, if on the next date on which any amount would be payable in respect of the 2027 Senior Notes, HTUSA or any guarantor is or would be required to pay additional amounts as a result of certain tax related events.

If the Company undergoes a change of control, HTUSA will be required to make an offer to purchase all of the 2027 Senior Notes at a price in cash equal to 101% of the aggregate principal amount thereof plus accrued and unpaid interest to, but not including, the repurchase date, subject to certain exceptions. If the Company or certain of its subsidiaries engages in certain asset sales, HTUSA will be required under certain circumstances to make an offer to purchase the 2027 Senior Notes at 100% of the principal amount thereof, plus accrued and unpaid interest to the repurchase date.

The indenture governing the 2027 Senior Notes contains covenants that limit the ability of the Company and its restricted subsidiaries to, among other things, pay dividends or distributions, repurchase equity, prepay junior debt and make certain investments, incur additional debt and issue certain preferred stock, incur liens on assets, engage in certain asset sales, merge, consolidate with or merge or sell all or substantially all of their assets, enter into transactions with affiliates, designate subsidiaries as unrestricted subsidiaries, and allow to exist certain restrictions on the ability of restricted subsidiaries to pay dividends or make other payments to the Company. Certain of the covenants will be suspended during any period in which the 2027 Senior Notes receive investment grade ratings. The indenture governing the 2027 Senior Notes also includes customary events of default.

As of September 30, ~~2020,~~2021, the interest rate on the 2027 Senior Notes was 5.50% and the effective interest rate was 5.76%.

As of September 30, ~~2020,~~2021, the fair value of the 2027 Senior Notes was approximately ~~$636.0~~$632.3 million, categorized as a Level 2 instrument, as defined in Note 12.

~~On March 13, 2015, Horizon~~ ~~Therapeutics~~ ~~Investment~~ ~~Limited (formerly known as Horizon Pharma Investment Limited) (“Horizon Investment”), a wholly owned subsidiary of the Company,~~ completed a private placement of $400.0 million aggregate principal amount of Exchangeable Senior Notes to certain investment banks acting as initial purchasers who subsequently resold the Exchangeable Senior Notes to qualified institutional buyers as defined in Rule 144A under the Securities Act of 1933, as amended. The net proceeds from the offering of the Exchangeable Senior Notes were approximately $387.2 million, after deducting the initial purchasers’ discount and offering expenses payable by Horizon Investment.

The Exchangeable Senior Notes were fully and unconditionally guaranteed, on a senior unsecured basis, by the Company (the “Guarantee”). The Exchangeable Senior Notes and the Guarantee were Horizon Investment’s and the Company’s senior unsecured obligations. The Exchangeable Senior Notes accrued interest at an annual rate of 2.5% payable semiannually in arrears on March 15 and September 15 of each year, beginning on September 15, 2015. The Exchangeable Senior Notes were scheduled to mature on March 15, 2022. The exchange rate was 34.8979 ordinary shares of the Company per $1,000 principal amount of the Exchangeable Senior Notes (equivalent to an initial exchange price of approximately $28.66 per ordinary share).

~~The Company recorded the Exchangeable Senior Notes under the guidance in ASC Topic 470-20,~~ ~~Debt with Conversion and Other Options,~~ and separated them into a liability component and equity component. The initial carrying amount of the liability component of $268.9 million was determined by measuring the fair value of a similar liability that does not have an associated equity component. The initial carrying amount of the equity component of $119.1 million represented by the embedded conversion option was determined by deducting the fair value of the liability component of $268.9 million from the initial proceeds of $387.2 million ascribed to the convertible debt instrument as a whole. The initial debt discount of $131.1 million was charged to interest expense over the life of the Exchangeable Senior Notes using the effective interest rate method.

~~On June 3, 2020, Horizon Investment issued a notice of redemption (the “Redemption Notice”) for all of the outstanding Exchangeable Senior Notes.~~ ~~From June 3, 2020 through July 30, 2020, the Company issued an aggregate of 13,898,414 of its ordinary shares~~ ~~to noteholders as a result of exchanges of $398.3 million in aggregate principal amount of Exchangeable Senior Notes following the issuance of the Redemption Notice.~~

On August 3, 2020, the Company redeemed the remaining $1.7 million in aggregate principal amount of Exchangeable Senior Notes and made aggregate cash payments to the holders of such Exchangeable Senior Notes of $1.8 million, including accrued interest. During the three and nine months ended September 30, 2020, the Company recorded a loss on debt extinguishment of $14.6 million and $31.9 million, respectively, related to the Exchangeable Senior Notes.

~~The~~As of September 30, 2021, the Company ~~has~~had the following office space lease agreements in place for real properties:

As of September 30, ~~2020~~2021 and December 31, ~~2019,~~2020, the Company had right-of-use lease assets included in other assets of ~~$36.3~~$76.4 million and ~~$39.8~~$34.4 million, respectively; current lease liabilities included in accrued expenses and other current liabilities of ~~$4.5~~$3.6 million and ~~$4.4~~$4.1 million, respectively; and non-current lease liabilities included in other long-term liabilities of ~~$43.7~~$94.8 million and ~~$46.5~~$43.2 million, respectively, in its condensed consolidated balance sheets. ~~During~~

In February 2021, the ~~nine months ended September 30, 2020,~~Company vacated the Lake Forest leased office building. As a result of the Company vacating the Lake Forest office, the Company recorded an impairment charge of ~~$1.1~~$12.4 million ~~related to~~during the ~~Novato, Californiaoffice lease, which was obtained through~~nine months ended September 30, 2021, using an ~~acquisition in~~income approach based on market prices for similar properties provided by a ~~prior year.~~third-party. This charge was reported within ~~selling, general and administrative expenses~~impairment of long-lived assets in the condensed consolidated statement of comprehensive ~~income (loss).~~income.

The Company recognizes rent expense on a monthly basis over the lease term based on a straight-line method. Rent expense was ~~$1.8~~$2.8 million and ~~$1.6~~$1.8 million for the three months ended September 30, ~~2020~~2021 and ~~2019,~~2020, respectively, and ~~$5.2~~$6.8 million and ~~$4.6~~$5.2 million for the nine months ended September 30, ~~2020~~2021 and ~~2019,~~2020, respectively.

The table below reconciles the undiscounted cash flows for each of the first five years and total of the remaining years to the ~~operating~~ lease liabilities recorded on the Company’s condensed consolidated balance sheet as of September 30, ~~2020~~2021 (in thousands):

2020 (October to December)	$	2,024
2021		7,242
2021 (October to December)				$	1,592
2022		6,066			6,144
2023		5,919			9,724
2024		6,537			10,538
2025					10,523
Thereafter		39,845			96,776
Total lease payments		67,633			135,297
Imputed interest		(19,435	)		(36,844	)
Total operating lease liabilities	$	48,198
Total lease liabilities				$	98,453

The weighted-average discount rate and remaining lease term for ~~operating~~ leases as of September 30, ~~2020~~2021 was ~~7.09%~~4.78% and ~~9.96~~15.47 years, respectively.

Under the Company’s supply agreement with AGC Biologics A/S (formerly known as CMC Biologics A/S) (“AGC Biologics”), the Company has agreed to purchase certain minimum annual order quantities of TEPEZZA drug substance. In addition, the Company must provide AGC Biologics with rolling forecasts of TEPEZZA drug substance requirements, with a portion of the forecast being a firm and binding order. At September 30, 2021, the Company had binding purchase commitments with AGC Biologics for TEPEZZA drug substance of €134.5 million ($155.8 million converted at a Euro-to-Dollar exchange rate as of September 30, 2021 of 1.1585), to be delivered through September 2023. Under the Company’s supply agreement with Catalent Indiana, LLC (“Catalent”), the Company must provide Catalent with rolling forecasts of TEPEZZA drug product requirements, with a portion of the forecast being a firm and binding order. At September 30, 2020, the Company had total purchase commitments, including the minimum annual order quantities and binding firm orders, with AGC Biologics for TEPEZZA drug substance of €130.7 million ($153.2 million converted at an exchange rate as of September 30, 2020 of 1.1722), to be delivered through September 2022. In addition,2021, the Company had binding purchase commitments with Catalent for TEPEZZA drug product of ~~$15.8~~$8.6 million, to be delivered through September ~~2021.~~2022.

~~Under an agreement with Boehringer Ingelheim Biopharmaceuticals GmbH~~On December 17, 2020, the Company announced that it expected a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production orders pursuant to the Defense Production Act of 1950 (“~~Boehringer Ingelheim Biopharmaceuticals”~~DPA”)~~, Boehringer Ingelheim Biopharmaceuticals is~~ that dramatically restricted capacity available for the production of TEPEZZA at its drug product contract manufacturer, Catalent. Pursuant to the DPA, Catalent was ordered to prioritize certain COVID-19 vaccine manufacturing at Catalent, resulting in the cancellation of previously guaranteed and contracted TEPEZZA drug product manufacturing slots in December 2020, which were required to ~~manufacture~~maintain TEPEZZA supply. To offset the reduced slots allowed by the DPA and ~~supply ACTIMMUNE and IMUKIN~~Catalent, the Company accelerated plans to increase the production scale of TEPEZZA drug product. In March 2021, the FDA approved a prior approval supplement to the ~~Company. Following~~TEPEZZA Biologics License Application (which was previously approved in January 2020), giving the ~~Company’s sale~~Company authorization to manufacture more TEPEZZA drug product resulting in an increased number of ~~the rights to IMUKIN in all territories outside of the United States, Canada and Japan to Clinigen Group plc (“Clinigen”), purchases of IMUKIN inventory are being resold to Clinigen.~~vials with each manufacturing slot. The Company ~~is required~~commenced resupply of TEPEZZA to ~~purchase minimum quantities of finished medicine during~~ the term of the agreement, which term extends to at least June 30, 2024. As of September 30, 2020, the minimum purchase commitment to Boehringer Ingelheim Biopharmaceuticals was $15.8 million (converted using a Dollar-to-Euro exchange rate of 1.1722 as of September 30, 2020) through June 2024.market in April 2021.

Under the Company’s agreement with Bio-Technology General (Israel) Ltd (“BTG Israel”), the Company has agreed to purchase certain minimum annual order quantities and is obligated to purchase at least 80 percent of its annual ~~world-wide~~worldwide bulk product requirements for KRYSTEXXA from BTG Israel. The term of the agreement runs until December 31, 2030, and will automatically renew for successive three-year periods unless earlier terminated by either party upon three years’ prior written notice. The agreement may be terminated earlier by either party in the event of a force majeure, liquidation, dissolution, bankruptcy or insolvency of the other party, uncured material breach by the other party or after January 1, 2024, upon three years’ prior written notice. Under the agreement, if the manufacture of the bulk product is moved out of Israel, the Company may be required to obtain the approval of the Israel Innovation Authority (formerly known as Israeli Office of the Chief Scientist) (“IIA”) because certain KRYSTEXXA intellectual property was initially developed with a grant funded by the IIA. The Company issues eighteen-month forecasts of the volume of KRYSTEXXA that the Company expects to order. The first nine months of the forecast are considered binding firm orders. At September 30, ~~2020,~~2021, the Company had a total purchase commitment, including the minimum annual order quantities and binding firm orders, with BTG Israel for KRYSTEXXA of ~~$36.0~~$33.0 million, to be delivered through December 2026. Additionally, there were other purchase orders relating to the manufacture of KRYSTEXXA of ~~$0.8~~$0.5 million outstanding at September 30, ~~2020.~~2021.

Under an agreement with Boehringer Ingelheim Biopharmaceuticals GmbH (“Boehringer Ingelheim Biopharmaceuticals”), Boehringer Ingelheim Biopharmaceuticals is required to manufacture and supply ACTIMMUNE and IMUKIN to the Company. Following the Company’s sale of the rights to IMUKIN in all territories outside of the United States, Canada and Japan to Clinigen Group plc (“Clinigen”), purchases of IMUKIN inventory are being resold to Clinigen. The Company is required to purchase minimum quantities of finished medicine during the term of the agreement, which term extends to at least September 30, 2024. As of September 30, 2021, the minimum purchase commitment to Boehringer Ingelheim Biopharmaceuticals was $14.8 million (converted using a Euro-to-Dollar exchange rate of 1.1585 as of September 30, 2021) through September 2024.

Excluding the above, additional purchase orders and other commitments relating to the manufacture of ~~RAVICTI,~~ BUPHENYL, DUEXIS, PROCYSBI, PENNSAID 2%, ~~DUEXIS,~~QUINSAIR, RAVICTI, RAYOS, TEPEZZA and ~~QUINSAIR~~UPLIZNA of ~~$12.2~~$19.1 million were outstanding at September 30, ~~2020.~~

The Company is subject to claims and assessments from time to time in the ordinary course of business. The Company’s management does not believe that any such matters, individually or in the aggregate, will have a material adverse effect on the Company’s business, financial condition, results of operations or cash flows. In addition, the Company from time to time has billing disputes with vendors in which amounts invoiced are not in accordance with the terms of their contracts.

In November 2015, the Company received a subpoena from the U.S. Attorney’s Office for the Southern District of New York requesting documents and information related to its patient assistance programs and other aspects of its marketing and commercialization activities. The Company is unable to predict how long this investigation will continue or its outcome, but it anticipates that it may continue to incur significant costs in connection with the investigation, regardless of the outcome. The Company may also become subject to similar investigations by other governmental agencies. The investigation by the U.S. Attorney’s Office and any additional investigations of the Company’s patient assistance programs and sales and marketing activities may result in damages, fines, penalties or other administrative sanctions against the Company.

On March 5, 2019, the Company received a civil investigative demand (“CID”) from the United States Department of Justice (“DOJ”) pursuant to the Federal False Claims Act regarding assertions that certain of the Company’s payments to pharmacy benefit managers (“PBMs”) were potentially in violation of the Anti-Kickback Statute. The CID requests certain documents and information related to the Company’s payments to PBMs, pricing and the Company’s patient assistance program regarding DUEXIS, VIMOVO and PENNSAID 2%. The Company is cooperating with the investigation. While the Company believes that its payments and programs are compliant with the Anti-Kickback Statute, no assurance can be given as to the timing or outcome of the DOJ’s investigation, or that it will not result in a material adverse effect on the Company’s business.

On April 1, 2020, the Company acquired Curzion for an upfront cash payment of $45.0 million with additional payments of up to $15.0 million contingent on the achievement of certain development and regulatory milestones. Under separate agreements, the Company is also required to make contingent payments upon the achievement of certain development and regulatory milestones and certain net sales thresholds. These separate agreements also include mid to high-single-digit royalty payments based on the portion of annual worldwide net sales.TEPEZZA

Under the acquisition agreement for River Vision, the Company agreed to pay up to $325.0 million upon the attainment of various milestones, composed of $100.0 million related to FDA approval and $225.0 million related to net sales thresholds for TEPEZZA. The Company made the $100.0 million milestone payment related to FDA approval during the first quarter of 2020.

The aggregate potential milestone payments of $225.0 million ~~are~~were payable based on certain TEPEZZA worldwide net sales thresholds being achieved as noted in the following table:

The agreement also includes a royalty payment of 3 percent of the portion of annual worldwide net sales exceeding $300.0 ~~million (if any).~~million.

S.R. One and Lundbeckfond, as two of the former River Vision stockholders, both held rights to receive approximately 35.66% of any future TEPEZZA payments. As a result of the Company’s agreements with S.R. One and Lundbeckfond in April 2020, the Company’s remaining net obligations to make TEPEZZA ~~payments for sales milestones~~sales-based milestone and ~~royalties~~royalty payments to the former stockholders of River Vision was reduced by approximately 70.25%, after including payments to a third party.

Under the Company’s license agreement with Roche, the Company is required to pay Roche up to CHF103.0 million ~~($111.8 million when converted using a CHF-to-Dollar exchange rate at September 30, 2020 of 1.0859)~~ upon the attainment of various development, regulatory and sales milestones for TEPEZZA.~~During the years ended December 31, 2019 and 2017,~~ ~~CHF3.0 million ($3.0 million when converted using a CHF-to-Dollar exchange rate at the date of payment of 1.0023) and~~ ~~CHF2.0 million~~ ~~($2.0 million when converted using a CHF-to-Dollar exchange rate at the date of payment of 1.0169), respectively,~~ ~~was paid in relation to these milestones.~~ The Company made a milestone payment of CHF5.0 million ($5.2 million when converted using a CHF-to-Dollar exchange rate at the date of payment of 1.0382) related to FDA approval during the first quarter of 2020. The agreement with Roche also includes tiered royalties on annual worldwide net sales between 9 and 12 percent.

As of September 30, 2020, the Company recorded a liability of $121.2 million in accrued expenses representing net sales milestones for TEPEZZA. During the second quarter of 2020, the Company recorded $67.0 million in relationThe Company’s remaining obligation to Roche relating to the ~~expected~~ attainment ~~in 2020~~ of various ~~net sales~~TEPEZZA development and regulatory milestones ~~payable under the acquisition agreement for River Vision and CHF30.0~~is CHF43.0 million ($~~32.6~~46.2 million when converted using a CHF-to-Dollar exchange rate ~~as of~~at September 30, ~~2020~~2021 of 1.0859) in relation to the expected attainment in 2020 of various net sales milestones payable to Roche. During the third quarter of 2020, the Company recorded an additional CHF20.0 million ($21.7 million when converted using a CHF-to-Dollar exchange rate as of September 30, 2020 of 1.0859) in relation to the expected attainment in 2020 of various net sales milestones payable to Roche. The timing of the payments is dependent on when the applicable milestone thresholds are attained. The Company expects to pay these applicable milestones during the first quarter of 2021.In addition, the Company recorded $120.8 million as a finite lived intangible asset representing the developed technology for TEPEZZA on the condensed consolidated balance sheet as of September 30, 2020 and the net foreign exchange loss of $0.4 million relating to remeasurement of the liability was recorded in the condensed consolidated statement of comprehensive income (loss) in the three months ended September 30, 2020.1.0748).

Under the Company’s license agreement with Lundquist Institute (formerly known as Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center) (“Lundquist”), the Company is required to pay Lundquist a royalty payment of less than 1 percent of TEPEZZA net sales.The royalty terminates upon the expiration date of the longest-lived Lundquist patent rights, which is December 2021 for the U.S. rights.

Under the Company’s license agreement with Boehringer Ingelheim Biopharmaceuticals, the Company is required to pay Boehringer Ingelheim Biopharmaceuticals milestone payments totaling less than $2.0 ~~million.~~million upon the achievement of certain TEPEZZA sales milestones.

On June 18, 2021, the Company entered into a global agreement with Arrowhead for ARO-XDH, a previously undisclosed discovery-stage investigational RNAi therapeutic being developed by Arrowhead as a potential treatment for uncontrolled gout. Arrowhead granted the Company a worldwide exclusive license to develop, manufacture and commercialize products based on the RNAi therapeutic.Arrowhead will conduct all research and preclinical development activities for the RNAi therapeutic products. The Company must use commercially reasonable efforts in, and will be responsible for, clinical development and commercialization of the RNAi therapeutic products.Under the terms of the agreement, the Company paid Arrowhead an upfront cash payment of $40.0 million in July 2021 and agreed to pay additional potential future milestone payments of up to $660.0 million contingent on the achievement of certain development, regulatory and commercial milestones, and low to mid-teens royalties on worldwide calendar year net sales of licensed products.

On November 21, 2020, the Company entered into a global agreement with Halozyme that gives the Company exclusive access to Halozyme’s ENHANZE drug delivery technology for SC formulation of medicines targeting IGF-1R. The Company is using ENHANZE to develop a SC formulation of TEPEZZA. Under the terms of the agreement, the Company paid Halozyme an upfront cash payment of $30.0 million in December 2020 and agreed to pay additional potential future milestone payments of up to $160.0 million contingent on the satisfaction of certain development and sales thresholds.

On April 1, 2020, the Company acquired Curzion for an upfront cash payment of $45.0 million with additional payments of up to $15.0 million contingent on the achievement of certain development and regulatory milestones. Under separate agreements with two additional parties, the Company is also required to make contingent payments upon the achievement of certain development and regulatory milestones and certain net sales thresholds. These separate agreements also include mid to high-single-digit royalty payments based on the portion of annual worldwide net sales.

During the ~~third quarter of~~year ended December 31, 2020, the Company committed to invest as a strategic limited partner in ~~two~~four venture capital funds: Forbion Growth Opportunities Fund I C.V. ~~(the “Forbion Fund”) and~~, Forbion Capital Fund V C.V., Aisling Capital V, L.P. ~~(the “Aisling Fund”). The Company is committed to investing an aggregate $34.6 million in the two funds, comprising of a $20.0 million commitment to the Aisling~~and RiverVest Venture Fund and a €13.0 million ($15.2 million when converted using a EUR-to-Dollar exchange rate at September 30, 2020 of 1.1722) commitment to the Forbion Fund, over each fund’s respective investment periods.V, L.P. As of September 30, ~~2020,~~2021, the total carrying amount of the Company’s investments in these funds was $20.7 million, which is included in other assets in the condensed consolidated balance sheet, and includes $9.8 million in net cash payments for investments made during the nine months ended September 30, 2021. As of September 30, 2021, the Company’s total future commitments to these funds were $44.7 million. During the nine months ended September 30, 2021, the Company recorded investment income under the equity method of $0.3 million in the other income, net line item of the Company’s consolidated statement of comprehensive income related to these funds.

As of September 30, 2021, the Company had ~~invested $8.1~~$29.2 million ~~in relation~~of non-cancellable advertising commitments due within one year, primarily related to ~~the Aisling Fund~~agreements for advertising for TEPEZZA and €0.7 million in relation to the Forbion Fund ($0.9 million when converted using a EUR-to-Dollar exchange rate at the date of investment of 1.1937). Additionally, in October 2020, the Company committed to investing an aggregate $15.0 million as a strategic limited partner in a third venture capital fund, RiverVest Venture Fund V, L.P., over the fund’s investment period.KRYSTEXXA.

In the normal course of business, the Company enters into contracts and agreements that contain a variety of representations and warranties and provide for general indemnifications. The Company’s exposure under these agreements is unknown because it involves claims that may be made against the Company in the future, but have not yet been made. The Company may record charges in the future as a result of these indemnification obligations.

In accordance with its memorandum and articles of association, the Company has indemnification obligations to its officers and directors for certain events or occurrences, subject to certain limits, while they are serving at the Company’s request in such capacity. Additionally, the Company has entered into, and intends to continue to enter into, separate indemnification agreements with its directors and executive officers. These agreements, among other things, require the Company to indemnify its directors and executive officers for certain expenses, including attorneys’ fees, judgments, fines and settlement amounts incurred by a director or executive officer in any action or proceeding arising out of their services as one of the Company’s directors or executive officers, or any of the Company’s subsidiaries or any other company or enterprise to which the person provides services at the Company’s request. The Company also has a director and officer insurance policy that enables it to recover a portion of any amounts paid for current and future potential claims. All of the Company’s officers and directors have also entered into separate indemnification agreements with HTUSA.

On November 13, 2014, the Company received a Paragraph IV Patent Certification from Watson Laboratories, Inc., now known as Actavis Laboratories UT, Inc. (“Actavis UT”), advising that Actavis UT had filed an Abbreviated New Drug Application (“ANDA”) with the FDA for a generic version of PENNSAID 2%. On December 23, 2014, June 30, 2015, August 11, 2015 and September 17, 2015, the Company filed four separate suits against Actavis UT and Actavis plc (collectively “Actavis”), in the United States District Court for the District of New Jersey, with each of the suits seeking an injunction to prevent approval of the ANDA. The lawsuits alleged that Actavis has infringed nine of the Company’s patents covering PENNSAID 2% by filing an ANDA seeking approval from the FDA to market a generic version of PENNSAID 2% prior to the expiration of certain of the Company’s patents listed in the FDA’s Orange Book (the “Orange Book”). These 4 suits were consolidated into a single suit. On October 27, 2015 and on February 5, 2016, the Company filed 2 additional suits against Actavis, in the United States District Court for the District of New Jersey, for patent infringement of 3 additional Company patents covering PENNSAID 2%.

~~On August 17, 2016, the District Court issued a~~ ~~Markman~~ opinion holding certain of the asserted claims of seven of the Company’s patents covering PENNSAID 2% invalid as indefinite. On March 16, 2017, the Court granted Actavis’ motion for summary judgment of non-infringement of the asserted claims of three of the Company’s patents covering PENNSAID 2%. In view of the ~~Markman~~ and summary judgment decisions, a bench trial was held from March 21, 2017 through March 30, 2017, regarding a claim of one of the Company’s patents covering PENNSAID 2%. On May 14, 2017, the Court issued its opinion upholding the validity of the claim of the patent, which Actavis had previously admitted its proposed generic diclofenac sodium topical solution product would infringe. Actavis filed its Notice of Appeal on June 16, 2017. The Company also filed its Notice of Appeal of the District Court’s rulings on certain claims of the Company’s patents covering PENNSAID 2%. On October 10, 2019, the Federal Circuit Court of Appeals affirmed the District Court’s judgment of validity of U.S Patent No. 9,066,913 (the “‘913 patent”), and its finding that the Actavis generic product would infringe the ‘913 patent. The Federal Circuit also affirmed the District Court’s summary judgment finding that certain patents are invalid for indefiniteness and would not be infringed. On July 29, 2020, the Company filed a Petition for Certiorari to the United States Supreme Court seeking review of the Federal Circuit’s ruling invalidating certain patents. The petition is currently pending consideration.

On August 18, 2016, the Company filed suit in the United States District Court for the District of New Jersey against Actavis for patent infringement of four of the Company’s newly issued patents covering PENNSAID 2%. All four of such patents are listed in the Orange Book. This litigation is currently stayed by agreement of the parties.

On May 29, 2018, the Company received notice from Alkem Laboratories, Inc. (“Alkem”) that it had filed an ~~ANDA~~Abbreviated New Drug Application (“ANDA”) with the FDA seeking approval of a generic version of DUEXIS. The ANDA contained a Paragraph IV Patent Certification alleging that the patents covering DUEXIS are invalid and/or will not be infringed by Alkem’s manufacture, use or sale of the medicine for which the ANDA was submitted. The Company filed suit in the United States District Court of Delaware against Alkem on July 9, 2018, seeking an injunction to prevent the approval of Alkem’s ANDA and/or to prevent Alkem from selling a generic version of DUEXIS. The litigation went to trial on September 14, 2020. On November 30, 2020, the District Court issued an adverse judgment against the Company, invalidating U.S Patent No. 8,607,033 and finding that Alkem’s generic product would not infringe the ~~parties are awaiting~~‘033 patent. Following an adverse claim construction ruling, the District Court entered a judgment that the Alkem generic product would not infringe U.S. Patent No. 8,607,451, subject to the Company’s right to appeal the District Court’s ~~judgment.~~claim construction ruling. On December 23, 2020, the Company initiated an appeal of the adverse judgments on the ‘033 and ‘451 patents with the Federal Circuit Court of Appeals. The Federal Circuit Court of Appeals held oral argument on October 4, 2021.

On August 3, 2021, the FDA granted final approval for Alkem’s generic version of DUEXIS. On August 4, 2021, Alkem launched its generic version of DUEXIS in the United States, and the Company now faces generic competition with respect to DUEXIS.

On September 26, 2018, the Company received notice from Teva Pharmaceuticals USA, Inc. (“Teva USA”) that it had filed an ANDA with the FDA seeking approval of a generic version of DUEXIS. The ANDA contained a Paragraph IV Patent Certification alleging that the patents covering DUEXIS are invalid and/or will not be infringed by Teva USA’s manufacture, use or sale of the medicine for which the ANDA was submitted. The Company filed suit in the United States District Court of New Jersey against Teva USA on July 2, 2020, seeking to prevent Teva USA from selling a generic version of DUEXIS. The parties are currently engaged in discovery. The court has not yet set a trial date.

On May 24, 2021, the Company received notice from Torrent Pharmaceuticals Limited (“Torrent”) that it had filed an ANDA with the FDA seeking approval of a generic version of DUEXIS. The ANDA contained a Paragraph IV Patent Certification alleging that the patents covering DUEXIS are invalid and/or will not be infringed by Torrent’s manufacture, use or sale of the medicine for which the ANDA was submitted. The Company filed suit in the United States District Court of New Jersey against Torrent on July 7, 2021, seeking to prevent Torrent from selling a generic version of DUEXIS.

On February 18, 2020, the FDA granted final approval for Dr. Reddy’s Laboratories Inc. and Dr. Reddy’s Laboratories Ltd. (collectively, “Dr. Reddy’s”) generic version of VIMOVO. On February 27, 2020, Dr. Reddy’s launched its generic version of VIMOVO in the United States, and the Company now faces generic competition with respect to VIMOVO. The Company continues to assert claims of infringement against Dr. Reddy’s based on U.S. Patent No. 8,858,996 and U.S. Patent No. 9,161,920 in the District Court for the District of New Jersey. Settlements were reached with four other generic companies: (i) Teva Pharmaceuticals Industries Limited (formerly known as Actavis Laboratories FL, Inc., which itself was formerly known as Watson Laboratories, Inc. – Florida) and Actavis Pharma, Inc., (ii) Lupin ~~Limited (“Lupin”) and Lupin Pharmaceuticals, Inc.~~, (iii) Mylan Pharmaceuticals Inc., Mylan Laboratories Limited, and Mylan Inc. (collectively, “Mylan”), and (iv) Ajanta Pharma Ltd. and Ajanta Pharma USA Inc. Under the settlement agreements, the license entry date was August 1, 2024; however, the entry date under all four licenses was accelerated and the licenses became effective upon Dr. Reddy’s launch of its generic version of VIMOVO on February 27, 2020.

On November 19, 2018, the District Court granted Dr. Reddy’s and Mylan’s summary judgment ruling that U.S Patent Numbers 9,220,698 and 9,393,208 are invalid, and on January 21, 2019, it entered final judgment against the ‘698 and ‘208 patents and U.S. Patent Number 8,945,621. On February 21, 2019, the Company appealed the adverse judgments on the ‘208 and ‘698 patents to the Federal Circuit Court of Appeals. This appeal remains pending before the Federal Circuit.

On December 4, 2017, Mylan filed a Petition for inter partes review (“IPR”) against the ‘208 patent. The Patent Trial and Appeals Board (“PTAB”) instituted an IPR proceeding on Mylan’s Petition on June 14, 2018. On July 2, 2018, Dr. Reddy’s filed a motion seeking to join Mylan’s ‘208 IPR. On April 1, 2019, the PTAB granted Dr. Reddy’s request to join the Mylan ‘208 IPR. On September 6, 2019, the PTAB issued a Final Written Decision invalidating the ‘208 patent on the basis of obviousness. On November 18, 2019, the Company filed an appeal with the Federal Circuit Court of Appeals to review the PTAB’s ruling invalidating the ‘208 patent. On April 17, 2020, the Federal Circuit vacated the PTAB’s decision and remanded the case to the PTAB for proceedings consistent with the Federal Circuit’s decision in ~~Arthrex, Inc. v. Smith & Nephew, Inc.~~

On July 22, 2020, the Company received notice from Anchen Pharmaceuticals, Inc. (“Anchen”) that it had filed an ANDA with the FDA seeking approval of a generic version of VIMOVO. The ANDA previously contained a Paragraph III Patent Certification, and the notice advised that Anchen has now made a Paragraph IV Patent Certification alleging that the patents covering VIMOVO are invalid and/or will not be infringed by Anchen’s manufacture, use or sale of the medicine for which the ANDA was submitted.

On June 27, 2020, the Company received notice from Lupin Limited (“Lupin”) that it had filed an ANDA with the FDA seeking approval of a generic version of PROCYSBI. The ANDA contained a Paragraph IV Patent Certification alleging that the patents covering PROCYSBI are invalid and/or will not be infringed by Lupin’s manufacture, use or sale of the medicine for which the ANDA was submitted. The Company filed suit in the United States District Court of New Jersey against Lupin on August 11, 2020, seeking to prevent Lupin from selling a generic version of PROCYSBI. On September 30, 2021, the Company entered into a settlement agreement with Lupin resolving both the PROCYSBI patent litigation with respect to PROCYSBI capsules and potential future patent litigation involving PROCYSBI granules. Under the Company’s settlement agreement with Lupin, Lupinmay enter the market on March 31, 2030, or earlier under certain circumstances.

During the three months ended September 30, 2020, the Company issued 13.6 million ordinary shares in connection with the closing of its underwritten public equity offering on August 11, 2020. The Company received net proceeds of approximately $919.8 million after deducting underwriting discounts and other offering expenses payable by the Company in connection with such offering.

The Company’s equity incentive plans at September 30, ~~2020~~2021 included its 2011 Equity Incentive Plan, as amended, 2014 Employee Share Purchase Plan, as amended, ~~(“2014 ESPP”),~~ Amended and Restated 2014 Equity Incentive Plan (“2014 EIP”), 2014 Non-Employee Equity Plan, as amended (“2014 Non-Employee Plan”), 2020 Employee Share Purchase Plan (“2020 ESPP”), Amended and Restated 2020 Equity Incentive Plan, as amended (“2020 EIP”), and Amended and Restated 2018 Equity Incentive Plan (“2018 EIP”).

On February ~~19, 2020,~~17, 2021, the Compensation Committee of the Company’s Board of Directors (the “Compensation Committee”) ~~adopted,~~approved amending the 2020 EIP, subject to shareholder approval, ~~the 2020 EIP, as successor to and continuation of the 2014 EIP,~~ including increasing the number of ordinary shares available for the grant of equity awards to the Company’s employees by an additional ~~6,900,000~~7,000,000 shares. On April ~~30, 2020,~~29, 2021, the shareholders of the Company approved such amendment to the 2020 EIP.

On February 19, 2020, the Compensation Committee adopted, subject to shareholder approval, the 2020 ESPP, as successor to and continuation of the 2014 ESPP, including increasing the number of ordinary shares available for issuance to the Company’s employees pursuant to the exercise of purchase rights by an additional 2,500,000 shares. On April 30, 2020, the shareholders of the Company approved the 2020 ESPP.

As of September 30, ~~2020,~~2021, an aggregate of ~~3,360,057~~2,519,726 ordinary shares were authorized and available for future issuance under the 2020 ESPP, an aggregate of ~~12,435,109~~16,040,670 ordinary shares were authorized and available for future grants under the 2020 EIP, ~~and~~ an aggregate of ~~574,193~~526,895 ordinary shares were authorized and available for future grants under the 2014 Non-Employee ~~Plan.~~Plan and an aggregate of 2,287,664 ordinary shares were authorized and available for future grants under the 2018 EIP.

The following table summarizes stock option activity during the nine months ended September 30, ~~2020:~~2021:

	Options			Weighted Average Exercise Price		Weighted Average Contractual Term Remaining (in years)		Aggregate Intrinsic Value (in thousands)		Options			Weighted Average Exercise Price		Weighted Average Contractual Term Remaining (in years)		Aggregate Intrinsic Value (in thousands)
Outstanding as of December 31, 2019		9,564,202		$	19.85		5.43	$	156,270
Outstanding as of December 31, 2020											7,129,615		$	21.24		4.60	$	370,073
Assumed in acquisition⁽¹⁾											1,318,053			41.23		—		—
Exercised		(2,159,733	)		15.73		—		—		(1,658,347	)		24.34		—		—
Forfeited		(61,278	)		16.10		—		—		(103,757	)		47.22		—		—
Expired		(26,020	)		22.87		—		—		(234	)		17.31		—		—
Outstanding as of September 30, 2020		7,317,171			21.09		4.84		414,067
Exercisable as of September 30, 2020		7,110,608		$	21.11		4.77	$	402,269
Outstanding as of September 30, 2021											6,685,330			24.01		4.12		571,773
Exercisable as of September 30, 2021											6,159,795		$	22.49		3.80	$	536,203

The following table summarizes restricted stock unit activity for the nine months ended September 30, ~~2020:~~2021:

	Number of Units			Weighted Average Grant-Date Fair Value Per Unit		Number of Units			Weighted Average Grant-Date Fair Value Per Unit
Outstanding as of December 31, 2019		6,541,224		$	18.77
Outstanding as of December 31, 2020							5,909,120		$	27.87
Granted		2,598,930			36.55		2,077,701			76.26
Vested		(2,735,510	)		18.07		(3,069,611	)		23.83
Forfeited		(388,440	)		25.12		(315,478	)		61.57
Outstanding as of September 30, 2020		6,016,204		$	26.13
Outstanding as of September 30, 2021							4,601,732		$	50.21

The grant-date fair value of restricted stock units is the closing price of the Company’s ordinary shares on the date of grant.

The following table summarizes performance stock unit awards (“PSUs”) activity for the nine months ended September 30, ~~2020:~~2021:

	Number of Units			Weighted Average Grant-Date Fair Value Per Unit		Average Illiquidity Discount			Recorded Weighted Average Fair Value Per Unit		Number of Units			Weighted Average Grant-Date Fair Value Per Unit		Average Illiquidity Discount			Recorded Weighted Average Fair Value Per Unit
Outstanding as of December 31, 2019		3,558,900
Outstanding as of December 31, 2020												2,610,924
Granted		587,802		$	42.38		8.1	%	$	38.94		450,577		$	93.73		8.64	%	$	85.64
Forfeited		(219,254	)		25.59		(1.4)	%		25.94		(24,450	)		93.73		9.21	%		85.10
Vested		(1,399,127	)		20.84		0.0	%		20.84		(2,131,964	)		23.18		3.44	%		22.39
Performance Based Adjustment (1)		89,941			20.24		0.0	%		20.24		623,129			31.41		7.69	%		29.00
Outstanding as of September 30, 2020		2,618,262
Outstanding as of September 30, 2021												1,528,216

On January 4, ~~2019,~~2021, the Company awarded PSUs to key executive participants (“~~2019~~2021 PSUs”). The ~~2019~~2021 PSUs utilize ~~two~~three long-term performance ~~metrics,~~metrics: a ~~short-term~~ component tied to ~~business performance~~technical operations milestones for the Company over the next two years, a component tied to research and development milestones for the Company over the next three years and a ~~long-term~~ component tied to relative three-year compounded annual ~~shareholder rate of return (“TSR”),~~TSR as follows:

On January 3, 2020, the Company awarded PSUs to key executive participants (“2020 PSUs”). The 2020 PSUs utilize two performance ~~metrics,~~metrics: a short-term component tied to business performance and a long-term component tied to relative compounded annual TSR, as follows:

As a result of the ~~continued~~ impact of the COVID-19 pandemic on certain aspects of the Company’s business in 2020, the performance goals associated with certain of the Company’s performance-based equity awards no longer reflected the Company’s expectations, causing the awards to lose their incentive to employees. Accordingly, on July 28, 2020 the Compensation Committee approved a modification to 57% of the 2020 Net Sales PSUs awarded on January 3, 2020 that were to vest based on KRYSTEXXA 2020 net sales. Those 2020 Net Sales PSUs related to KRYSTEXXA may now be earned based on net sales of KRYSTEXXA achieved by the end of a modified 18-month performance period ~~ending July 1,~~that ended on June 30, 2021 instead of a 12-month performance period ending December 31, 2020. As a result, the first one-third of any 2020 PSUs earned ~~will vest~~vested on July 1, 2021 and the vesting of the remaining two-thirds is unchanged and will vest one-third each on January 5, 2022 and on January 5, 2023. There were ~~twelve~~12 participants impacted by the modification. The total compensation cost resulting from the modification iswas approximately $12.0 million and ~~will be~~is being recognized over the remaining requisite service period.

All PSUs outstanding at September 30, ~~2020~~2021 may vest in a range of between 0% and 200%, with the exception of the modified KRYSTEXXA 2020 Net Sales PSUs which are ~~now~~ capped at 150%, based on the performance metrics described above. The Company accounts for the ~~2019~~2020 PSUs and ~~2020~~2021 PSUs as equity-settled awards in accordance with ASC ~~718.~~718, Compensation-Stock Compensation. Because the value of the ~~2019~~2020 Relative TSR PSUs and ~~2020~~2021 Relative TSR PSUs are dependent upon the attainment of a level of TSR, it requires the impact of the market condition to be considered when estimating the fair value of the ~~2019~~2020 Relative TSR PSUs and ~~2020~~2021 Relative TSR PSUs. As a result, the Monte Carlo model is applied and the most significant valuation assumptions used related to the ~~2020~~2021 PSUs during the nine months ended September 30, ~~2020,~~2021, include:

Valuation date stock price	$	36.10		$	72.54
Expected volatility		47.3	%		45.8	%
Risk free rate		1.5	%		0.2	%

The value of the ~~2020 Net Sales~~2021 Tech Ops PSUs and 2021 R&D PSUs is calculated at the end of each quarter based on the expected payout percentage based on estimated full-period performance against targets, and the Company adjusts the expense quarterly.

On January 4, 2019, the Company awarded a company-wide grant of PSUs (the “TEPEZZA PSUs”). Vesting of the TEPEZZA PSUs was contingent upon receiving shareholder approval of amendments to the 2014 EIP, which approval was received on May 2, 2019. The TEPEZZA PSUs were generally eligible to vest contingent upon receiving approval of the TEPEZZA biologics license application from the FDA no later than September 30, 2020 and the employee’s continued service with the Company. In January 2020, the Company received TEPEZZA approval from the FDA and the Company started recognizing the expense related to the TEPEZZA PSUs on that date. As of September 30, ~~2020,~~2021, there were ~~704,262~~68,459 TEPEZZA PSUs ~~outstanding. For~~outstanding, for members of the executive committee, ~~one-third~~ ~~of the TEPEZZA PSUs vested on the FDA approval date and one-third will~~expected to vest on ~~each of the first two anniversaries of the FDA approval date,~~January 21, 2022, subject to the ~~employee’s~~employees’ continued service through the ~~applicable~~ vesting ~~dates.~~date. For all other participants, one-half of the TEPEZZA PSUs vested on the FDA approval date and one-half ~~will vest~~vested on the one-year anniversary of the FDA approval date, subject to the employee’s continued service through the vesting date.

The following table summarizes share-based compensation expense included in the Company’s condensed consolidated statements of operations for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands):

	For the Nine Months Ended September 30,				For the Nine Months Ended September 30,
	2020		2019		2021		2020
Share-based compensation expense
Cost of goods sold	$	5,543	$	2,892	$	6,875	$	5,543
Research and development		11,381		6,931		32,851		11,381
Selling, general and administrative		96,910		57,243		130,668		96,910
Total share-based compensation expense	$	113,834	$	67,066	$	170,394	$	113,834

During the nine months ended September 30, ~~2020~~2021 and ~~2019,~~2020, the Company recognized ~~$24.4~~$77.1 million and ~~$5.9~~$24.4 million of tax benefit, respectively, related to share-based compensation resulting primarily from the fair value of equity awards at the time of the exercise of stock options and vesting of restricted stock units and PSUs. As of September 30, ~~2020,~~2021, the Company estimates that pre-tax unrecognized compensation expense of ~~$158.7~~$248.3 million for all unvested share-based awards, including stock options, restricted stock units and PSUs, will be recognized through the second quarter of 2023. The Company expects to satisfy the exercise of stock options and future distribution of shares for restricted stock units and PSUs by issuing new ordinary shares which have been reserved under the 2020 ~~EIP.~~

On January 5, 2018, the Compensation Committee approved a performance cash incentive program for the Company’s executive leadership team, including its executive officers (the “Cash Incentive Program”). Participants receiving awards under the Cash Incentive Program are eligible to earn a cash bonus based upon the achievement of specified Company goals, which both performance criteria were met on or before December 31, 2018. The Company determined that the cash bonus award under the Cash Incentive Program is to be paid out at the maximum 150% target level of $14.1 million. The first and second installments were paid in January 2019 and January 2020, respectively,EIP and the remaining installment will vest and become payable in January 2021, subject to the participant’s continued services with the Company through such vesting date, the date of any earlier change in control, or a termination due to death or disability.

The Company accounted for the Cash Incentive Program as a deferred compensation plan under ASC 710 and is recognizing the payout expense using straight-line recognition through the end of the 36-month vesting period. During the three and nine months ended September 30, 2020, the Company recorded an expense of $0.9 million and $2.8 million, respectively, to the condensed consolidated statement of comprehensive income (loss) related to the Cash Incentive Program.2018 EIP.

The Company accounts for income taxes based upon an asset and liability approach. Deferred tax assets and liabilities represent the future tax consequences of the differences between the financial statement carrying amounts of assets and liabilities versus the tax basis of assets and liabilities. Under this method, deferred tax assets are recognized for deductible temporary differences and operating loss and tax credit carryforwards. Deferred tax liabilities are recognized for taxable temporary differences. Deferred tax assets are reduced by valuation allowances when, in the opinion of management, it is more likely than not that some portion or all of the deferred tax assets will not be realized. Deferred tax assets and liabilities are recorded at the currently enacted rates which will be in effect at the time when the temporary differences are expected to reverse in the country where the underlying assets and liabilities are located. The impact of tax rate changes on deferred tax assets and liabilities is recognized in the period in which the change is enacted.

The following table presents the benefit for income taxes for the three and nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands):

During the three and nine months ended September 30, 2021, the Company recorded a benefit for income taxes of $19.3 million and $109.5 million, respectively. During the three and nine months ended September 30, 2020, the Company recorded a benefit for income taxes of $91.1 million and $27.1 million, respectively. ~~During the three and nine months ended September 30, 2019, the Company recorded a benefit for income taxes of $30.6 million and $37.4 million, respectively.~~

The ~~increase~~decrease in benefit for income taxes recorded during the three months ended September 30, ~~2020~~2021 compared to the three months ended September 30, ~~2019~~2020 resulted primarily from the mix of pre-tax income and losses incurred in various tax ~~jurisdictions,~~jurisdictions. This decrease in benefit was partially offset by the recognition of a $51.3 million tax benefit due to post-acquisition operational integration activities during the three months ended September 30, 2021 which resulted in an intercompany sale of inventory and a change to a legacy Viela entity’s future operational activities. This change reduced the state tax rate expected to apply to the reversal of temporary differences between the book values and tax bases of certain assets acquired through the Viela acquisition, which resulted in a reduction in the associated deferred tax asset resulting from an intra-company transfer of intellectual property from a U.S. subsidiary to an Irish subsidiary and an increase in the tax benefits recognized on share-based compensation. These increases in benefit were partially offset by tax expense recognized on U.S. taxable income generated from the intra-company transfer of intellectual property.liability.

The ~~decrease~~increase in benefit for income taxes recorded during the nine months ended September 30, ~~2020~~2021 compared to the nine months ended September 30, ~~2019~~2020 resulted primarily from an increase in the ~~mix of pre-tax income and losses incurred in various~~ tax ~~jurisdictions, tax expense~~benefits recognized on ~~U.S. taxable income generated~~share-based compensation and the recognition of a $51.3 million tax benefit due to post-acquisition operational integration activities during the three months ended September 30, 2021 which resulted in an intercompany sale of inventory and a change to a legacy Viela entity’s future operational activities. This change reduced the state tax rate expected to apply to the reversal of temporary differences between the book values and tax bases of certain assets acquired through the Viela acquisition, which resulted in a reduction in the associated deferred tax liability. A deferred tax asset resulting from an ~~intra-company~~intercompany transfer and license of intellectual property from a U.S. subsidiary to an Irish subsidiary ~~and~~was recognized during the nine months ended September 30, 2021. During the nine months ended September 30, 2020, the Company recorded a $15.2 million provision ~~recorded~~ following the publication, on April 8, 2020, by the U.S. Department of the Treasury, of Final Regulations for Section ~~267A (commonly referred to as the “Anti-Hybrid Rules”).~~267A. The Final Regulations for Section 267A permanently disallow for U.S. tax purposes certain interest expense accrued to a foreign related party during the year ended December 31, 2019. As a result, the Company recorded a write off of a deferred tax asset related to this interest expense during the nine months ended September 30, 2020 and recognized a corresponding tax provision of $15.2 million. There was no similar provision recorded during the nine months ended September 30, 2021. These ~~decreases~~increases in benefit ~~are~~during the nine months ended September 30, 2021 compared to the nine months ended September 30, 2020 were partially offset by ~~the recognition of a deferred~~ tax ~~asset in the Irish subsidiary resulting~~expense recognized on U.S. taxable income generated from the ~~intra-company~~intercompany transfer and license of intellectual property and ~~an increase~~the mix of pre-tax income and losses incurred in ~~the~~various tax ~~benefits recognized on share-based compensation.~~jurisdictions.

ITEM 2. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS

The following discussion and analysis should be read in conjunction with our condensed consolidated financial statements and the related notes that appear elsewhere in this report. This discussion contains forward-looking statements reflecting our current expectations that involve risks and uncertainties which are subject to safe harbors under the Securities Act of 1933, as amended, ~~or the Securities Act,~~ and the Securities Exchange Act of 1934, as amended, or the Exchange Act. These forward-looking statements include, but are not limited to, statements concerning our strategy and other aspects of our future operations, future financial position, future revenues, projected costs, expectations regarding demand and acceptance for our medicines, growth opportunities and trends in the market in which we operate, prospects and plans and objectives of management. The words “anticipates”, “believes”, “estimates”, “expects”, “intends”, “may”, “plans”, “projects”, “will”, “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements and you should not place undue reliance on our forward-looking statements. These forward-looking statements involve risks and uncertainties that could cause our actual results to differ materially from those in the forward-looking statements, including, without limitation, the risks set forth in Part II, Item 1A, “Risk Factors” in this report and in our other filings with the Securities and Exchange Commission, or SEC. We do not assume any obligation to update any forward-looking statements.

Unless otherwise indicated or the context otherwise requires, references to “Horizon”, “we”, “us” and “our” refer to Horizon Therapeutics plc and its consolidated subsidiaries.

We are focused on ~~researching, developing~~the discovery, development and ~~commercializing~~commercialization of medicines that address critical needs for people impacted by rare, autoimmune and ~~rheumatic~~severe inflammatory diseases. Our pipeline is purposeful: we apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives.

~~On January 21, 2020, the U.S. Food and Drug Administration, or FDA, approved TEPEZZA~~® ~~(teprotumumab-trbw), for the treatment of thyroid eye disease, or TED, a serious, progressive and vision-threatening rare autoimmune condition.~~

We have two reportable segments, ~~(i)~~ the orphan segment ~~(previously the orphan~~ and ~~rheumatology segment), our strategic growth business, and (ii)~~ the inflammation segment, and ~~we report net sales and segment operating income for each segment. Effective~~our commercial portfolio is currently composed of 12 medicines in the ~~first quarter~~areas of ~~2020,~~rare diseases, gout, ophthalmology and inflammation.

In July 2021, we ~~(i) reorganized~~completed the purchase of a drug product manufacturing facility from EirGen Pharma Limited, or EirGen, a subsidiary of OPKO Health, Inc., in Waterford, Ireland for $67.9 million. Refer to Note 4, Acquisitions, Divestitures and other Arrangements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further details.

On March 15, 2021, we completed the acquisition of Viela Bio, Inc., or Viela. The acquisition expanded our commercial ~~operations and moved responsibility for and reporting of RAYOS~~medicine portfolio by adding an additional rare disease medicine, UPLIZNA^® to ~~the inflammation segment and (ii) renamed the orphan and rheumatology segment the~~our orphan segment. ~~Net sales generated by TEPEZZA, which was approved in the first quarter~~The Viela acquisition provides multiple opportunities to drive long-term growth and solidify our future as an innovation-driven biotech company. Viela’s mid-stage biologics pipeline, research and development team and on-market medicine UPLIZNA, made it a complementary strategic fit with our pipeline, commercial portfolio and therapeutic areas of ~~2020, are reported as part of the renamed orphan segment.~~focus.

As of September 30, ~~2020,~~2021, our ~~medicine~~commercial portfolio consisted of the ~~following:~~following medicines:

Since January 1, ~~2019,~~2020, we completed the following acquisitions and divestitures:

OnBeginning in March ~~11,~~ 2020, the World Health Organization made the assessment that a novel strain of coronavirus, which causes the COVID-19 disease, can be characterized as a pandemic. The President of the United States declared the COVID-19 pandemic a national emergency and many states and municipalities in the ~~Unites~~United States took aggressive actions to reduce the spread of the ~~disease,~~COVID-19 pandemic, including limiting non-essential gatherings of people, ceasing all non-essential travel, ordering certain businesses and government agencies to cease non-essential operations at physical locations and issuing “shelter-in-place” orders which direct individuals to shelter at their places of residence (subject to limited exceptions). Similarly, the Irish government ~~has~~ limited gatherings of people and encouraged employees to work from their ~~homes,~~homes. In recent months, vaccines and ~~may implement~~treatments have enabled a resumption of more ~~aggressive policies~~normal business practices and initiatives in many countries, including the ~~future. In addition, in mid-March 2020 we implemented work-from-home policies for all employees~~United States and moved to a “virtual” model with respect to our physician, patient and partner support activities. As certain U.S. states have started to reduce restrictions, we are seeing physicians’ offices beginning to reopen, which reopening varies on a state-by-state basis. As a result, our sales representatives in some areas have transitioned to being back out in the field and are working on ways to re-engage patients and physicians. However, as COVID-19 cases have increased in certain areas, certain U.S. states have started to reimplement restrictions and we have seen some physician offices re-establish limits on in-person visits.Ireland. While our financial results during the nine months ended September 30, ~~2020~~2021 were strong and we continue to have a significant amount of available liquidity, ~~we anticipate~~ the COVID-19 pandemic tomay have a negative impact on net sales during the ~~remaining quarter~~remainder of ~~2020.~~2021, including due to the emergence of new variants of the virus and potential actions to combat their transmission. In addition, our clinical trials have been and may in the future be affected by the COVID-19 pandemic as referred to below.

Economic and health conditions in the United States and across most of the world are continuing to change rapidly because of the COVID-19 pandemic. Although COVID-19 is a global issue that is altering business and consumer activity, the pharmaceutical industry is considered a critical and essential industry in the United States and many other countries and, therefore, we do not currently expect any significant extended shut downs of suppliers or distribution channels. WeIn respect of our medicines, we believe we have sufficient inventory of raw materials and finished goods ~~for all of our medicines. We~~and we expect patients to be able to continue to receive their medicines at a site of care, for our infused medicines, and from their current pharmacies, alternative pharmacies or, if necessary, by direct shipment from our third-party providers that have such ~~capability.~~ capability, for our other medicines.

The launch of our ~~new~~ infused medicine for thyroid eye disease, or TED, TEPEZZA, ~~has~~which was approved by the U.S. Food and Drug Administration, or FDA, on January 21, 2020, significantly exceeded our expectations. In early 2019, we initiated our pre-launch disease awareness, market development and market access efforts with ~~the~~ multi-functional field-based teams beginning to engage with key stakeholders in July of 2019. ~~These~~We believe these pre-launch efforts, the severity and acute nature of TED, and a highly motivated patient population have generated significant demand for the medicine. For the year ended December 31, 2020, we recorded TEPEZZA net sales of $820.0 million, which was more than 20 times greater than our February 2020 estimate of TEPEZZA full year 2020 net sales of $30.0 million to $40.0 million. While we ~~anticipate~~experienced a much higher number of new patients in 2020 than our ~~prior~~initial estimates, the impact from COVID-19 ~~has~~ slowed the generation of patient enrollment forms for TEPEZZA, which drive new patient starts.

On December 17, 2020, we announced that we expected a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production orders pursuant to the Defense Production Act of 1950, or DPA, that dramatically restricted capacity available for the production of TEPEZZA at our drug product contract manufacturer, Catalent Indiana, LLC, or Catalent. Pursuant to the DPA, Catalent was ordered to prioritize certain COVID-19 vaccine manufacturing at Catalent, resulting in the cancellation of previously guaranteed and contracted TEPEZZA drug product manufacturing slots in December 2020, which were required to maintain TEPEZZA supply. To offset the reduced slots, we accelerated plans to increase the production scale of TEPEZZA drug product at Catalent.

In March 2021, the FDA approved a prior approval supplement to the TEPEZZA Biologics License Application, or BLA (which was previously approved in January 2020), giving us authorization to manufacture more TEPEZZA drug product resulting in an increased number of vials with each manufacturing slot. We commenced resupply of TEPEZZA to the market in April 2021. In addition, we are making progress with our second drug product manufacturer and estimate that TEPEZZA commercial supply from this manufacturer, assuming FDA approval, will begin shipping by the end of 2021. During the third quarter of 2021, we were informed that one of our contract manufacturers is manufacturing an adjuvant for a COVID-19 vaccine. The adjuvant is being manufactured on a different line to the line used to manufacture our medicine. We do not expect the manufacturing of this adjuvant to impact the supply of our medicine. Other than Catalent and the other previously mentioned contract manufacturer, we are not aware of any manufacturing facilities that are part of the supply chain for our medicines that are being utilized for the manufacture of vaccines for COVID-19. At this time, we consider the inventories on hand of our medicines to be sufficient to meet our commercial requirements.

As a result of the prior supply disruption, we delayed the start of an FDA-required post-marketing study to evaluate safety of TEPEZZA in a larger patient population and retreatment rates relative to how long patients receive the medicine given the supply disruption. The FDA-required post-marketing study was initiated in October 2021. We also delayed the start of our planned TEPEZZA clinical trial in chronic TED and an exploratory trial of TEPEZZA in diffuse cutaneous systemic sclerosis. The TEPEZZA clinical trial in chronic TED was initiated in the third quarter of 2021, and we expect to initiate an exploratory trial of TEPEZZA in diffuse cutaneous systemic sclerosis in the fourth quarter of 2021.

KRYSTEXXA is an infused medicine for uncontrolled gout and was also achieving rapid growth prior to the COVID-19 pandemic. While the vast majority of patients on therapy have maintained therapy, many new patients delayed infusions due to shelter-in-place guidelines and patients voluntarily delaying visits to healthcare providers and infusion ~~centers, many new patients have delayed infusions.~~centers. Patient visits to physicians ~~have~~ substantially declined during 2020, which ~~has~~ resulted in a reduction of new patients. ~~We expect patient~~While there continues to be some impact on demand for KRYSTEXXA, we have seen improvements as healthcare systems have adapted to ~~begin to return~~cope with the ~~return of healthcare activity, although~~pandemic and vaccines have been widely administered in the United States.

UPLIZNA is an infused medicine for neuromyelitis optica spectrum disorder and we ~~cannot predict when healthcare activities will return~~acquired through the Viela acquisition in March 2021. While there continues to ~~normal levels~~be some impact on demand for UPLIZNA primarily due to limited patient access to healthcare providers and infusion centers, we have also seen improvements as healthcare systems have adapted to cope with the ~~continued uncertainty with respect to~~pandemic and vaccines have been widely administered in the ~~COVID-19 pandemic.~~ United States.

Our other orphan segment medicines, RAVICTI, PROCYSBI and ACTIMMUNE, treat serious, chronic diseases with serious consequences if left untreated. It is therefore critical for patients to maintain therapy. Patient motivation to continue treatment is high, and therefore ~~we expect~~net sales for these three medicines ~~to be relatively~~were stable during 2020 and the nine months ended September 30, 2021, with less impact from COVID-19 compared to our other medicines.

In regard to the inflammation segment, ~~we are experiencing~~the impact of COVID-19 has significantly reduced ~~demand given~~as healthcare systems have adapted to cope with the ~~absence of~~pandemic and vaccines have been widely administered in the United States, thereby facilitating the return to mainly in-person engagement by our sales representatives with healthcare providers and reduced levels of non-essential patient visits to physicians. This impact has been somewhat mitigated by the virtual engagement efforts of our sales representatives, as well as the use of telemedicine by many physicians, which allows them to continue to see patients and prescribe medicines.providers. In addition, with our HorizonCares program, most patients do not need to physically visit a pharmacy to obtain a prescription because the vast majority of these medicines are delivered to a patient’s home through mail or local courier, depending on the participating pharmacy.

Our clinical trials have been and may in the future be affected by COVID-19 or its variants. As referred to above, our clinical trials ~~may be affected by COVID-19. Clinical~~for TEPEZZA have been delayed due to the impact of the TEPEZZA supply disruption at Catalent. In addition, clinical site initiation and patient enrollment may be delayed due to prioritization of hospital and healthcare resources toward COVID-19. Current or potential patients in our ongoing or planned clinical trials may also choose to not enroll, not participate in follow-up clinical visits or drop out of the trial as a result of, or a precaution against, contracting COVID-19. Further, some patients may not be able or willing to comply with clinical trial protocols if quarantines impede patient movement or interrupt healthcare services. Some clinical sites in the United States have slowed or stopped further enrollment of new patients in clinical trials, denied access to site monitors or otherwise curtailed certain operations. Similarly, our ability to recruit and retain principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19, may be adversely impacted. These events could delay our clinical trials, increase the cost of completing our clinical trials and negatively impact the integrity, reliability or robustness of the data from our clinical trials.

We are continuing to actively monitor the possible impacts from the COVID-19 pandemic and may take further actions to alter our business operations as may be required by federal, state or local authorities or that we determine are in the best interests of patients. There is significant uncertainty about the duration and potential impact of the COVID-19 pandemic. This means that our results could change at any time and the contemplated impact of the COVID-19 pandemic on our business results and outlook represents our estimate based on the information available as of ~~today’s date.~~the date of this Quarterly Report on Form 10-Q.

Horizon ~~today~~ is a leading, high-growth, ~~biopharma company~~innovation-driven, profitable biotech company. We are focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, ~~diseases, delivering innovative therapies to patients~~autoimmune and ~~generating value for our shareholders.~~severe inflammatory diseases. Our strategy is to expand our development-stage pipeline for long-term sustainable ~~growth and~~growth; to maximize the benefit and value of our on-market medicines, with particular focus on our current key rare disease growth ~~drivers~~driver medicines, TEPEZZA and ~~KRYSTEXXA, both rare disease medicines. We believe our strategy allows more patients~~KRYSTEXXA; and to ~~benefit from our on-market medicines and the medicines we develop as part of our pipeline.~~build a global presence. Our vision is to build healthier communities, urgently and responsibly, which we believe generates value for our many stakeholders, including our shareholders.

AsOur research and development strategy is to expand our pipeline with early-to late-stage programs for sustainable growth. We are pursuing this strategy by (i) acquiring and developing medicines for indications that address unmet needs in rare, autoimmune and severe inflammatory diseases, particularly those in our therapeutic areas of ~~September 30, 2020,~~focus; (ii) leveraging our ~~orphan segment consisted~~internal research as well as research-based partnerships and collaborations to drive earlier-stage innovation; and (iii) maximizing the range of potential diseases our pipeline medicine candidates can impact. The March 2021 acquisition of Viela and the addition of its mid-stage biologics pipeline significantly expanded our pipeline. Furthermore, after evaluating the acquired medicine candidates, we announced the addition of five additional Phase 2 programs in new disease states for two of the candidates. These new programs expanded our therapeutic areas of focus, which now include neuroimmunology, dermatology and respiratory, in addition to rheumatology, ophthalmology, nephrology and endocrinology. We continue to expect to initiate a total of eight clinical trials in 2021, five of which have already been initiated. For our on-market rare disease medicines, including our current key growth driver medicines, TEPEZZA and KRYSTEXXA, ~~RAVICTI, PROCYSBI, ACTIMMUNE, BUPHENYL and QUINSAIR.~~

TEPEZZA is the first and only FDA-approved medicine for the treatment of TED, a serious, progressive and vision-threatening rare autoimmune condition. TEPEZZA was launched commercially in the United States shortly after receiving FDA approval for the treatment of TED on January 21, 2020. The FDA approval was obtained well in advance of the TEPEZZA Prescription Drug User Fee Act action date of March 8, 2020, after an accelerated review of the medicine and its statistically significant Phase 3 data. We believe TEPEZZA represents a significant driver of potential future growth for Horizon.

~~Our comprehensive post-launch commercial~~our commercialization strategy ~~for TEPEZZA aims~~includes efforts to enable more TED patients to benefit from TEPEZZA. We are doing this by: (i) driving continued TEPEZZA uptake in the treatment of acute and chronic TED through continued promotion of TEPEZZA to treating physicians; (ii) continuing to develop the TED market by increasing physicianincrease awareness of the ~~disease severity, the urgency~~conditions each medicine is designed to ~~diagnose~~treat, enhancing efforts to identify target patients and treat, as well as the benefits of treatment with TEPEZZA; (iii) driving accelerated disease identification and time to treatment through our digital, broadcast and television marketing campaigns; (iv) enhancing the patient journey with our high-touch, patient-centric model as well as support for the patient and site-of-care referral processes; and (v) expanding access for TED patients.

Our first-quarter 2020 launch followed significant market-preparation initiatives in TEPEZZA in 2019 to drive awareness about TED in the medical and patient community and establish a potential pathway for treatment. Our pre-launch market preparation initiatives have proven effective in driving the highly successful launch of TEPEZZA, which has significantly exceeded expectations. To drive the continued strong growth and adoption of TEPEZZA, we are investing in significant expansion efforts in multiple areas: our U.S. infrastructure, which we expect to double in size to approximately 200 employees; our marketing initiatives, our long-term supply capacity and development efforts in pursuing expansion outside the United States.

~~Our clinical strategy for TEPEZZA is~~ to maximize the value of the ~~medicine for patients.~~medicines through investment in clinical trials. In ~~July 2020,~~addition, we ~~announced new topline results from our OPTIC-X open-label clinical trial, an extension trial of OPTIC,~~are pursuing a global expansion strategy, which ~~was the~~includes bringing TEPEZZA ~~Phase 3 pivotal confirmatory~~ ~~clinical trial, as well as data from the OPTIC 48-week off-treatment follow-up period.~~ ~~OPTIC-X results demonstrated that 89 percent of~~to patients ~~who received placebo during OPTIC and then entered OPTIC-X and received TEPEZZA achieved the primary endpoint of 2 mm or more reduction in proptosis at Week 24. These patients had~~with TED ~~diagnoses for an average of one year compared with an average of six months for patients in OPTIC. The results~~outside of the ~~OPTIC 48-week off-treatment follow-up period demonstrated that~~United States, including Japan, where we are engaging with the majority of TEPEZZA patients who were proptosis responders at Week 24 of OPTIC maintained their proptosis response at Week 72, nearly a year off treatment. Of the small number of TEPEZZA patients who relapsed during the OPTIC follow-up period, the majority experienced improvements in proptosis with an additional course of TEPEZZA in OPTIC-X. ~~The OPTIC-X~~Pharmaceuticals and ~~OPTIC 48-week follow-up period data underscore the long-term durability of TEPEZZA, the potential for retreatment~~Medical Devices Agency and the ~~efficacy of TEPEZZA in patients with longer duration of TED.~~

Additionally, in 2020, we announced three new TEPEZZA development programs. We plan to initiate a randomized, placebo-controlled trial of TEPEZZA in patients with chronic TED by year-end 2020 to support the broad indication received upon FDA approval. We have initiated a pharmacokinetic trial to explore subcutaneous dosing of TEPEZZA, which is currently administered by infusion. The objective of the trial is to inform the potential for additional administration options for TEPEZZA, which could provide greater flexibility for patients and physicians. We expect to initiate an exploratory trial by year-end 2020 for TEPEZZA in the treatment of diffuse cutaneous systemic sclerosis, or dcSSc, as part of our evaluation of additional indications for TEPEZZA. dcSSc is a rare, autoimmune rheumatic fibrotic disease with no FDA-approved therapies and of the highest mortality rates among rheumatic diseases. Scientific literature suggests that the mechanism of action of TEPEZZA could have an impact on fibrotic processes such as those that are relevant to dcSSc.

~~Furthering our objective to drive greater awareness about TED and the TEPEZZA~~Japanese medical community, several TED and TEPEZZA-related sessions will take place at the November 2020 virtual American Academy of Ophthalmology 2020 annual meeting, including additional details on OPTIC 48-week off-treatment durability of response as well as OPTIC-X treatment results. The virtual American Society of Ophthalmic Plastic and Reconstructive Surgery Fall Scientific Symposium, also in November 2020, will include a presentation on the recent case report published in the American Journal of Ophthalmology on the treatment of a patient with chronic TED. Additionally, case reports of improvement of dysthyroid optic neuropathy after treatment with TEPEZZA will be presented at both meetings.

Our other key growth driver is KRYSTEXXA, the only approved biologic indicated for the treatment of uncontrolled gout, or gout that is refractory (unresponsive) to conventional therapies. We are focused on optimizing and maximizing the benefit the medicine offers for patients as well as maximizing its peak U.S. net sales potential, which we are doing through: (i) our patient-centric commercialization efforts; (ii) investing in the clinical evaluation of the use of immunomodulation with KRYSTEXXA; and (iii) investing in education, patient and physician outreach that demonstrates the benefits KRYSTEXXA offers in treating uncontrolled gout.

We are driving growth for KRYSTEXXA in three ways: (i) by supporting the continued adoption of the use of KRYSTEXXA with immunomodulators to increase the complete response rate of KRYSTEXXA; (ii) by increasing new and existing accounts; and (iii) by accelerating uptake by nephrologists.

Our immunomodulation strategy includes (i) investing in research with our MIRROR immunomodulation clinical program; (ii) supporting additional research in immunomodulation and (iii) driving awareness in the medical community about immunomodulation as an option to increase the complete rate of response, duration of therapy and safety profile of KRYSTEXXA so that more patients with uncontrolled gout can benefit from the medicine.

Loss of response is a phenomenon not uncommon with biologics. Immunomodulation therapy has frequently been used with biologics in disease states such as rheumatoid arthritis or inflammatory bowel disease to increase the response rate, and as such it is a common practice in the rheumatology community, given the biologic medicines many rheumatologists use. The body of evidence supporting the immunomodulation approach for KRYSTEXXA is growing. Results of several trials and case series using KRYSTEXXA with immunomodulators have demonstrated response rates ranging between 70 and 100 percent, significantly higher than the 42 percent response rate achieved in the KRYSTEXXA Phase 3 clinical program, which evaluated the use of KRYSTEXXA alone.

Data from the RECIPE trial, an investigator-initiated study partially supported by Horizon, were recently announced in conjunction with a presentation to be made at the 2020 American College of Rheumatology annual meeting in November 2020. RECIPE was the first randomized controlled trial, or RCT, to evaluate the effect of co-administration of KRYSTEXXA with an immunomodulator to increase the complete response rate. The primary endpoint of the trial was the proportion of patients with serum uric acid less than or equal to 6 mg/dL at 12 weeks. Of patients who received KRYSTEXXA co-administered with the immunomodulator mycophenolate mofetil, or MMF, 86 percent achieved this outcome, compared to 40 percent of placebo patients on KRYSTEXXA alone (p-value 0.01).community. Furthermore, after 12 weeks off MMF therapy but continuing on KRYSTEXXA therapy, 68 percent of immunomodulation patients achieved a sustained response, compared to 30 percent of placebo patients. The combination was well tolerated with no new safety signals. The RECIPE trial data further support our KRYSTEXXA immunomodulation strategy.

We are currently evaluating the efficacy and safety of the concomitant use of KRYSTEXXA with the immunomodulator methotrexate in our MIRROR placebo-controlled RCT. Methotrexate is the immunomodulation agent most used by rheumatologists. Initiated in June 2019, MIRROR RCT completed enrollment of 145 patients in August 2020 and is the largest randomized controlled trial to evaluate immunomodulation with KRYSTEXXA. The MIRROR RCT is designed to enable the potential submission of results to the FDA to update the medicine’s prescribing information. The MIRROR RCT was preceded by our MIRROR open-label trial, completed in 2019, which demonstrated a 79 percent complete response rate for patients using KRYSTEXXA with methotrexate. While our immunomodulation clinical program focuses on methotrexate, our immunomodulation strategy for KRYSTEXXA provides flexibility for physicians in the choice of immunomodulation agent and dose to use with their patients.

~~In addition to our immunomodulation program,~~ we are investing in ~~additional programs~~our European infrastructure to ~~maximize~~support the ~~value~~potential first-quarter 2022 approval of KRYSTEXXA. In October 2019, we initiated the PROTECT open-label trial to evaluate the use of KRYSTEXXA in adult uncontrolled gout patients who have undergone a kidney transplant, a population that was not originally studied in the KRYSTEXXA pivotal trials. Managing uncontrolled gout is one of the most common and significant unmet needs of kidney transplant patients. We have achieved more than 75 percent enrollment in the PROTECT trial and expect to complete enrollmentUPLIZNA by the ~~end of 2020. Interim data from~~European Medicines Agency for neuromyelitis optica spectrum disorder, which has been granted orphan designation by the ~~PROTECT trial were presented in October 2020 at~~European Commission. In addition, to support the virtual American Society of Nephrology (ASN) Kidney Week. The data presented are encouraging with respect to the ability of KRYSTEXXA to treat uncontrolled gout in this very sensitive transplant population without compromising kidney function. Also, in October 2020, we announced enrollment of the first patient in an open-label trial we are conducting to evaluate the impact of administering KRYSTEXXA over a significantly shorter infusion duration. A shorter infusion duration could meaningfully impact the experience and convenience for patients, physicians and sites of care who use KRYSTEXXA, which is currently administered over a two-hour or longer timeframe.

~~As part~~global growth of our ~~overall strategy to expand~~on-market medicines, including TEPEZZA, KRYSTEXXA and UPLIZNA, and our ~~development-stage~~ pipeline ~~for sustainable growth, in April 2020 we acquired Curzion and its lysophosphatidic acid 1 receptor (LPAR~~₁) antagonist candidate, now known as HZN-825, which has demonstrated early clinical signals of benefit in dcSSC. We expect to begin a Phase 2b pivotal trial to evaluate HZN-825 in the treatment of dcSSc in the first half of 2021. On November 2, 2020, as part of our strategy to further explore the potential fibrosis-mediating benefits of LPAR1 antagonism, we announced plans for a development program for HZN-825 in interstitial lung disease, or ILD. The most common ILD is idiopathic pulmonary fibrosis, or IPF, a rare progressive lung disease with a median survival period of less than five years. We anticipate initiating the first trial in an ILD, a Phase 2b trial in the IPF indication, in mid-2021.

Our strategy for RAVICTI, our medicine for the treatment of urea cycle disorders, is to drive growth through increased awareness and diagnosis of urea cycle disorders; to drive conversion to RAVICTI from older-generation nitrogen scavengers, such as generic forms of sodium phenylbutyrate based on the medicine’s differentiated benefits; to position RAVICTI as the first line of therapy; and to increase compliance rates.

Our strategy for PROCYSBI, our medicine for the treatment of nephropathic cystinosis, is to drive conversion of patients from older-generation immediate-release capsules of cysteamine bitartrate; to increase the use of the medicine by diagnosed but untreated patients; to identify previously undiagnosed patients who are suitable for treatment; to position PROCYSBI as a first line of therapy; and to increase compliance rates.

In February 2020, the FDA approved PROCYSBI Delayed-Release Oral Granules in Packets for adults and children one year of age and older living with nephropathic cystinosis. The PROCYSBI Delayed-Release Oral Granules in Packets product is the same as the currently available PROCYSBI capsules product except in respect of the packaging format. This dosage form, which became commercially available in April 2020, provides another administration option for patients in addition to the PROCYSBI capsules.

Our strategy for ACTIMMUNE, our medicine for the treatment of chronic granulomatous disease, includes increasing awareness and diagnosis of chronic granulomatous disease and increasing compliance rates.

As of September 30, 2020, our inflammation segment consisted of our medicines PENNSAID 2%, DUEXIS, RAYOS and VIMOVO. Our strategy for our inflammation segment medicines is to educate physicians about these clinically differentiated medicines and the benefits they offer. Patients are able to fill prescriptions for these medicines through pharmacies participating in our HorizonCares patient assistance program, as well as other pharmacies. We offer discount-card and other programs to patients under which the patient receives a discount on his or her prescription. In certain circumstances when a patient’s prescription is rejected by a managed care vendor, we will pay for the full cost of the prescription. In addition, we have entered into business arrangements with pharmacy benefit managers, or PBMs, and other payers to secure formulary status and reimbursement of our inflammation segment medicines. The business arrangements with the PBMs generally require us to pay administrative fees and rebates to the PBMs and other payers for qualifying prescriptions. Effective in the first quarter of 2020, we reorganized our commercial operations and moved responsibility for and reporting of RAYOS to the inflammation segment.

On February 18, 2020, the FDA granted final approval for Dr. Reddy’s Laboratories Inc. and Dr. Reddy’s Laboratories Ltd., or collectively Dr. Reddy’s, generic version of VIMOVO. On February 27, 2020, Dr. Reddy’s launched its generic version of VIMOVO in the United States, and we now face generic competition with respect to VIMOVO, which has negatively impacted net sales of VIMOVO in 2020. Patent litigation against Dr. Reddy’s for infringement continues with respect to certain patents in the New Jersey District Court. We have repositioned our promotional efforts previously directed to VIMOVO to our other inflammation segment medicines and expect that our VIMOVO net sales will continue to decrease in future periods.

~~We market all of our~~biologic medicines, in the ~~United States through our field sales forces, which numbered approximately 445 representatives as~~second quarter of ~~September 30, 2020.~~ 2021 we acquired a biologic drug product manufacturing facility in Waterford, Ireland. Subject to completing the build-out, validation and regulatory approval processes, we expect that the first medicine manufactured at the facility to be approved for release in 2023.

The table below should be referenced in connection with a review of the following discussion of our results of operations for the three months ended September 30, ~~2020,~~2021, compared to the three months ended September 30, ~~2019.~~2020.

	For the Three Months Ended September 30,									For the Three Months Ended September 30,
	2020			2019			Change			2021			2020			Change
	(in thousands)									(in thousands)
Net sales	$	636,427		$	335,466		$	300,961		$	1,036,992		$	636,427		$	400,565
Cost of goods sold		151,475			89,949			61,526			251,640			151,475			100,165
Gross profit		484,952			245,517			239,435			785,352			484,952			300,400
Operating expenses:
Research and development		30,206			24,572			5,634			93,549			30,206			63,343
Selling, general and administrative		226,164			172,326			53,838			360,260			226,164			134,096
Total operating expenses		256,370			196,898			59,472			453,809			256,370			197,439
Operating income		228,582			48,619			179,963			331,543			228,582			102,961
Other expense, net:
Loss on debt extinguishment		(14,602	)		(41,371	)		26,769
Interest expense, net		(12,185	)		(20,428	)		8,243			(22,977	)		(12,185	)		(10,792	)
Foreign exchange loss		(753	)		(40	)		(713	)		(476	)		(753	)		277
Other income, net		717			890			(173	)
Loss on debt extinguishment											—			(14,602	)		14,602
Other (expense) income, net											(849	)		717			(1,566	)
Total other expense, net		(26,823	)		(60,949	)		34,126			(24,302	)		(26,823	)		2,521
Income (loss) before benefit for income taxes		201,759			(12,330	)		214,089
Income before benefit for income taxes											307,241			201,759			105,482
Benefit for income taxes		(91,081	)		(30,564	)		(60,517	)		(19,302	)		(91,081	)		71,779
Net income	$	292,840		$	18,234		$	274,606		$	326,543		$	292,840		$	33,703

Net sales. Net sales increased ~~$300.9~~$400.6 million, or ~~89.7%~~63%, to $1,037.0 million during the three months ended September 30, 2021, from $636.4 million during the three months ended September 30, ~~2020, from $335.5 million during the three months ended September 30, 2019.~~2020. The increase in net sales during the three months ended September 30, ~~2020~~2021 was primarily due to an increase in net sales in our orphan segment of ~~$303.8~~$416.2 million, primarily due to ~~post-launch~~an increase in TEPEZZA net sales of ~~TEPEZZA~~$329.5 million, an increase in KRYSTEXXA net sales of ~~$286.9 million.~~$49.6 million and net sales generated for UPLIZNA of $18.7 million when compared to the three months ended September 30, 2020.

The following table reflects net sales by medicine for the three months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages):

	Three Months Ended September 30,				Change			Change			Three Months Ended September 30,				Change			Change
	2020		2019		$			%			2021		2020		$			%
TEPEZZA	$	286,870	$	—	$	286,870		100		%	$	616,361	$	286,870	$	329,491			115	%
KRYSTEXXA		108,470		99,576		8,894			9	%		158,097		108,470		49,627			46	%
RAVICTI		64,648		59,954		4,694			8	%		76,323		64,648		11,675			18	%
PROCYSBI		43,112		40,397		2,715			7	%		49,346		43,112		6,234			14	%
ACTIMMUNE		28,312		27,861		451			2	%		30,063		28,312		1,751			6	%
UPLIZNA												18,677		—		18,677			100	%
BUPHENYL		3,229		3,036		193			6	%		1,868		3,229		(1,361	)		(42	)%
QUINSAIR		163		211		(48	)		(23	)%		302		163		139			85	%
Orphan segment net sales	$	534,804	$	231,035	$	303,769			131	%	$	951,037	$	534,804	$	416,233			78	%

PENNSAID 2%		50,314		42,091		8,223			20	%		47,963		50,314		(2,351	)		(5	)%
DUEXIS		27,899		29,889		(1,990	)		(7	)%		20,915		27,899		(6,984	)		(25	)%
RAYOS		18,132		19,359		(1,227	)		(6	)%		14,873		18,132		(3,259	)		(18	)%
VIMOVO		5,278		13,092		(7,814	)		(60	)%		2,204		5,278		(3,074	)		(58	)%
Inflammation segment net sales	$	101,623	$	104,431	$	(2,808	)		(3	)%	$	85,955	$	101,623	$	(15,668	)		(15	)%

Total net sales	$	636,427	$	335,466	$	300,961			90	%	$	1,036,992	$	636,427	$	400,565			63	%

TEPEZZA. ~~On January 21, 2020, the FDA approved TEPEZZA for the treatment of TED.~~ Net sales ~~generated for TEPEZZA~~increased $329.5 million, or 115%, to $616.4 million during the three months ended September 30, ~~2020 were~~2021, from $286.9 ~~million.~~million during the three months ended September 30, 2020. Net sales increased by approximately $337.9 million due to volume growth, partially offset by a decrease of approximately $8.4 million resulting from lower net pricing.

KRYSTEXXA. Net sales increased ~~$8.9~~$49.6 million, or 9%46%, to $158.1 million during the three months ended September 30, 2021 from $108.5 million during the three months ended September 30, ~~2020 from $99.6~~2020. Net sales increased by approximately $35.3 million due to volume growth and $14.3 million due to higher net pricing, despite the ongoing challenges associated with the COVID-19 pandemic.

RAVICTI. Net sales increased $11.6 million, or 18%, to $76.3 million during the three months ended September 30, 2019. Net sales increased by approximately $7.7 million due to higher net pricing and $1.2 million due to volume growth. As a result of the COVID-19 pandemic, KRYSTEXXA net sales were negatively impacted during the three months ended September 30, 2020, due to reduced willingness of patients to visit physician offices and infusion centers.

~~RAVICTI. Net sales increased $4.7 million, or 8%, to~~2021, from $64.7 million during the three months ended September 30, ~~2020, from $60.0 million during the three months ended September 30, 2019.~~2020. Net sales increased by approximately ~~$4.1~~$9.8 million due to volume growth and ~~$0.6~~$1.8 million due to higher net pricing.

PROCYSBI. Net sales increased ~~$2.7~~$6.2 million, or 7%14%, to $49.3 million during the three months ended September 30, 2021, from $43.1 million during the three months ended September 30, ~~2020, from $40.4~~2020. Net sales increased by approximately $4.1 million due to higher net pricing and $2.1 million due to volume growth.

ACTIMMUNE. Net sales increased $1.8 million, or 6%, to $30.1 million during the three months ended September 30, ~~2019.~~2021, from $28.3 million during the three months ended September 30, 2020. Net sales increased by approximately ~~$3.6~~$1.9 million due to higher net pricing, partially offset by a decrease of approximately ~~$0.9~~$0.1 million resulting from lower sales volume.

~~ACTIMMUNE~~UPLIZNA. Net sales generated for UPLIZNA during the three months ended September 30, 2021 were $18.7 million. We began recognizing UPLIZNA sales following our acquisition of Viela on March 15, 2021.

At September 30, 2021, we determined that there was an indicator to trigger an interim impairment analysis of the inflammation reporting unit’s $56.2 million goodwill balance. The fair value of the inflammation reporting unit exceeds its carrying value by more than 30% as of September 30, 2021, the interim testing date, resulting in no impairment. In order to evaluate the sensitivity of the fair value calculations on the goodwill impairment test, we applied a hypothetical 10 percent decrease to the fair values of the reporting unit. A 10% decrease in fair value would reduce the headroom between the reporting unit’s fair value and its carrying value to approximately 19%.

We anticipate that an impairment of the inflammation reporting unit’s goodwill could occur in the next 12 to 18 months if the reporting unit does not achieve currently forecasted nets sales and profitability estimates.

PENNSAID 2%. Net sales ~~increased $0.4~~decreased $2.3 million, or 2%5%, to ~~$28.3~~$48.0 million during the three months ended September 30, ~~2020,~~2021, from $27.9 million during the three months ended September 30, 2019. Net sales increased by approximately $2.4 million due to higher net pricing, partially offset by a decrease of approximately $2.0 million resulting from lower sales volume.

As a result of the COVID-19 pandemic, sales volumes for our inflammation medicines have been negatively impacted due to reduced demand given the absence of in-person engagement by our sales representatives with health care providers and reduced levels of non-essential patient visits to physicians.

~~PENNSAID 2%. Net sales increased $8.2 million, or 20%, to~~ $50.3 million during the three months ended September 30, 2020, from $42.1 million during the three months ended September 30, 2019. Net sales increased by approximately $17.8 million due to higher net pricing primarily due to lower utilization of our patient assistance programs, partially offset by a decrease of approximately $9.6 million resulting from lower sales volume.

~~DUEXIS. Net sales decreased $2.0 million, or 7%, to $27.9 million during the three months ended September 30, 2020, from $29.9 million during the three months ended September 30, 2019.~~2020. Net sales decreased by approximately ~~$4.8~~$5.9 million ~~resulting from~~due to lower sales volume, partially offset by an increase of approximately ~~$2.8~~$3.6 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs.

~~RAYOS~~DUEXIS. Net sales decreased ~~$1.3~~$7.0 million, or 6%25%, to $20.9 million during the three months ended September 30, 2021, from $27.9 million during the three months ended September 30, 2020. The decrease in net sales was primarily due to the impact of generic competition on DUEXIS.

On August 3, 2021, the FDA granted final approval for Alkem Laboratories, Inc.’s, or Alkem, generic version of DUEXIS and on August 4, 2021, Alkem launched its generic version of DUEXIS in the United States. While patent litigation against Alkem continues in the Federal Circuit Court of Appeals, we now face generic competition for DUEXIS, which has negatively impacted net sales of DUEXIS. As a result, we have repositioned our promotional efforts previously directed to DUEXIS to the other inflammation segment medicines and expect that our DUEXIS net sales will continue to decrease in future periods.

RAYOS. Net sales decreased $3.2 million, or 18%, to $14.9 million during the three months ended September 30, 2021, from $18.1 million during the three months ended September 30, ~~2020, from $19.4 million during the three months ended September 30, 2019.~~2020. Net sales decreased by approximately ~~$3.7~~$3.8 million due to lower sales volume, partially offset by an increase of ~~$2.4~~$0.6 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs.

VIMOVO. Net sales decreased ~~$7.8~~$3.1 million, or ~~60%~~58%, to $2.2 million during the three months ended September 30, 2021, from $5.3 million during the three months ended September 30, ~~2020, from $13.1 million during the three months ended September 30, 2019.~~2020. Net sales decreased by approximately ~~$11.1~~$3.0 million due to lower sales volume ~~partially offset by an increase~~as a result of ~~$2.4~~generic competition and $0.1 million ~~resulting from higher net pricing primarily~~ due to lower ~~utilization of our patient assistance programs and an increase of $0.9 million related to authorized generic VIMOVO sales in the third quarter of 2020.~~net pricing.

The table below reconciles our gross to net sales for the three months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in millions, except percentages):

	Three Months Ended September 30, 2020						Three Months Ended September 30, 2019						Three Months Ended September 30, 2021						Three Months Ended September 30, 2020
	Amount			% of Gross Sales			Amount			% of Gross Sales			Amount			% of Gross Sales			Amount			% of Gross Sales
Gross sales	$	1,114.9			100.0	%	$	953.4			100.0	%	$	1,444.4			100.0	%	$	1,114.9			100.0	%
Adjustments to gross sales:
Prompt pay discounts														(11.5	)		(0.8	)%		(13.1	)		(1.2	)%
Medicine returns		(6.7	)		(0.6	)%		(9.1	)		(1.0	)%		(4.4	)		(0.3	)%		(6.7	)		(0.6	)%
Prompt pay discounts		(13.1	)		(1.2	)%		(17.4	)		(1.8	)%
Co-pay and other patient assistance														(114.9	)		(7.9	)%		(222.1	)		(19.9	)%
Commercial rebates and wholesaler fees		(85.9	)		(7.7	)%		(112.6	)		(11.8	)%		(77.6	)		(5.4	)%		(85.9	)		(7.7	)%
Government rebates and chargebacks		(150.7	)		(13.5	)%		(132.6	)		(13.9	)%		(199.0	)		(13.8	)%		(150.7	)		(13.5	)%
Co-pay and other patient assistance		(222.1	)		(19.9	)%		(346.2	)		(36.3	)%
Total adjustments		(478.5	)		(42.9	)%		(617.9	)		(64.8	)%		(407.4	)		(28.2	)%		(478.5	)		(42.9	)%
Net sales	$	636.4			57.1	%	$	335.5			35.2	%	$	1,037.0			71.8	%	$	636.4			57.1	%

During the three months ended September 30, 2020, commercial rebates and wholesaler fees, as a percentage of gross sales, decreased to 7.7% from 11.8% during the three months ended September 30, 2019, primarily as a result of an increased proportion of orphan segment medicines sold and the impact of generic competition on VIMOVO sales.

~~During the three months ended September 30, 2020,~~2021, co-pay and other patient assistance costs, as a percentage of gross sales, decreased to ~~19.9%~~8.0% from ~~36.3%~~19.9% during the three months ended September 30, ~~2019,~~2020, primarily due to ~~lower utilization~~a decreased proportion of ~~our patient assistance programs and~~inflammation segment medicines sold, including the impact of generic competition on ~~VIMOVO~~DUEXIS sales.

Cost of Goods Sold. Cost of goods sold increased ~~$61.5~~$100.1 million to $251.6 million during the three months ended September 30, 2021, from $151.5 million during the three months ended September 30, ~~2020, from $90.0 million during the three months ended September 30, 2019.~~2020. The increase in cost of goods sold during the three months ended September 30, ~~2020~~2021 compared to three months ended September 30, ~~2019,~~2020, was primarily due to ~~a $30.8 million~~an increase in sales volumes, an increase in royalty expense, ~~and a $7.7 million~~an increase in amortization ~~expense. These increases are mainly related~~expense and the recording of inventory step-up expense during the three months ended September 30, 2021. Royalty expense increased by $46.9 million primarily due to royalties payable on net sales of TEPEZZA, which ~~was launched~~increased significantly in the third quarter of 2021 compared to the third quarter of 2020. Amortization expense increased $24.7 million primarily due to the acquisition of the UPLIZNA developed technology intangible asset in the first quarter of ~~2020,~~2021 and we recorded inventory step-up expense of $8.9 million related to UPLIZNA based on the ~~amortization~~acquired units of inventory sold during the ~~TEPEZZA developed technology intangible asset, which commenced in~~three months ended September 30, 2021. In addition, we recorded a $7.5 million DUEXIS inventory reserve due to the ~~first quarter~~impact of ~~2020.~~generic competition on DUEXIS sales. As a percentage of net sales, cost of goods sold was 24.3% during the three months ended September 30, 2021, compared to 23.8% during the three months ended September 30, ~~2020, compared to 26.8% during the three months ended September 30, 2019.~~2020. The ~~decrease~~increase in cost of goods sold as a percentage of net sales was primarily due to a change in the mix of medicines sold.

Research and Development Expenses. Research and development expenses increased ~~$5.6~~$63.3 million to $93.5 million during the three months ended September 30, 2021, from $30.2 million during the three months ended September 30, ~~2020, from $24.6 million during the three months ended September 30, 2019.~~2020. The increase was primarily attributable to a ~~$6.4~~$32.9 million increase in clinical trial and manufacturing development costs and ~~$2.4~~a $21.7 million increase in employee-related costs, ~~partially offset by~~reflecting increased activity in our research and development pipeline as well as the addition of our medicine candidates and development programs following the acquisition of Viela in March 2021.

We expect our research and development expenses to significantly increase for the remainder of 2021 as a ~~milestone payment~~result of ~~$3.0 million to Roche related to the TEPEZZA BLA submission to the FDA that was incurred during the third quarter of 2019.~~our on-going and planned clinical trials for our pipeline including new medicine candidates and development programs acquired in 2021.

Selling, General and Administrative Expenses. Selling, general and administrative expenses increased ~~$53.8~~$134.1 million to $360.2 million during the three months ended September 30, 2021, from $226.1 million during the three months ended September 30, ~~2020, from $172.3~~2020. The increase was primarily attributable to an increase in TEPEZZA commercial activities and integration costs following the acquisition of Viela in March 2021. These include an increase of $66.5 million related to marketing program costs, an increase of $41.6 million in employee-related costs and an increase of $8.4 million in consulting costs.

We expect our selling, general and administrative expenses to significantly increase for the remainder of 2021 as a result of the increase in the U.S. commercial and field-based organization for TEPEZZA and global expansion activities.

Interest Expense, Net. Interest expense, net, increased $10.8 million to $23.0 million during the three months ended September 30, ~~2019.~~2021, from $12.2 million during the three months ended September 30, 2020. The increase was primarily ~~attributable~~due to an increase in interest expense of ~~$25.4~~$10.6 million, ~~in employee costs and an increase of $16.5 million~~primarily related to ~~marketing program costs. These increases were mainly due~~an additional $1.6 billion aggregate principal amount of term loans borrowed pursuant to an amendment to our Credit Agreement. Refer to Note 13, Debt Agreements, of the ~~launch~~Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of ~~TEPEZZA.~~this Quarterly Report on Form 10-Q for further detail.

Loss on Debt Extinguishment. During the three months ended September 30, 2020, we recorded a loss on debt extinguishment of $14.6 million in the condensed consolidated statements of comprehensive income, ~~(loss),~~ which reflects the partial exchange of our 2.5% Exchangeable Senior Notes due 2022, or the Exchangeable Senior Notes. As of September 30, 2020, $400.0 million in aggregate principal amount of Exchangeable Senior Notes had been exchanged for ordinary shares and cash payments. ~~See~~Refer to Note 13, Debt Agreements, of the Notes toUnaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further detail.

~~During the three months ended September 30, 2019, we recorded a loss on debt extinguishment of $41.4 million in the condensed consolidated statements of comprehensive income (loss),~~ which reflected the early redemption premiums and the write-off of the deferred financing fees and debt discount fees related to the prepayment of $525.0 million of our 2023 Senior Notes, and our 8.750% Senior Notes due 2024, or the 2024 Senior Notes, and the write-off of the deferred financing fees and debt discount fees related to the ~~$100.0 million term loan repayment.~~

~~Interest Expense, Net~~. Interest expense, net, decreased $8.2 million to $12.2 million during the three months ended September 30, 2020, from $20.4 million during the three months ended September 30, 2019. The decrease was primarily due to a decrease in interest expense of $12.3 million, primarily related to the decrease in the principal amount of our term loans in July 2019, redemption of our remaining 6.625% Senior Notes due 2023, or the 2023 Senior Notes, in August 2019, redemption of our 2024 Senior Notes, in August 2019 and the exchange of our Exchangeable Senior Notes, partially offset by a decrease in interest income of $4.1 million.

Benefit for Income Taxes. During the three months ended September 30, ~~2020,~~2021, we recorded a benefit for income taxes of ~~$91.1~~$19.3 million and a benefit for income taxes of ~~$30.6~~$91.1 million during the three months ended September 30, ~~2019.~~2020. The ~~increase~~decrease in benefit for income taxes recorded during the three months ended September 30, ~~2020~~2021 compared to the three months ended September 30, ~~2019~~2020 resulted primarily from the mix of pre-tax income and losses incurred in various tax ~~jurisdictions,~~jurisdictions. This decrease in benefit was partially offset by the recognition of a $51.3 million tax benefit due to post-acquisition operational integration activities during the three months ended September 30, 2021 which resulted in an intercompany sale of inventory and a change to a legacy Viela entity’s future operational activities. This change reduced the state tax rate expected to apply to the reversal of temporary differences between the book values and tax bases of certain assets acquired through the Viela acquisition, which resulted in a reduction in the associated deferred tax asset resulting from an intra-company transfer of intellectual property from a U.S. subsidiary to an Irish subsidiary and an increase in the tax benefits recognized on share-based compensation. These increases in benefit were partially offset by tax expense recognized on U.S. taxable income generated from the intra-company transfer of intellectual property.liability.

~~See~~Refer to Note 11, Segment and Other Information, of the Notes toUnaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for a reconciliation of our segment operating income to our total income ~~(loss)~~ before benefit for income taxes for the three months ended September 30, ~~2020~~2021 and ~~2019.~~2020.

The following table reflects our orphan segment net sales and segment operating income for the three months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages).

	For the Three Months Ended September 30,									For the Three Months Ended September 30,
	2020		2019		Change		% Change			2021		2020		Change		% Change
Net sales	$	534,804	$	231,035	$	303,769		131	%	$	951,037	$	534,804	$	416,233		78	%
Segment operating income		274,687		79,695		194,992		245	%		476,225		274,687		201,538		73	%

The increase in orphan segment net sales during the three months ended September 30, ~~2020~~2021 is described in the Consolidated Results section above.

Segment operating income. Orphan segment operating income increased ~~$195.0~~$201.5 million to $476.2 million during the three months ended September 30, 2021, from $274.7 million during the three months ended September 30, ~~2020, from $79.7 million during the three months ended September 30, 2019.~~2020. The increase was primarily attributable to an increase in net sales of ~~$303.8~~$416.2 million ~~primarily due to post-launch sales of TEPEZZA~~ as described above, partially offset by an increase in selling, general and administrative expenses of ~~$44.1~~$109.3 million, ~~primarily due to increased costs relating to the launch of TEPEZZA and~~ an increase of ~~$32.0~~$51.9 million in royalty expense primarily related to an increase in royalties payable on net sales of ~~TEPEZZA.~~TEPEZZA during the third quarter of 2021 compared to the third quarter of 2020 and an increase in research and development expenses of $46.6 million. The increase in selling, general and administrative expenses were mainly due to an increase in the commercial and field-based organization for TEPEZZA, and the increase in research and development expenses was primarily due to incremental net operating expense from Viela after we acquired it on March 15, 2021.

The following table reflects our inflammation segment net sales and segment operating income for the three months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages).

	For the Three Months Ended September 30,										For the Three Months Ended September 30,
	2020		2019		Change			% Change			2021		2020		Change			% Change
Net sales	$	101,623	$	104,431	$	(2,808	)		(3	%)	$	85,955	$	101,623	$	(15,668	)		(15	%)
Segment operating income		55,098		49,766		5,332			11	%		34,129		55,098		(20,969	)		(38	%)

The decrease in inflammation segment net sales during the three months ended September 30, ~~2020~~2021 is described in the Consolidated Results section above.

Segment operating income. Inflammation segment operating income ~~increased $5.3~~decreased $21.0 million to $34.1 million during the three months ended September 30, 2021, from $55.1 million during the three months ended September 30, ~~2020, from $49.8 million during the three months ended September 30, 2019.~~2020. The ~~increase~~decrease was primarily attributable to a decrease in net sales of $15.7 million as described above and ~~marketing costs~~a $7.5 million inventory reserve for DUEXIS due to the impact of ~~$5.9~~generic competition on DUEXIS sales, partially offset by a decrease in selling, general and administrative expenses of $2.6 million.

The table below should be referenced in connection with a review of the following discussion of our results of operations for the nine months ended September 30, ~~2020,~~2021, compared to the nine months ended September 30, ~~2019.~~2020.

	For the Nine Months Ended September 30,									For the Nine Months Ended September 30,
	2020			2019			Change			2021			2020			Change
	(in thousands)									(in thousands)
Net sales	$	1,455,115		$	936,484		$	518,631		$	2,211,946		$	1,455,115		$	756,831
Cost of goods sold		370,406			267,254			103,152			553,003			370,406			182,597
Gross profit		1,084,709			669,230			415,479			1,658,943			1,084,709			574,234
Operating expenses:
Research and development		138,483			74,611			63,872			291,076			138,483			152,593
Selling, general and administrative		696,271			511,720			184,551			1,047,456			696,271			351,185
Loss on sale of assets		—			10,963			(10,963	)
Impairment of long-lived asset											12,371			—			12,371
Gain on sale of asset											(2,000	)		—			(2,000	)
Total operating expenses		834,754			597,294			237,460			1,348,903			834,754			514,149
Operating income		249,955			71,936			178,019			310,040			249,955			60,085
Other expense, net:
Interest expense, net		(48,100	)		(69,991	)		21,891			(59,018	)		(48,100	)		(10,918	)
Foreign exchange (loss) gain											(1,363	)		306			(1,669	)
Loss on debt extinguishment		(31,856	)		(58,835	)		26,979			—			(31,856	)		31,856
Foreign exchange gain (loss)		306			(25	)		331
Other income (expense), net		1,791			(193	)		1,984
Other income, net											2,113			1,791			322
Total other expense, net		(77,859	)		(129,044	)		51,185			(58,268	)		(77,859	)		19,591
Income (loss) before benefit for income taxes		172,096			(57,108	)		229,204
Income before benefit for income taxes											251,772			172,096			79,676
Benefit for income taxes		(27,143	)		(37,359	)		10,216			(109,537	)		(27,143	)		(82,394	)
Net income (loss)	$	199,239		$	(19,749	)	$	218,988
Net income										$	361,309		$	199,239		$	162,070

Net sales. Net sales increased ~~$518.6~~$756.8 million, or ~~55.4%~~52%, to $2,211.9 million during the nine months ended September 30, 2021, from $1,455.1 million during the nine months ended September 30, ~~2020, from $936.5 million during the nine months ended September 30, 2019.~~2020. The increase in net sales during the nine months ended September 30, ~~2020~~2021 was primarily due to an increase in net sales in our orphan segment of ~~$558.7~~$795.6 million, primarily due to ~~post-launch sales of~~an increase in TEPEZZA ~~of $476.3 million and higher~~ net sales of $595.4 million, an increase in KRYSTEXXA net sales of $118.3 million and ~~RAVICTI~~net sales generated for UPLIZNA of $35.0 million when compared to the nine months ended September 30, ~~2019,~~2020. This was partially offset by a decrease in net sales in our inflammation segment of ~~$40.1~~$38.8 million.

The following table reflects net sales by medicine for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages):

	Nine Months Ended September 30,				Change			Change			Nine Months Ended September 30,				Change			Change
	2020		2019		$			%			2021		2020		$			%
TEPEZZA	$	476,257	$	—	$	476,257		100		%	$	1,071,681	$	476,257	$	595,424			125	%
KRYSTEXXA		276,920		231,634		45,286			20	%		395,171		276,920		118,251			43	%
RAVICTI		191,386		160,299		31,087			19	%		217,566		191,386		26,180			14	%
PROCYSBI		122,812		121,142		1,670			1	%		142,484		122,812		19,672			16	%
ACTIMMUNE		83,152		78,883		4,269			5	%		86,603		83,152		3,451			4	%
UPLIZNA												35,025		—		35,025			100	%
BUPHENYL		8,389		8,173		216			3	%		5,790		8,389		(2,599	)		(31	)%
QUINSAIR		499		550		(51	)		(9	)%		733		499		234			47	%
Orphan segment net sales	$	1,159,415	$	600,681	$	558,734			93	%	$	1,955,053	$	1,159,415	$	795,638			69	%

PENNSAID 2%		126,925		143,751		(16,826	)		(12	)%		142,721		126,925		15,796			12	%
DUEXIS		87,044		89,412		(2,368	)		(3	)%		62,490		87,044		(24,554	)		(28	)%
RAYOS		50,800		59,067		(8,267	)		(14	)%		43,551		50,800		(7,249	)		(14	)%
VIMOVO		30,931		41,751		(10,820	)		(26	)%		8,131		30,931		(22,800	)		(74	)%
MIGERGOT		—		1,822		(1,822	)	(100		)%
Inflammation segment net sales	$	295,700	$	335,803	$	(40,103	)		(12	)%	$	256,893	$	295,700	$	(38,807	)		(13	)%

Total net sales	$	1,455,115	$	936,484	$	518,631			55	%	$	2,211,946	$	1,455,115	$	756,831			52	%

TEPEZZA. ~~On January 21, 2020, the FDA approved TEPEZZA for the treatment of TED.~~ Net sales ~~generated for TEPEZZA~~increased $595.4 million, or 125%, to $1,071.7 million during the nine months ended September 30, 2021, from $476.3 million during the nine months ended September 30, 2020. Net sales increased by approximately $591.5 million due to volume growth and $3.9 million resulting from higher net pricing primarily due to the utilization of our patient assistance programs being lower than initial expectations. On December 17, 2020, ~~were $476.3 million.~~we announced that we expected a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production orders pursuant to the DPA, that dramatically restricted capacity available for the production of TEPEZZA at our drug product contract manufacturer, Catalent.In March 2021, the FDA approved a prior approval supplement to the TEPEZZA BLA (which was previously approved in January 2020), giving us authorization to manufacture more TEPEZZA drug product resulting in an increased number of vials with each manufacturing slot. We commenced resupply of TEPEZZA to the market in April 2021. Refer to the Impact of COVID-19 section above for further information.

KRYSTEXXA. Net sales increased ~~$45.3~~$118.3 million, or ~~20%~~43%, to $395.2 million during the nine months ended September 30, 2021 from $276.9 million during the nine months ended September 30, ~~2020 from $231.6~~2020. Net sales increased by approximately $78.3 million due to volume growth and $40.0 million due to higher net pricing.

RAVICTI. Net sales increased $26.2 million, or 14%, to $217.6 million during the nine months ended September 30, 2019. Net sales increased by approximately $27.5 million due to volume growth and $17.8 million due to higher net pricing. As a result of the COVID-19 pandemic, KRYSTEXXA net sales were negatively impacted during the nine months ended September 30, 2020, due to reduced willingness of patients to visit physician offices and infusion centers.

~~RAVICTI. Net sales increased $31.1 million, or 19%, to~~2021, from $191.4 million during the nine months ended September 30, ~~2020, from $160.3~~2020. Net sales increased by approximately $28.5 million due to volume growth, partially offset by a decrease of approximately $2.3 million due to lower net pricing.

PROCYSBI. Net sales increased $19.7 million, or 16%, to $142.5 million during the nine months ended September 30, ~~2019. Net sales increased by approximately $17.7 million due to higher net pricing and an increase of approximately $13.4 million due to higher sales volume.~~

~~PROCYSBI. Net sales increased $1.7 million, or 1%, to~~2021, from $122.8 million during the nine months ended September 30, ~~2020, from $121.1~~2020. Net sales increased by approximately $11.5 million due to higher net pricing and $8.2 million due to volume growth.

ACTIMMUNE. Net sales increased $3.4 million, or 4%, to $86.6 million during the nine months ended September 30, ~~2019.~~2021, from $83.2 million during the nine months ended September 30, 2020. Net sales increased by approximately ~~$3.2~~$5.3 million due to higher net pricing, partially offset by a decrease of approximately ~~$1.5~~$1.9 million ~~due to~~resulting from lower sales volume.

~~ACTIMMUNE~~UPLIZNA. . Net sales ~~increased $4.3 million, or 5%, to $83.2 million~~generated for UPLIZNA during the nine months ended September 30, ~~2020, from $78.9~~2021 were $35.0 million. We began recognizing UPLIZNA sales following our acquisition of Viela on March 15, 2021.

Sales volumes for our inflammation medicines were negatively impacted during the nine months ended September 30, ~~2019. Net sales increased by approximately $6.7 million due to higher net pricing, partially offset by a decrease of approximately $2.4 million resulting from lower sales volume.~~

As2021 as a result of the COVID-19 pandemic ~~sales volumes for our inflammation medicines have been negatively impacted~~ due to reduced demand ~~given the absence~~resulting from a reduced level of both in-person engagement by our sales representatives with health care providers and ~~reduced levels of~~ non-essential patient visits to physicians. In recent months, the impact of COVID-19 has significantly reduced as healthcare systems have adapted to cope with the pandemic and vaccines have been widely administered in the United States, thereby facilitating the return to mainly in-person engagement by our sales representatives with healthcare providers.

PENNSAID 2%. Net sales ~~decreased $16.9~~increased $15.8 million, or 12%, to $142.7 million during the nine months ended September 30, 2021, from $126.9 million during the nine months ended September 30, ~~2020, from $143.8 million during the nine months ended September 30, 2019.~~2020. Net sales ~~decreased~~increased by approximately $45.2 million due to lower sales volume, partially offset by an increase of approximately $28.3 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs.

~~DUEXIS~~. Net sales decreased $2.4 million, or 3%, to $87.0 million during the nine months ended September 30, 2020, from $89.4 million during the nine months ended September 30, 2019. Net sales decreased by approximately $23.5 million resulting from lower sales volume, partially offset by an increase of $21.1 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs.

~~RAYOS~~. Net sales decreased $8.3 million, or 14%, to $50.8 million during the nine months ended September 30, 2020, from $59.1 million during the nine months ended September 30, 2019. Net sales decreased by approximately $19.2 million due to lower sales volume, partially offset by an increase of $10.9 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs.

~~VIMOVO~~. Net sales decreased $10.9 million, or 26%, to $30.9 million during the nine months ended September 30, 2020, from $41.8 million during the nine months ended September 30, 2019. Net sales decreased by approximately $32.9 million due to lower sales volume, partially offset by an increase of $18.7$22.6 million resulting from higher net pricing primarily due to lower utilization of our patient assistance programs, ~~and an increase~~partially offset by a decrease of ~~$3.3~~approximately $6.8 million ~~related~~resulting from lower sales volume.

DUEXIS. Net sales decreased $24.5 million, or 28%, to ~~authorized generic VIMOVO sales~~$62.5 million during the nine months ended September 30, 2021, from $87.0 million during the nine months ended September 30, 2020.

~~MIGERGOT. On June 28, 2019, we sold~~Net sales decreased by approximately $15.3 million resulting from lower sales volume, primarily due to the impact of generic competition on DUEXIS, and a decrease of approximately $9.2 million due to lower net pricing primarily due to higher utilization of our ~~rights to MIGERGOT.~~patient assistance programs.

43On August 3, 2021, the FDA granted final approval for Alkem’s generic version of DUEXIS and on August 4, 2021, Alkem launched its generic version of DUEXIS in the United States. While patent litigation against Alkem continues in the Federal Circuit Court of Appeals, we now face generic competition for DUEXIS, which has negatively impacted net sales of DUEXIS. As a result, we have repositioned our promotional efforts previously directed to DUEXIS to the other inflammation segment medicines and expect that our DUEXIS net sales will continue to decrease in future periods.

RAYOS. Net sales decreased $7.2 million, or 14%, to $43.6 million during the nine months ended September 30, 2021, from $50.8 million during the nine months ended September 30, 2020. Net sales decreased by approximately $6.9 million due to lower sales volume and $0.3 million resulting from lower net pricing.

VIMOVO. Net sales decreased $22.8 million, or 74%, to $8.1 million during the nine months ended September 30, 2021, from $30.9 million during the nine months ended September 30, 2020. Net sales decreased by approximately $20.4 million due to lower sales volume as a result of generic competition and $2.4 million due to lower net pricing.

The table below reconciles our gross to net sales for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in millions, except percentages):

	Nine Months Ended September 30, 2020						Nine Months Ended September 30, 2019						Nine Months Ended September 30, 2021						Nine Months Ended September 30, 2020
	Amount			% of Gross Sales			Amount			% of Gross Sales			Amount			% of Gross Sales			Amount			% of Gross Sales
Gross sales	$	2,816.4			100.0	%	$	2,889.9			100.0	%	$	3,529.1			100.0	%	$	2,816.4			100.0	%
Adjustments to gross sales:
Prompt pay discounts														(37.0	)		(1.0	)%		(38.7	)		(1.4	)%
Medicine returns		(11.6	)		(0.4	)%		(19.9	)		(0.7	)%		(12.0	)		(0.3	)%		(11.6	)		(0.4	)%
Prompt pay discounts		(38.7	)		(1.4	)%		(53.0	)		(1.8	)%
Co-pay and other patient assistance														(515.3	)		(14.6	)%		(662.6	)		(23.5	)%
Commercial rebates and wholesaler fees		(223.5	)		(7.9	)%		(342.6	)		(11.9	)%		(220.8	)		(6.3	)%		(223.5	)		(7.9	)%
Government rebates and chargebacks		(424.9	)		(15.1	)%		(366.7	)		(12.7	)%		(532.1	)		(15.1	)%		(424.9	)		(15.1	)%
Co-pay and other patient assistance		(662.6	)		(23.5	)%		(1,171.2	)		(40.5	)%
Total adjustments		(1,361.3	)		(48.3	)%		(1,953.4	)		(67.6	)%		(1,317.2	)		(37.3	)%		(1,361.3	)		(48.3	)%
Net sales	$	1,455.1			51.7	%	$	936.5			32.4	%	$	2,211.9			62.7	%	$	1,455.1			51.7	%

During the nine months ended September 30, 2020, commercial rebates and wholesaler fees, as a percentage of gross sales, decreased to 7.9% from 11.9% during the nine months ended September 30, 2019, primarily as a result of an increased proportion of orphan segment medicines sold and the impact of generic competition on VIMOVO sales.

During the nine months ended September 30, 2020, government rebates and chargebacks, as a percentage of gross sales, increased to 15.1% from 12.7% during the nine months ended September 30, 2019, primarily as a result of an increased proportion of orphan segment medicines sold. Government rebates and chargebacks as a percentage of gross sales are typically higher for medicines in the orphan segment compared to medicines in the inflammation segment.

~~During the nine months ended September 30, 2020,~~2021, co-pay and other patient assistance costs, as a percentage of gross sales, decreased to ~~23.5%~~14.6% from ~~40.5%~~23.5% during the nine months ended September 30, ~~2019,~~2020, primarily due to ~~lower utilization~~a decreased proportion of ~~our patient assistance programs and~~inflammation segment medicines sold, including the impact of generic competition on ~~VIMOVO~~DUEXIS sales.

Cost of Goods Sold. Cost of goods sold increased ~~$103.1~~$182.6 million to $553.0 million during the nine months ended September 30, 2021, from $370.4 million during the nine months ended September 30, ~~2020, from $267.3 million during the nine months ended September 30, 2019.~~2020. The increase in cost of goods sold during the nine months ended September 30, ~~2020~~2021 compared to the nine months ended September 30, ~~2019,~~2020, was primarily due to ~~a $50.2 million~~an increase in sales volumes, an increase in royalty expense, ~~and a $17.9 million~~an increase in amortization ~~expense. These increases are mainly related~~expense and the recording of inventory step-up expense during the nine months ended September 30, 2021. Royalty expense increased by $79.9 million primarily due to royalties payable on net sales of TEPEZZA, which ~~was launched~~increased significantly during the nine months ended September 30, 2021 compared to the nine months ended September 30, 2020. Amortization expense increased $54.3 million primarily due to the acquisition of the UPLIZNA developed technology intangible asset in the first quarter of ~~2020,~~2021 and we recorded inventory step-up expense of $16.9 million related to UPLIZNA based on the ~~amortization~~acquired units on inventory sold during the nine months ended September 30, 2021. In addition, we recorded a $7.5 million DUEXIS inventory reserve due to the impact of ~~the TEPEZZA developed technology intangible asset, which commenced in the first quarter of 2020.~~generic competition on DUEXIS sales. As a percentage of net sales, cost of goods sold was 25.0% during the nine months ended September 30, 2021, compared to 25.4% during the nine months ended September 30, ~~2020, compared to 29.0% during the nine months ended September 30, 2019.~~2020. The decrease in cost of goods sold as a percentage of net sales was primarily due to a change in the mix of medicines sold.

Research and Development Expenses. Research and development expenses increased ~~$63.9~~$152.6 million to $291.1 million during the nine months ended September 30, 2021, from $138.5 million during the nine months ended September 30, ~~2020, from $74.6 million~~2020. The increase during the nine months ended September 30, 2019. The increase was primarily attributable to the $45.0 million acquisition of Curzion during the nine months ended September 30, 2020. Pursuant to ASC 805 (as amended by ASU No. 2017-01), we accounted for the Curzion acquisition as the purchase of an in-process research and development asset and, pursuant to ASC 730, recorded the purchase price as a research and development expense during the nine months ended September 30, 2020. Additionally. ~~clinical trial and manufacturing development costs increased $16.6 million during the nine months ended September 30, 2020~~2021 compared to the nine months ended September 30, ~~2019.~~2020, was primarily attributable to a $91.2 million increase in clinical trial and manufacturing development costs reflecting increased activity in our research and development pipeline as well as the addition of our medicine candidates and development programs following the acquisition of Viela in March 2021. In addition, we recognized $40.0 million of an upfront cash payment in relation to the agreement with Arrowhead Pharmaceuticals, Inc., or Arrowhead, during the nine months ended September 30, 2021 and employee-related costs increased by $46.9 million. This was partially offset by the $45.0 million upfront payment for the acquisition of Curzion, which was expensed as in-process research and development, or IPR&D, during the nine months ended September 30, 2020.

We expect our research and development expenses to significantly increase for the remainder of 2021 and future periods as a result of our on-going and planned clinical trials for our pipeline including new medicine candidates and development programs acquired in 2021.

Selling, General and Administrative Expenses. Selling, general and administrative expenses increased ~~$184.6~~$351.1 million to $1,047.4 million during the nine months ended September 30, 2021, from $696.3 million during the nine months ended September 30, ~~2020, from $511.7~~2020. The increase was primarily attributable to costs associated with the Viela acquisition in March 2021 and an increase in TEPEZZA commercial activities. These include an increase of $114.0 million in employee-related costs, an increase of $130.8 million in marketing program costs and an increase of $48.1 million in consulting costs, primarily related to the integration of Viela. In addition, $28.6 million of transaction costs were incurred during the nine months ended September 30, 2021 relating to the Viela acquisition.

Impairment of long-lived asset. During the nine months ended September 30, 2021, we recorded an impairment charge of $12.4 million as a result of vacating the Lake Forest office. Refer to Note 14, Lease Obligations, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further detail.

Gain on sale of asset. During the nine months ended September 30, 2021, gain on sale of asset represents a $2.0 million contingent consideration payment related to the sale of MIGERGOT in 2019. The contingent consideration was earned during the second quarter of 2021 and it was received in July 2021.

Interest Expense, Net. Interest expense, net, increased $10.9 million to $59.0 million during the nine months ended September 30, 2019. The increase was primarily attributable to an increase of $104.2 million in employee costs and an increase of $39.6 million related to marketing program costs. These increases are mainly due to the launch of TEPEZZA.

~~Loss on Sale of Assets.~~ ~~During the~~ ~~nine~~ ~~months ended September 30, 2019, we sold our rights to MIGERGOT for cash proceeds of $6.0 million, and we recorded a loss of $11.0 million on the sale.~~

~~Interest Expense, Net. Interest expense, net, decreased $21.9 million to~~2021, from $48.1 million during the nine months ended September 30, ~~2020, from $70.0 million during the nine months ended September 30, 2019.~~2020. The ~~decrease~~increase was primarily due to ~~a decrease~~an increase in interest expense of ~~$33.5~~$7.4 million, primarily related to ~~the decrease in the~~an additional $1.6 billion aggregate principal amount of ~~our~~ term loans ~~in March 2019~~borrowed pursuant to an amendment to our Credit Agreement and ~~July 2019, redemption of our 2023 Senior Notes in May 2019 and in August 2019, redemption of our 2024 Senior Notes in August 2019 and the exchange of our Exchangeable Senior Notes, partially offset by~~ a decrease in interest income of ~~$11.6 million.~~$3.6 million. Refer to Note 13, Debt Agreements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further detail.

Loss on Debt Extinguishment. During the nine months ended September 30, 2020, we recorded a loss on debt extinguishment of $31.9 million in the condensed consolidated statements of comprehensive income, ~~(loss),~~ which reflects the exchange of our Exchangeable Senior Notes. As of September 30, 2020, $400.0 million in aggregate principal amount of Exchangeable Senior Notes were fully extinguished and exchanged for ordinary shares or cash. ~~See~~Refer to Note 13, Debt Agreements, of the Notes toUnaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further detail.

During the nine months ended September 30, 2019, we recorded a loss on debt extinguishment of $58.8 million in the condensed consolidated statements of comprehensive income (loss), which reflected the early redemption premiums and the write-off of the deferred financing fees and debt discount fees related to the prepayment of $775.0 million of our 2023 Senior Notes and 2024 Senior Notes and the write-off of the deferred financing fees and debt discount fees related to the $400.0 million of term loan repayments.

Benefit for Income Taxes. During the nine months ended September 30, ~~2020,~~2021, we recorded a benefit for income taxes of ~~$27.1~~$109.5 million and a benefit for income taxes of ~~$37.4~~$27.1 million during the nine months ended September 30, ~~2019.~~2020. The ~~decrease~~increase in benefit for income taxes recorded during the nine months ended September 30, ~~2020~~2021 compared to the nine months ended September 30, ~~2019~~2020 resulted primarily from an increase in the ~~mix of pre-tax income and losses incurred in various~~ tax ~~jurisdictions, tax expense~~benefits recognized on ~~U.S. taxable income generated~~share-based compensation and the recognition of a $51.3 million tax benefit due to post-acquisition operational integration activities during the nine months ended September 30, 2021 which resulted in an intercompany sale of inventory and a change to a legacy Viela entity’s future operational activities. This change reduced the state tax rate expected to apply to the reversal of temporary differences between the book values and tax bases of certain assets acquired through the Viela acquisition, which resulted in a reduction in the associated deferred tax liability. A deferred tax asset resulting from an ~~intra-company~~intercompany transfer and license of intellectual property from a U.S. subsidiary to an Irish subsidiary ~~and~~was recognized during the nine months ended September 30, 2021. During the nine months ended September 30, 2020, we recorded a $15.2 million provision ~~recorded~~ following the publication, on April 8, 2020, by the U.S. Department of the Treasury, of Final Regulations for Section ~~267A, or commonly referred to as the Anti-Hybrid Rules.~~267A. The Final Regulations for Section 267A permanently disallow for U.S. tax purposes certain interest expense accrued to a foreign related party during the year ended December 31, 2019. As a result, we recorded a write off of a deferred tax asset related to this interest expense during the nine months ended September 30, 2020 and recognized a corresponding tax provision of $15.2 million. There was no similar provision recorded during the nine months ended September 30, 2021. These ~~decreases~~increases in benefit ~~are~~during the nine months ended September 30, 2021 compared to the nine months ended September 30, 2020 were partially offset by ~~the recognition of a deferred~~ tax ~~asset in the Irish subsidiary resulting~~expense recognized on U.S. taxable income generated from the ~~intra-company~~intercompany transfer and license of intellectual property and ~~an increase~~the mix of pre-tax income and losses incurred in ~~the~~various tax ~~benefits recognized on share-based compensation.~~jurisdictions.

~~See~~Refer to Note 11, Segment and Other Information, of the Notes toUnaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for a reconciliation of our segment operating income to our total income ~~(loss)~~ before benefit for income taxes for the nine months ended September 30, ~~2020~~2021 and ~~2019.~~2020.

The following table reflects our orphan segment net sales and segment operating income for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages).

	For the Nine Months Ended September 30,									For the Nine Months Ended September 30,
	2020		2019		Change		% Change			2021		2020		Change		% Change
Net sales	$	1,159,415	$	600,681	$	558,734		93	%	$	1,955,053	$	1,159,415	$	795,638		69	%
Segment operating income		480,584		180,095		300,489		167	%		798,514		480,584		317,930		66	%

The increase in orphan segment net sales during the nine months ended September 30, ~~2020~~2021 is described in the Consolidated Results section above.

Segment operating income. Orphan segment operating income increased ~~$300.5~~$317.9 million to $798.5 million during the nine months ended September 30, 2021, from $480.6 million during the nine months ended September 30, ~~2020, from $180.1 million during the nine months ended September 30, 2019.~~2020. The increase was primarily attributable to an increase in net sales of ~~$558.7~~$795.6 million ~~primarily due to post-launch sales of TEPEZZA~~ as described above, partially offset by an increase in selling, general and administrative expenses of ~~$146.7~~$243.1 million, ~~primarily due to increased costs relating to the launch~~an increase in research and development expenses of ~~TEPEZZA~~$127.7 million and an increase of ~~$55.2~~$88.8 million in royalty expense primarily related to an increase in royalties payable on net sales of ~~TEPEZZA.~~TEPEZZA during the nine months ended September 30, 2021compared to the nine months ended September 30, 2020. The increase in selling, general and administrative expenses were mainly due to an increase in the commercial and field-based organization for TEPEZZA, and the increase in research and development expenses was primarily due to incremental net operating expense from Viela after we acquired it on March 15, 2021.

The following table reflects our inflammation segment net sales and segment operating income for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands, except percentages).

	For the Nine Months Ended September 30,										For the Nine Months Ended September 30,
	2020		2019		Change			% Change			2021		2020		Change			% Change
Net sales	$	295,700	$	335,803	$	(40,103	)		(12	%)	$	256,893	$	295,700	$	(38,807	)		(13	%)
Segment operating income		145,136		161,685		(16,549	)		(10	%)		123,576		145,136		(21,560	)		(15	%)

The decrease in inflammation segment net sales during the nine months ended September 30, ~~2020~~2021 is described in the Consolidated Results section above.

Segment operating income. Inflammation segment operating income decreased ~~$16.6~~$21.5 million to $123.6 million during the nine months ended September 30, 2021, from $145.1 million during the nine months ended September 30, ~~2020, from $161.7 million during the nine months ended September 30, 2019.~~2020. The decrease was primarily attributable to a decrease in net sales of ~~$40.1~~$38.8 million as described above and a $7.5 million inventory reserve for DUEXIS due to the impact of generic competition on DUEXIS sales, partially offset by a decrease in ~~sales~~selling, general and ~~marketing costs~~administrative expenses of ~~$20.5~~$21.2 million.

EBITDA, or earnings before interest, taxes, depreciation and amortization, adjusted EBITDA, non-GAAP net income and non-GAAP earnings per share are used and provided by us as non-GAAP financial measures. These non-GAAP financial measures are intended to provide additional information on our performance, operations and profitability. Adjustments to our GAAP figures as well as EBITDA exclude acquisition/divestiture-related costs, upfront, progress and milestone payments related to license and collaboration agreements, drug substance harmonization costs, fees related to refinancing activities and restructuring and realignment costs, ~~litigation settlements and charges related to discontinuation of the Friedreich’s ataxia program,~~ as well as non-cash items such as share-based compensation, inventory step-up expense, depreciation and amortization, ~~non-cash interest expense,~~ long-lived assets impairment charges, loss on debt extinguishments, ~~loss~~gain on sale of assets and other non-cash adjustments. Certain other special items or substantive events may also be included in the non-GAAP adjustments periodically when their magnitude is significant within the periods incurred. We maintain an established non-GAAP cost policy that guides the determination of what costs will be excluded in non-GAAP measures. We believe that these non-GAAP financial measures, when considered together with the GAAP figures, can enhance an overall understanding of our financial and operating performance. The non-GAAP financial measures are included with the intent of providing investors with a more complete understanding of our historical financial results and trends and to facilitate comparisons between periods. In addition, these non-GAAP financial measures are among the indicators our management uses for planning and forecasting purposes and measuring our performance. For example, adjusted EBITDA is used by us as one measure of management performance under certain incentive compensation arrangements. These non-GAAP financial measures should be considered in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The non-GAAP financial measures used by us may be calculated differently from, and therefore may not be comparable to, non-GAAP financial measures used by other companies.

Reconciliations of reported GAAP net income ~~(loss)~~ to EBITDA, adjusted EBITDA and non-GAAP net income, and the related per share amounts, were as follows (in thousands, except share and per share amounts):

	For the Three Months Ended September 30,						For the Nine Months Ended September 30,						For the Three Months Ended September 30,						For the Nine Months Ended September 30,
	2020			2019			2020			2019			2021			2020			2021			2020
GAAP net income (loss)	$	292,840		$	18,234		$	199,239		$	(19,749	)
GAAP net income													$	326,543		$	292,840		$	361,309		$	199,239
Depreciation ⁽¹⁾		5,157			1,658			19,229			4,574			4,112			5,157			11,956			19,229
Amortization and step-up:
Intangible amortization expense ⁽²⁾		65,353			57,662			190,677			172,762			90,368			65,353			245,260			190,677
Inventory step-up expense(3)		—			—			—			90			8,912			—			16,914			—
Interest expense, net (including amortization of debt discount and deferred financing costs)		12,185			20,428			48,100			69,991			22,977			12,185			59,018			48,100
Benefit for income taxes		(91,081	)		(30,564	)		(27,143	)		(37,359	)		(19,302	)		(91,081	)		(109,537	)		(27,143	)
EBITDA		284,454			67,418			430,102			190,309			433,610			284,454			584,920			430,102
Other non-GAAP adjustments:
Share-based compensation ⁽³⁾⁽⁴⁾		30,356			18,151			113,834			67,066			54,804			30,356			170,394			113,834
Loss on debt extinguishment ⁽⁴⁾		14,602			41,371			31,856			58,835
Acquisition/divestiture-related costs ⁽⁵⁾		199			67			47,296			2,613			9,228			199			88,166			47,296
Drug substance harmonization costs ⁽⁶⁾		193			80			483			394
Litigation settlement ⁽⁶⁾														5,000			—			5,000			—
Upfront, progress and milestones payments related to license and collaboration agreements ⁽⁷⁾		—			3,073			3,000			9,073			4,000			—			53,500			3,000
Impairment of long-lived assets ⁽⁸⁾		—			—			1,072			—
Fees related to refinancing activities ⁽⁹⁾		—			262			54			1,437
Loss on sale of assets⁽¹⁰⁾		—			—			—			10,963
Charges related to discontinuation of Friedreich’s ataxia program ⁽¹¹⁾		—			—			—			1,221
Litigation settlements ⁽¹²⁾		—			—			—			1,000
Restructuring and realignment costs⁽¹³⁾		—			—			—			33
Manufacturing plant start-up costs ⁽⁸⁾														1,712			—			1,712			—
Restructuring and realignment costs ⁽⁹⁾														680			—			7,703			—
Fees related to refinancing activities ⁽¹⁰⁾														—			—			—			54
Loss on debt extinguishment ⁽¹¹⁾														—			14,602			—			31,856
Impairment of long-lived assets ⁽¹²⁾														—			—			12,371			1,072
Drug substance harmonization costs ⁽¹³⁾														—			193			—			483
Gain on sale of asset ⁽¹⁴⁾														—			—			(2,000	)		—
Total of other non-GAAP adjustments		45,350			63,004			197,595			152,635			75,424			45,350			336,846			197,595
Adjusted EBITDA	$	329,804		$	130,422		$	627,697		$	342,944		$	509,034		$	329,804		$	921,766		$	627,697

	For the Three Months Ended September 30,						For the Nine Months Ended September 30,						For the Three Months Ended September 30,						For the Nine Months Ended September 30,
	2020			2019			2020			2019			2021			2020			2021			2020
GAAP net income (loss)	$	292,840		$	18,234		$	199,239		$	(19,749	)
GAAP net income													$	326,543		$	292,840		$	361,309		$	199,239
Non-GAAP adjustments:
Depreciation ⁽¹⁾		5,157			1,658			19,229			4,574			4,112			5,157			11,956			19,229
Amortization and step-up:
Intangible amortization expense ⁽²⁾		65,353			57,662			190,677			172,762			90,368			65,353			245,260			190,677
Amortization of debt discount and deferred financing costs ⁽¹⁴⁾		1,208			5,447			12,025			17,069
Amortization of debt discount and deferred financing costs ⁽¹⁵⁾														1,500			1,208			3,740			12,025
Inventory step-up expense(3)		—			—			—			90			8,912			—			16,914			—
Share-based compensation ⁽³⁾⁽⁴⁾		30,356			18,151			113,834			67,066			54,804			30,356			170,394			113,834
Loss on debt extinguishment ⁽⁴⁾		14,602			41,371			31,856			58,835
Acquisition/divestiture-related costs ⁽⁵⁾		199			67			47,296			2,613			9,228			199			88,166			47,296
Drug substance harmonization costs ⁽⁶⁾		193			80			483			394
Litigation settlement ⁽⁶⁾														5,000			—			5,000			—
Upfront, progress and milestones payments related to license and collaboration agreements⁽⁷⁾		—			3,073			3,000			9,073			4,000			—			53,500			3,000
Impairment of long-lived assets ⁽⁸⁾		—			—			1,072			—
Fees related to refinancing activities ⁽⁹⁾		—			262			54			1,437
Loss on sale of assets ⁽¹⁰⁾		—			—			—			10,963
Charges related to discontinuation of Friedreich’s ataxia program ⁽¹¹⁾		—			—			—			1,221
Litigation settlements ⁽¹²⁾		—			—			—			1,000
Restructuring and realignment costs ⁽¹³⁾		—			—			—			33
Manufacturing plant start-up costs ⁽⁸⁾														1,712			—			1,712			—
Restructuring and realignment costs ⁽⁹⁾														680			—			7,703			—
Fees related to refinancing activities ⁽¹⁰⁾														—			—			—			54
Loss on debt extinguishment ⁽¹¹⁾														—			14,602			—			31,856
Impairment of long-lived assets ⁽¹²⁾														—			—			12,371			1,072
Drug substance harmonization costs ⁽¹³⁾														—			193			—			483
Gain on sale of asset ⁽¹⁴⁾														—			—			(2,000	)		—
Total of pre-tax non-GAAP adjustments		117,068			127,771			419,526			347,130			180,316			117,068			614,716			419,526
Income tax effect of pre-tax non-GAAP adjustments ⁽¹⁵⁾		(23,063	)		(21,919	)		(80,122	)		(52,291	)
Other non-GAAP income tax adjustments ⁽¹⁶⁾		5,331			—			20,541			(1,452	)
Income tax effect of pre-tax non-GAAP adjustments ⁽¹⁶⁾														(37,102	)		(23,063	)		(148,353	)		(80,122	)
Other non-GAAP income tax adjustments ⁽¹⁷⁾														(56,007	)		5,331			(25,126	)		20,541
Total non-GAAP adjustments		99,336			105,852			359,945			293,387			87,207			99,336			441,237			359,945
Non-GAAP Net Income	$	392,176		$	124,086		$	559,184		$	273,638
Non-GAAP net income													$	413,750		$	392,176		$	802,546		$	559,184

Non-GAAP Earnings Per Share:
Weighted average ordinary shares – Basic		212,320,219			186,470,141			198,413,779			181,949,838			226,096,747			212,320,219			225,053,704			198,413,779

Non-GAAP Earnings Per Share – Basic
GAAP income (loss) per share – Basic	$	1.38		$	0.10		$	1.00		$	(0.11	)
GAAP earnings per share – Basic													$	1.44		$	1.38		$	1.61		$	1.00
Non-GAAP adjustments		0.47			0.57			1.82			1.61			0.39			0.47			1.96			1.82
Non-GAAP earnings per share – Basic	$	1.85		$	0.67		$	2.82		$	1.50		$	1.83		$	1.85		$	3.57		$	2.82

Non-GAAP Net Income	$	392,176		$	124,086		$	559,184		$	273,638
Non-GAAP net income													$	413,750		$	392,176		$	802,546		$	559,184
Effect of assumed exchange of Exchangeable Senior Notes, net of tax		223			—			3,789			—			—			223			—			3,789
Numerator - non-GAAP Net Income	$	392,399		$	124,086		$	562,973		$	273,638
Numerator - non-GAAP net income													$	413,750		$	392,399		$	802,546		$	562,973

Weighted average ordinary shares – Diluted
Weighted average ordinary shares – Basic		212,320,219			186,470,141			198,413,779			181,949,838			226,096,747			212,320,219			225,053,704			198,413,779
Ordinary share equivalents		12,959,618			7,701,826			19,431,212			7,747,931			10,102,042			12,959,618			10,202,720			19,431,212
Denominator - weighted average ordinary shares – Diluted		225,279,837			194,171,967			217,844,991			189,697,769			236,198,789			225,279,837			235,256,424			217,844,991

Non-GAAP Earnings Per Share – Diluted
GAAP income (loss) per share – Diluted	$	1.31		$	0.09		$	0.95		$	(0.11	)
GAAP earnings per share – Diluted													$	1.38		$	1.31		$	1.54		$	0.95
Non-GAAP adjustments		0.43			0.55			1.63			1.61			0.37			0.43			1.87			1.63
Diluted earnings per share effect of ordinary share equivalents		—			—			—			(0.06	)
Non-GAAP earnings per share – Diluted	$	1.74		$	0.64		$	2.58		$	1.44		$	1.75		$	1.74		$	3.41		$	2.58

During the nine months ended September 30, 2020, we recognized a $3.0 million progress payment in relation to our agreement with HemoShear, which was paid in July 2020.

During the nine months ended September 30, 2020, we recorded an impairment charge of $1.1 million related to the Novato, California office lease, which was obtained through an acquisition.

During the nine months ended September 30, 2019, we recorded an upfront, progress and milestone payments related to license and collaboration agreements of $9.1 million which was composed of a $3.0 million milestone payment to Roche relating to the TEPEZZA BLA submission to the FDA during the third quarter of 2019, an upfront cash payment of $2.0 million and a progress payment of $4.0 million in relation to the collaboration agreement with HemoShear.

During the nine months ended September 30, ~~2019,~~2020, following the publication of the Anti-Hybrid Rules on April 8, 2020, we ~~released~~recorded a ~~reserve that was originally established and treated as~~write off of a ~~non-GAAP adjustment~~deferred tax asset related to ~~an uncertain~~certain interest expense accrued to a foreign related party during the year ended December 31, 2019 and recognized a corresponding one-time tax ~~position in connection with an acquisition~~provision, resulting in a non-GAAP tax adjustment of ~~$1.5~~$15.2 million.

We also recognized a U.S. federal tax liability on U.S. taxable income generated from an intercompany transfer of intellectual property from a U.S. subsidiary to an Irish subsidiary, which was partially offset by the recognition of a deferred tax asset in the Irish subsidiary, resulting in a non-GAAP tax adjustment of $5.3 million.

~~We have incurred losses on a GAAP basis in most fiscal years since our inception in June 2005 and, as~~As of September 30, ~~2020,~~2021, we had ~~an accumulated deficit~~retained earnings of ~~$406.4~~$145.4 million. We expect that our sales and marketing expenses will continue to increase as a result of the commercialization of our medicines ~~including as a result of the commercial launch of TEPEZZA,~~and global expansion initiatives, but we believe these cost increases will be more than offset by higher net sales and gross profits in future periods. Additionally, we expect that our research and development costs will increase as we acquire or develop more development-stage medicine candidates and advance our candidates through the clinical development and regulatory approval processes. In particular, we expect to incur substantial costs in connection with advancing our pipeline of medicine candidates and development programs in on-going and planned clinical trials.

~~Following~~Between December 2020 and April 2021, we experienced a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production orders pursuant to the DPA. Refer to the Impact of COVID-19 section above for further information. Due to the timing of new patients starting therapy and the restarting of therapy for existing patients following the supply disruption, we expect some variability in net sales of TEPEZZA for the remainder of 2021.

Further, following the highly successful launch of TEPEZZA, which ~~has~~ significantly exceeded our expectations, we are in the process of expanding our production capacity to meet anticipated future demand for TEPEZZA. As of September 30, ~~2020,~~2021, we had total purchase commitments, including the minimum annual order quantities and binding firm orders, with AGC Biologics A/S (formerly known as CMC Biologics A/S) for TEPEZZA drug substance of ~~€130.7~~€134.5 million ($~~153.2~~155.8 million converted at ana Euro-to-Dollar exchange rate as of September 30, ~~2020~~2021 of ~~1.1722)~~1.1585), to be delivered through September ~~2022.~~2023. In addition, we had binding purchase commitments with Catalent ~~Indiana, LLC~~ for TEPEZZA drug product of ~~$15.8~~$8.6 million, to be delivered through September ~~2021.~~ 2022.

We also expect to incur additional costs and to enter into additional purchase commitments in connection with our efforts to expand TEPEZZA production capacity in order to meet ~~this~~an anticipated increase in demand.

~~During~~In July 2021, we completed the ~~third quarter~~purchase of ~~2020, our accounts receivables increased significantly~~a drug product manufacturing facility from ~~$543.8 million as of June 30, 2020,~~EirGen for $67.9 million. Refer to $705.9 million as of September 30, 2020. This increase was primarily due to both the growth in and the timing of receipts for TEPEZZA sales. During the initial launch period, the payment terms for TEPEZZA were extended. On October 1, 2020, the permanent J-code for TEPEZZA was implemented and the payment terms for TEPEZZA have started to decline. We expect that cash inflows from TEPEZZA sales will increase significantly in the fourth quarter of 2020.

~~On August 11, 2020, we closed an underwritten public equity offering of 13.6 million ordinary shares at a price to the public of $71.0 per share,~~ Note 4, ~~resulting in net proceeds of approximately $919.8 million~~ ~~after deducting underwriting discounts~~Acquisitions, Divestitures and other ~~offering expenses payable by us. This included the exercise in full by the underwriters of their option to purchase up to 1.8 million additional ordinary shares.~~

~~On June 3, 2020, we issued a notice of redemption, or the Redemption Notice, for all our outstanding Exchangeable Senior Notes.~~ Arrangements~~From June 3, 2020 through July 30, 2020, we issued an aggregate of 13,898,414 of our ordinary shares~~ ~~to noteholders as a result of exchanges of $398.3 million in aggregate principal amount of Exchangeable Senior Notes following the issuance~~, of the Notes to ~~Redemption Notice. On August 3, 2020, we redeemed the remaining $1.7 million~~Unaudited Condensed Consolidated Financial Statements, included in ~~aggregate principal amount~~Item 1 of Exchangeable Senior Notes and made aggregate cash payments to the holders of such Exchangeable Senior Notes of $1.8 million, including accrued interest. During the three and nine months ended September 30, 2020, we recorded a lossthis Quarterly Report on ~~debt extinguishment of $14.6 million and $31.9 million, respectively.~~Form 10-Q for further details.

As a result of the COVID-19 pandemic and actions taken to slow its spread, the global credit and financial markets have experienced extreme volatility and disruptions, including diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. If the equity and credit markets deteriorate, it may make any additional debt or equity financing more difficult, more costly or more dilutive.

In February 2020, we purchased a three-building campus in Deerfield, Illinois, for total consideration and directly attributable transaction costs of $118.5 million. The Deerfield campus totals 70 acres and consists of approximately 650,000 square feet of office space. We ~~expect to move to the Deerfield campus in the first quarter of 2021 and market our Lake Forest office for sub-lease. We expect to make~~made significant capital expenditures during ~~the fourth quarter of 2020 and~~ the first quarter of 2021 in order to prepare the Deerfield campus for occupancy. ~~In addition, if~~Our office employees previously located in Lake Forest, Illinois moved to the Deerfield campus in February 2021 and we are ~~unable to sub-lease our existing~~marketing the Lake Forest office space for sublease. Vacating the Lake Forest leased office building in February 2021 represented a triggering event for impairment consideration of the right-of-use asset relating to this building. During the first quarter of 2021, we recorded an impairment charge of $12.4 million as a result of vacating the Lake Forest office. This charge was reported within impairment of long-lived assets in the condensed consolidated statement of comprehensive income. In addition, we recorded a liability of $6.1 million in the first quarter of 2021 for maintenance charges as a result of vacating the leased Lake Forest office.

During the first quarter of 2021, under our license agreement with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., or together referred to as Roche, we made a milestone payment of CHF50.0 million ($56.1 million when converted using a CHF-to-Dollar exchange rate at ~~rental rates similar~~the date of payment of 1.1228) in relation to the ~~rates~~attainment of TEPEZZA net sales milestones. The liability for this milestone payment was recorded during the year ended December 31, 2020. In April 2021, under ~~our existing lease~~the acquisition agreement for River Vision Development Corp., or River Vision, we made a TEPEZZA net sales milestone payment of $67.0 million. The liability for this milestone payment was recorded during the year ended December 31, 2020. There are no further TEPEZZA net sales milestone obligations remaining to Roche and the former River Vision stockholders. Our remaining obligation to Roche relating to the attainment of various TEPEZZA development and regulatory milestones is CHF43.0 million ($46.2 million when converted using a CHF-to-Dollar exchange rate at ~~all, we would be obligated to continue paying substantial rental payments through~~September 30, 2021 of 1.0748).

~~In July~~year ended December 31, 2020, we committed to invest as a strategic limited partner in ~~two~~four venture capital funds: Forbion Growth Opportunities Fund I C.V., ~~or the~~ Forbion Capital Fund ~~and~~V C.V., Aisling Capital V, ~~LP, or the Aisling Fund. We committed to investing an aggregate $34.6 million in the two funds, comprising of a $20.0 million commitment to the Aisling~~L.P. and RiverVest Venture Fund and a €13.0 million ($15.2 million when converted using a EUR-to-Dollar exchange rate at September 30, 2020 of 1.1722) commitment to the Forbion Fund, over each fund’s respective investment periods.V, L.P. As of September 30, ~~2020, we paid $8.1~~2021, the total carrying amount of our investments in these funds was $20.7 million, which is included in ~~relation~~other assets in the consolidated balance sheet, and our total future commitments to the Aisling Fund and €0.7 million in relation to the Forbion Fund ($0.9 million when converted using a EUR-to-Dollar exchange rate at the date of payment of 1.1937). Additionally, in October 2020, we committed to investing an aggregate $15.0 million as a strategic limited partner in a third venture capital fund, RiverVest Venture Fund V, L.P., over the fund’s investment period.these funds are $44.7 million.

We have financed our operations to date through equity financings, debt financings and the issuance of convertible notes, along with cash flows from operations during the last several years. As of September 30, ~~2020,~~2021, we had ~~$1,725.4~~$1,068.5 million in cash and cash equivalents and total debt with a book value of ~~$1,002.8~~$2,557.8 million and ~~principal~~face value of ~~$1,018.0~~$2,610.0 million. We believe our existing cash and cash equivalents and our expected cash flows from our operations will be sufficient to fund our business needs for at least the next ~~twelve~~12 months from the issuance of the financial statements in this Quarterly Report on Form 10-Q. We do not have any financial covenants or non-financial covenants that we expect to be affected by the economic disruptions and negative effects of the COVID-19 pandemic on the financial environment.

We have a significant amount of debt outstanding on a consolidated basis. For a description of our debt agreements, ~~see~~refer to Note 13, Debt Agreements,of the Notes toUnaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.This substantial level of debt could have important consequences to our business, including, but not limited to: making it more difficult for us to satisfy our obligations; requiring a substantial portion of our cash flows from operations to be dedicated to the payment of principal and interest on our indebtedness, therefore reducing our ability to use our cash flows to fund acquisitions, capital expenditures, and future business opportunities; limiting our ability to obtain additional financing, including borrowing additional funds; increasing our vulnerability to, and reducing our flexibility to respond to, general adverse economic and industry conditions; limiting our flexibility in planning for, or reacting to, changes in our business and the industry in which we operate; and placing us at a disadvantage as compared to our competitors, to the extent that they are not as highly leveraged. We may not be able to generate sufficient cash to service all of our indebtedness and may be forced to take other actions to satisfy our obligations under our indebtedness.

In addition, the indenture governing our 5.5% Senior Notes due 2027 and our Credit Agreement impose various covenants that limit our ability and/or our restricted subsidiaries’ ability to, among other things, pay dividends or distributions, repurchase equity, prepay junior debt and make certain investments, incur additional debt and issue certain preferred stock, incur liens on assets, engage in certain asset sales or merger transactions, enter into transactions with affiliates, designate subsidiaries as unrestricted subsidiaries; and allow to exist certain restrictions on the ability of restricted subsidiaries to pay dividends or make other payments to us.

During the nine months ended September 30, 2021, we issued an aggregate of 4.8 million of our ordinary shares in connection with stock option exercises and the vesting of restricted stock units and performance stock units. We received a total of $40.0 million in proceeds in connection with such stock option exercises. During the nine months ended September 30, 2021, we made payments of $158.1 million for employee withholding taxes relating to vesting of share-based awards.

The following table provides a summary of our cash position as of and cash flows for the nine months ended September 30, ~~2020~~2021 and ~~2019~~2020 (in thousands):

	As of and for the Nine Months Ended September 30,						As of and for the Nine Months Ended September 30,
	2020			2019			2021			2020
Cash, cash equivalents and restricted cash	$	1,728,976		$	887,710		$	1,072,386		$	1,728,976
Cash provided by (used in):
Operating activities		145,871			234,952			496,714			145,871
Investing activities		(398,641	)		(5,325	)		(2,957,267	)		(398,641	)
Financing activities		900,482			(302,832	)		1,460,411			900,482

During the nine months ended September 30, 2021, net cash provided by operating activities of $496.7 million was primarily attributable to cash collections from gross sales, partially offset by payments made related to patient assistance costs for our medicines and government rebates for our orphan segment medicines, payments related to selling, general and administrative expenses, including transaction costs related to the Viela acquisition, and payments related to research and development expenses.

During the nine months ended September 30, 2020, net cash provided by operating activities of $145.9 million was primarily attributable to cash collections from gross sales, partially offset by payments made related to patient assistance costs for our inflammation segment medicines and government rebates for our orphan segment medicines, payments related to selling, general and administrative expenses and research and development expenses.

During the nine months ended September 30, ~~2019,~~2021, net cash ~~provided by operating~~used in investing activities of ~~$234.9~~$2,957.3 million was primarily attributable to payments for acquisitions, net of $2,843.3 million which was primarily attributable to $2.6 billion paid in relation to the Viela acquisition, net of acquired cash. In addition, we made a milestone payment of CHF50.0 million ($56.1 million when converted using a CHF-to-Dollar exchange rate at the date of payment of 1.1228) under our license agreement with Roche and we made a milestone payment of $67.0 million to the former River Vision stockholders during the nine months ended September 30, 2021. In the third quarter of 2021, we completed the purchase of a drug product manufacturing facility from EirGen for $67.9 million, which included an upfront cash ~~collections from gross sales, partially offset by payments made related~~payment of $64.8 million and $3.1 million of additional transaction costs, legal fees and liabilities assumed and we paid an upfront cash payment of $40.0 million in relation to ~~patient assistance costs and commercial rebates for our inflammation segment medicines, and payments related to selling, general and administrative expenses and research and development expenses.~~

During the nine months ended September 30, 2020, net cash used in investing activities of $398.6 million was primarily attributable to payments for acquisitions of $262.3 million which consisted of $215.2 million of milestone payments associated with the acquisition of River Vision ~~Development Corp., or River Vision,~~ and our agreements with ~~F. Hoffmann-La~~ Roche, ~~Ltd and Hoffmann-La Roche Inc, or together referred to as Roche, with~~ S.R. One and ~~with~~ Lundbeckfond and $45.0 million due to the acquisition of Curzion in the second quarter of 2020. Additionally, $112.5 million was paid in the first quarter of 2020 in relation to the purchase of a three-building campus in Deerfield, Illinois.

During the nine months ended September 30, ~~2019,~~2021, net cash ~~used in investing~~provided by financing activities of ~~$5.3~~$1,460.4 million was primarily attributable to an additional $1.6 billion aggregate principal amount of term loans borrowed pursuant to an amendment to our Credit Agreement, the ~~purchases~~proceeds of ~~property and equipment~~which, in addition to a portion of ~~$11.3 million,~~our existing cash on hand, was used to pay the consideration for the Viela acquisition, partially offset by ~~proceeds from the MIGERGOT transaction~~$158.1 million payment of ~~$6.0 million.~~

During the nine months ended September 30, 2020, net cash provided by financing activities of $900.5 million was primarily attributable to the issuance of 13.6 million ordinary shares in connection with our underwritten public equity offering in August 2020. We received net proceeds of approximately $919.8 million after deducting underwriting discounts and other offering expenses payable by us in connection with such offering.

During the nine months ended September 30, 2019, net cash used in financing activities of $302.8 million was primarily attributable to the repayment of $400.0 million of the outstanding principal amount of term loans under our Credit Agreement, the repayment of the outstanding principal amount of our 2023 Senior Notes and 2024 Senior Notes of $775.0 million and related early redemption premiums of $39.5 million, partially offset by net proceeds from the issuance of our 2027 Senior Notes of $590.1 million and net proceeds from the issuance of ordinary shares of $326.8 million.

Financial Condition as of September 30, ~~2020~~2021 compared to December 31, ~~2019~~2020

Accounts receivable, net. Accounts receivable, net, increased ~~$297.2~~$115.7 million, from ~~$408.7~~$659.7 million as of December 31, ~~2019~~2020 to ~~$705.9~~$775.4 million as of September 30, ~~2020.~~2021. The increase was primarily due to ~~both~~higher gross sales of our medicines during the ~~growth in sales and~~third quarter of 2021 when compared to the ~~timing~~fourth quarter of receipts of accounts receivable for TEPEZZA sales. During the initial launch period, the payment terms for TEPEZZA were extended. On October 1, 2020, the permanent J-code for TEPEZZA was implemented and the payment terms for TEPEZZA have started to decline.2020.

Inventories, net. Inventories, net, increased ~~$23.3~~$162.1 million, from ~~$53.8~~$75.3 million as of December 31, ~~2019~~2020 to ~~$77.1~~$237.4 million as of September 30, ~~2020.~~2021. The increase was primarily ~~related~~due to ~~the increases~~stepped-up UPLIZNA inventory of ~~TEPEZZA inventory held.~~$151.6 million, which consisted of $120.9 million of stepped-up work in process, $20.6 million of stepped-up finished goods and $10.1 million stepped-up raw materials.

Prepaid expenses and other current assets. Prepaid expenses and other current assets increased ~~$76.7~~$76.8 million, from ~~$143.6~~$251.9 million as of December 31, ~~2019~~2020 to ~~$220.3~~$328.7 million as of September 30, ~~2020.~~2021. The increase was primarily due to an increase of $31.2 million in ~~advance~~upfront payments for ~~TEPEZZA~~ inventory ~~of $43.8 million~~ and an increase of $26.1 million in ~~prepaid income~~deferred charge for taxes ~~and income taxes receivable of $22.5 million.~~on intercompany profits.

Property, plant and equipment, net. Property, plant and equipment, net, increased ~~$126.2~~$96.8 million, from ~~$30.1~~$189.0 million as of December 31, ~~2019~~2020 to ~~$156.3~~$285.8 million as of September 30, ~~2020. In February 2020, we purchased~~2021. The increase was primarily due to additions of $46.2 million related to the purchase of a ~~three-building campus~~drug product manufacturing facility from EirGen in July 2021 and $42.3 million of additions related to the Deerfield ~~Illinois,~~ campus. Refer to Note 4, Acquisitions, Divestitures and other Arrangements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for ~~total consideration and directly attributable transaction costs~~further details of ~~$118.5 million.~~ the purchase of the drug product manufacturing facility.

Developed technology and other intangible assets, net. Developed technology and other intangible assets, net, increased ~~$145.2~~$1,268.2 million, from ~~$1,702.6~~$1,782.9 million as of December 31, ~~2019~~2020 to ~~$1,847.8~~$3,051.1 million as of September 30, ~~2020.~~2021. During the nine months ended September 30, ~~2020,~~2021, in connection with the acquisition of ~~River Vision and our agreements with Roche, S.R. One and Lundbeckfond,~~Viela, we capitalized ~~$336.0~~$1,493.0 million of developed technology related to ~~TEPEZZA.~~UPLIZNA. This was partially offset by amortization of developed technology of ~~$190.7~~$245.3 million during the nine months ended September 30, ~~2020.~~2021.

~~Accounts payable.~~In-process research and development. ~~Accounts payable~~On March 15, 2021, we completed the acquisition of Viela and acquired $910.0 million of IPR&D. On March 24, 2021, we announced that our strategic partner, Mitsubishi Tanabe Pharma Corporation, had received manufacturing and marketing approval of UPLIZNA in Japan. As a result, we transferred $30.0 million of IPR&D to developed technology. As of September 30, 2021, the remaining IPR&D relating to the Viela acquisition was $880.0 million.

Goodwill. Goodwill increased ~~$17.5~~$655.3 million, from ~~$21.5~~$413.7 million as of December 31, ~~2019~~2020 to ~~$39.0~~$1,069.0 million as of September 30, ~~2020. This increase was primarily~~2021 due to the ~~timing of invoices received.~~

~~Accrued expenses.~~ ~~Accrued expenses increased $186.6 million, from $235.2 million as of December 31, 2019~~Viela acquisition. Refer to $421.8 million as of September 30, 2020. As of September 30, 2020, we recorded a liability of $121.2 million in accrued expenses representing net sales milestones for TEPEZZA, composed of $67.0 million in relation to the expected attainment in 2020 of various net sales milestones payable under the acquisition agreement for River Vision and CHF50.0 million ($54.2 million when converted using a CHF-to-Dollar exchange rate as of September 30, 2020 of 1.0859) in relation to the expected attainment in 2020 of various net sales milestones payable to Roche. Additionally, accrued royalties increased by $30.6 million and payroll-related accrued expenses increased by $21.5 millionNote 4, .

~~Accrued trade discounts and rebates.~~ Accrued trade discounts and rebates decreased $143.6 million, from $466.4 million as of December 31, 2019 to $322.8 million as of September 30, 2020. This was primarily due to a decrease of $85.9 million in accrued co-payAcquisitions, Divestitures and other patient assistance costs primarily due to lower utilization of our patient assistance programs, the impact of generic competition on VIMOVO sales and the timing of payments, a $55.4 million decrease in accrued commercial rebates and wholesaler fees primarily due to the timing of payments and the impact of generic competition on VIMOVO sales and a $2.3 million decrease in accrued government rebates and chargebacks.

~~Exchangeable Senior Notes~~. On June 3, 2020, we issued the Redemption Notice for all of our outstanding Exchangeable Senior Notes with a redemption date of August 3, 2020. As of September 30, 2020, all $400.0 million in aggregate principal amount of Exchangeable Senior Notes had been exchanged or redeemed. See Note 13, ~~Debt Agreements~~Arrangements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further ~~detail.~~details of this acquisition.

Deferred tax assets, net. ~~Contractual Obligations~~Deferred tax assets, net, increased $222.1 million from $560.8 million as of December 31, 2020 to $782.9 million as of September 30, 2021

~~During~~primarily due to a benefit for income taxes recognized during the nine months ended September 30, 2021.

Other assets. Other assets increased $70.2 million, from $55.7 million as of December 31, 2020 to $125.9 million as of September 30, 2021. In October 2019, we entered into an agreement for lease relating to approximately 63,000 square feet of office space under construction in Dublin, Ireland. In May 2021, the construction of the office was completed by the lessor and the lease became effective. As a result, we recognized $60.9 million as a right-of-use asset and a corresponding lease liability on the condensed consolidated balance sheet.

Accrued trade discounts and rebates. Accrued trade discounts and rebates decreased $48.9 million, from $352.4 million as of December 31, 2020 to $303.5 million as of September 30, 2021. This was primarily due to a decrease in accrued co-pay and other patient assistance costs primarily due to a decreased proportion of inflammation segment medicines sold, including the impact of generic competition on DUEXIS sales, partially offset by an increase in accrued government rebates and chargebacks due to timing of receipt of invoices.

Long-term debt, net. Long-term debt, net increased $1,554.5 million from $1,003.4 million as of December 31, 2020 to $2,557.9 million as of September 30, 2021. The increase was primarily related to an additional $1.6 billion aggregate principal amount of term loans we borrowed pursuant to an amendment to our Credit Agreement, the proceeds of which, in addition to a portion of our existing cash on hand, was used to pay the consideration for the Viela acquisition. Refer to Note 13, Debt Agreements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.

Deferred tax liabilities, net. Deferred tax liabilities, net, increased $525.1 million from $66.5 million as of December 31, 2020 to $591.6 million as of September 30, 2021 primarily due to the Viela acquisition. Refer to Note 4, Acquisitions, Divestitures and other Arrangements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further details of this acquisition.

Other long-term liabilities. Other long-term liabilities increased $53.3 million, from $101.7 million as of December 31, 2020 to $155.0 million as of September 30, 2021. In October 2019, we entered into an agreement for lease relating to approximately 63,000 square feet of office space under construction in Dublin, Ireland. In May 2021, the construction of the office was completed by the lessor and the lease became effective. As a result, we recognized $60.9 million as a right-of-use asset and a corresponding lease liability on the condensed consolidated balance sheet.

As of September 30, 2021, there were no material changes ~~outside of the ordinary course of business~~ to our contractual obligations as previously disclosed in Part II, Item 7 of our Annual Report on Form 10-K for the fiscal year ended December 31, ~~2019,~~2020, except for our entry into the following commitments described below.

On ~~April 1, 2020,~~June 18, 2021, we ~~acquired Curzion~~entered into a global agreement with Arrowhead for ARO-XDH, a ~~$45.0 million~~previously undisclosed discovery-stage investigational RNA interference therapeutic, being developed by Arrowhead as a potential treatment for uncontrolled gout. Under the terms of the agreement, we paid Arrowhead an upfront cash payment of $40.0 million in July 2021 and ~~are obligated~~agreed to ~~make~~pay additional potential future milestone payments of up to $660.0 million contingent on the achievement of certain development, regulatory and ~~regulatory milestones.~~commercial milestones, and low to mid-teens royalties on worldwide calendar year net sales of licensed products. Refer to Note 4, Acquisitions, Divestitures and other Arrangements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q for further details.

On March 15, 2021, we completed the acquisition of Viela, in which we acquired all of the issued and outstanding shares of Viela’s common stock for $53.00 per share in cash. The ~~$45.0 million~~total consideration for the acquisition was ~~recorded as a research~~approximately $3.0 billion, including cash acquired of $342.3 million. We financed the transaction through cash on hand and ~~development expense~~$1.6 billion of aggregate principal amount of term loans pursuant to our existing credit agreement. Refer to Note 4, Acquisitions, Divestitures and other Arrangements, and Note 13, Debt Agreements, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in ~~the second quarter~~Item 1 of ~~2020.~~ this Quarterly Report on Form 10-Q for further details.

In ~~April 2020,~~October 2019, we entered into an agreement ~~with S.R. One and an agreement with Lundbeckfond pursuant~~for lease relating to ~~which we acquired all~~approximately 63,000 square feet of ~~S.R. One’s and Lundbeckfond’s beneficial rights to proceeds from certain contingent future TEPEZZA milestone and royalty payments~~office space under construction in ~~exchange for a one-time payment of $55.0 million to each~~Dublin, Ireland. In May 2021, the construction of the ~~respective parties. The total payments of $110.0 million were recorded as TEPEZZA developed technology intangible assets in~~office was completed by the ~~second quarter of 2020.~~lessor and the lease became effective. As a result, of our agreements with S.R. One and Lundbeckfond in April 2020, our remaining net obligations to make TEPEZZA payments to the former stockholders of River Vision was reduced by approximately 70.25%, after including payments to a third party.

~~In July 2020,~~ we committed to invest as a strategic limited partner in two venture capital funds: Forbion Growth Opportunities Fund I C.V., or the Forbion Fund, and the Aisling Capital V, LP, or the Aisling Fund. We committed to investing an aggregate $34.6recognized $60.9 million ~~in the two funds, comprising~~ of a ~~$20.0 million commitment~~lease liability on the condensed consolidated balance sheet. The lease is due to expire in May 2041.Refer to Note 14, Lease Obligations, of the ~~Aisling Fund and a €13.0 million ($15.2 million when converted using a EUR-to-Dollar exchange rate at September 30, 2020~~Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of 1.1722) commitment to the Forbion Fund, over each fund’s respective investment periods. As of September 30, 2020, we paid $8.1 million in relation to the Aisling Fund and €0.7 million in relation to the Forbion Fund ($0.9 million when converted using a EUR-to-Dollar exchange rate at the date of payment of 1.1937). Additionally, in October 2020, we committed to investing an aggregate $15.0 million as a strategic limited partner in a third venture capital fund, RiverVest Venture Fund V, L.P., over the fund’s investment period.

The preparation of financial statements in accordance with U.S. GAAP principles requires the use of estimates and assumptions that affect the reported amounts of assets and liabilities and the reported amounts of revenue and expenses. Certain of these policies are considered critical as these most significantly impact a company’s financial condition and results of operations and require the most difficult, subjective or complex judgments, often as a result of the need to make estimates about the effect of matters that are inherently uncertain. Actual results may vary from these estimates.

During the nine months ended September 30, 2021, there have been no significant changes in our application of our critical accounting policies. A summary of our ~~significant~~critical accounting policies is included in ~~Note 2~~Item 7 to our Annual Report on Form 10-K for the year ended December 31, ~~2019.~~2020.

~~During the nine months ended September 30, 2020, there were no significant changes in our application of our critical accounting policies.~~

Since our inception, we have not engaged in any off-balance sheet arrangements, including the use of structured finance, special purpose entities or variable interest entities, other than the indemnification agreements discussed in Note 15, Commitments and Contingencies, of the Notes to UnauditedCondensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.

We are exposed to various market risks, which include potential losses arising from adverse changes in market rates and prices, such as interest rates and foreign exchange fluctuations. We do not enter into derivatives or other financial instruments for trading or speculative purposes.

Interest Rate Risk. We are subject to interest rate fluctuation exposure through our borrowings under our Credit Agreement and our investment in money market accounts which bear a variable interest rate. Our approximately $418.0 million aggregate principal amount of senior secured term loans borrowed under our Credit Agreement in December 2019, or the December 2019 Term Loans, and loans under our incremental revolving credit facility, or Revolving Credit ~~Agreement~~Facility, bear interest, at our option, at a rate equal to the London Inter-Bank Offered Rate, or LIBOR, plus 2.25% per annum (subject to a 0.00% LIBOR floor), or the adjusted base rate plus 1.25% per annum with a step-down to LIBOR plus 2.00% per annum or the adjusted base rate plus 1.00% per annum at the time our leverage ratio is less than or equal to 2.00 to 1.00. The adjusted base rate is defined as the greatest of (a) LIBOR (using one-month interest period) plus 1.00%, (b) the prime rate, (c) the federal funds rate plus 0.50%, and (d) 1.00%. Our December 2019 Term Loans are based on LIBOR. The one-month LIBOR rate as of October 20, 2021, which was the most recent date the interest rate on the December 2019 Term Loans was fixed, was 0.13%, and as a result, the interest rate on our December 2019 Term Loans is currently 2.38% per annum. As of September 30, 2021, the Revolving Credit Facility was undrawn. Our $1.6 billion aggregate principal amount of senior secured term loans borrowed under our ~~incremental revolving credit facility,~~Credit Agreement in March 2021, or ~~Revolving Credit Facility,~~the 2028 Term Loans, bear interest, at our option, at a rate equal to ~~either~~ LIBOR, plus ~~an applicable margin of 2.25%~~2.00% per annum (subject to a 0.50% LIBOR ~~floor of 0.00%)~~floor), or the adjusted base rate plus ~~1.25%~~1.00% per annum with a step-down to LIBOR plus ~~2.00%~~1.75% per annum or the adjusted base rate plus ~~1.00%~~0.75% per annum at the time our leverage ratio is less than or equal to 2.00 to 1.00. Our ~~approximately $418.0 million of senior secured term loans under the Credit Agreement is~~2028 Term Loans are based on LIBOR. ~~As of September 30, 2020, the Revolving Credit Facility was undrawn.~~ The one-month LIBOR rate as of October ~~13, 2020,~~20, 2021, which was the most recent date the interest rate on the ~~term loan~~2028 Term Loans was fixed, was ~~0.19%~~0.13%, and as a result, the interest rate on our ~~borrowings~~2028 Term Loans is currently ~~2.19%~~2.50% per annum. Because the United Kingdom Financial Conduct Authority, which regulates LIBOR, intends to phase out the use of LIBOR by the end of 2021, future borrowings under our Credit Agreement could be subject to reference rates other than LIBOR.

An increase in the LIBOR of 100 basis points above the current LIBOR rate would increase our interest expense related to the Credit Agreement by ~~$4.18~~$14.1 million per year.

The goals of our investment policy are to preserve capital, fulfill liquidity needs and maintain fiduciary control of cash. To achieve our goal of maximizing income without assuming significant market risk, we maintain our excess cash and cash equivalents in money market ~~funds.~~funds, time deposits and U.S. federal government securities. Because of the short-term maturities of our cash equivalents, we do not believe that a decrease in interest rates would have any material negative impact on the fair value of our cash equivalents.

Foreign Currency Risk. Our purchase costs of TEPEZZA drug substance and ACTIMMUNE inventory are principally denominated in Euros and are subject to foreign currency risk. In addition, we are obligated to pay certain milestones and a royalty on sales of TEPEZZA to Roche in Swiss Francs, which obligations are subject to foreign currency risk. We have contracts relating to RAVICTI, QUINSAIR and PROCYSBI for sales in Canada which sales are subject to foreign currency risk. We also incur certain operating expenses in currencies other than the U.S. dollar in relation to our Irish operations and foreign subsidiaries. Therefore, we are subject to volatility in cash flows due to fluctuations in foreign currency exchange rates, particularly changes in the Euro and the Swiss ~~Franc and the Canadian dollar.~~ Franc.

Inflation Risk. We do not believe that inflation has had a material impact on our business or results of operations during the periods for which the condensed consolidated financial statements are presented in this report.

Credit Risk. Historically, our accounts receivable balances have been highly concentrated with a select number of customers, consisting primarily of large wholesale pharmaceutical distributors who, in turn, sell the medicines to pharmacies, hospitals and other customers. As of September 30, ~~2020~~2021 and December 31, ~~2019,~~2020, our top four customers accounted for approximately ~~94%~~96% and ~~84%~~93%, respectively, of our total outstanding accounts receivable balances.

Evaluation of Disclosure Controls and Procedures. As required by paragraph (b) of Rules 13a-15 and 15d-15 promulgated under the Exchange Act, our management, including our Chief Executive Officer and Chief Financial Officer, conducted an evaluation as of the end of the period covered by this report of the effectiveness of our disclosure controls and procedures as defined in Exchange Act Rules 13a-15(e) and 15d-15(e). Based on that evaluation, our Chief Executive Officer and Chief Financial Officer concluded that our disclosure controls and procedures were effective as of September 30, ~~2020~~2021, the end of the period covered by this report.

Changes in Internal Control Over Financial Reporting. During the quarter ended September 30, ~~2020,~~2021, there have been no material changes to our internal control over financial reporting, as defined in Rules 13a-15(f) and 15d-15(f), that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

For a description of our legal proceedings, ~~see~~refer to Note 16, Legal Proceedings, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.

We face many risks and uncertainties, as more fully described in this section under the heading “Risk Factors.” Some of these risks and uncertainties are summarized below. The summary below does not contain all of the information that may be important to you, and you should read this summary together with the more detailed discussion of these risks and uncertainties contained in “Risk Factors.”

You should consider carefully the risks described below, together with all of the other information included in this report, and in our other filings with the Securities and Exchange Commission, or SEC, before deciding whether to invest in or continue to hold our ordinary shares. The risks described below are all material risks currently known, expected or reasonably foreseeable by us. If any of these risks actually occurs, our business, financial condition, results of operations or cash flow could be seriously harmed. This could cause the trading price of our ordinary shares to decline, resulting in a loss of all or part of your investment.

The risk factors set forth below with an asterisk (*) next to the title are new risk factors or risk factors containing changes, including any material changes, from the risk factors previously disclosed in Item 1A of our Annual Report on Form 10-K for the year ended December 31, ~~2019,~~2020, as filed with the SEC.

The COVID-19 global pandemic has and may continue to adversely impact our business, including the commercialization of our medicines, our supply chain, our clinical trials, our liquidity and access to capital markets and our business development activities.*

On March 11, 2020, the World Health Organization made the assessment that a novel strain of coronavirus, which causes the COVID-19 disease, ~~can be characterized as~~was a pandemic. The President of the United States declared the COVID-19 pandemic a national emergency and many states and municipalities in the ~~Unites~~United States took aggressive actions to reduce the spread of the disease, including limiting non-essential gatherings of people, ceasing all non-essential travel, ordering certain businesses and government agencies to cease non-essential operations at physical locations and issuing “shelter-in-place” orders which direct individuals to shelter at their places of residence (subject to limited exceptions). Similarly, the Irish government has limited gatherings of people and encouraged employees to work from their homes, and may implement more aggressive policies in the future. In ~~addition,~~recent months, vaccines and treatments have enabled a resumption to more normal business practices and initiatives in ~~mid-March 2020 we implemented work-from-home policies for all employees~~many countries, including the United States and moved to a “virtual” model with respect to our physician, patient and partner support activities. As certain U.S. states have started to reduce restrictions, we are seeing physician offices beginning to reopen, which reopening varies on a state-by-state basis. As a result, our sales representatives in some areas have transitioned to being back out in the field and are working on ways to re-engage patients and physicians. However, as COVID-19 cases have increased in certain areas, certain U.S. states have started to reimplement restrictions and we have seen some physician offices re-establish limits on in-person visits.Ireland. Restrictions in response to COVID-19, including new variants of the virus, may continue to fluctuate in U.S. states and other geographies and we cannot guarantee that additional U.S. states that have previously reduced restrictions will not reimplement them or that other states will reduce restrictions in the near-term. The effects of government actions and our policies and those of third parties to reduce the spread of COVID-19 may negatively impact productivity and our ability to market and sell our medicines, cause disruptions to our supply chain and ongoing and future clinical trials and impair our ability to execute our business development strategy. These and other disruptions in our operations and the global economy could negatively impact our business, operating results and financial condition.

The commercialization of our medicines has been and may continue to be adversely impacted by COVID-19 and actions taken to slow its spread. For example, patients have postponed visits to healthcare provider facilities, certain healthcare providers have temporarily closed their offices or are restricting patient visits, healthcare provider employees may become generally unavailable and there could be disruptions in the operations of ~~payors,~~payers, distributors, logistics providers and other third parties that are necessary for our medicines to be prescribed, reimbursed and administered to patients. In addition, due to reduced willingness of patients to visit physician offices and infusion centers, sales of KRYSTEXXA have been negatively impacted, and this impact may continue in future quarters until healthcare activities and patient visits return to normal levels. In addition, while we experienced a much higher number of new patients in 2020 for TEPEZZA than our initial estimates, the impact from COVID-19 slowed the generation of patient enrollment forms for TEPEZZA, which drive new patient starts, and this impact may continue following the end of the TEPEZZA supply disruption. It is also possible that a prolonged period of “shelter-in-place” orders and social distancing behaviors and the associated reduction of physician office visits could force various healthcare practices to permanently close or to consolidate with larger practices or healthcare groups, which could cause us to lose previously-established physician relationships. We cannot predict how long the COVID-19 pandemic will continue to negatively impact sales of our medicines and we expect that even after government-mandated restrictions are lifted, our sales force activities, healthcare provider operations and patients’ willingness to visit healthcare facilities will continue to be limited.We also cannot predict how effective any of our virtual patient, physician and partner support initiatives will be with respect to marketing and supporting the administration and reimbursement of our ~~medicines, or when we will be able to resume other in-person sales and marketing activities.~~medicines.

Quarantines,, shelter-in-place and similar government orders, or the perception that such orders, shutdowns or other restrictions on the conduct of business operations could occur, related to COVID-19 or other infectious diseases could impact personnel at third-party manufacturing facilities upon which we rely, or the availability or cost of materials, which could disrupt the supply chain for our medicines. In particular, some of our suppliers of certain materials used in the production of our medicines are located in regions that have been subject to COVID-19-related actions and policies that limit the conduct of normal business operations. To the extent our suppliers and service providers are unable to comply with their obligations under our agreements with them or they are otherwise unable to deliver or are delayed in delivering goods and services to us due to COVID-19,, our ability to continue meeting commercial demand for our medicines in the United States or advancing development of our medicine candidates may become impaired. For example, On December 17, 2020, we announced that we expected a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production pursuant to the Defense Production Act of 1950, or DPA, that have dramatically restricted capacity available for the production of TEPEZZA at our drug product contract manufacturer, Catalent Indiana, LLC, or Catalent. In March 2021, the FDA approved a prior approval supplement to the TEPEZZA Biologics License Application, or BLA (which was previously approved in January 2020), giving us authorization to manufacture more TEPEZZA drug product resulting in an increased number of vials with each manufacturing slot. We commenced resupply of TEPEZZA to the market in April 2021. However, our ability to continue TEPEZZA supply is dependent on future committed manufacturing slots for TEPEZZA not being cancelled and being run successfully, which could be impacted by additional government-mandated COVID-19 vaccine production orders and other risks associated with our reliance on our third-party manufacturers discussed below. If we were to experience another disruption of TEPEZZA supply, it would have a material adverse effect on our operating results and ability to achieve our financial projections in 2021. Refer to the Impact of COVID-19 section in Item 2 of this Quarterly Report on Form 10-Q for further information. At this time, we consider ~~our~~the inventories on hand of our medicines to be sufficient to meet our commercial requirements.

~~In addition, our~~Our clinical trials may be affected by COVID-19. ~~Clinical~~As described in the Impact of COVID-19 section in Item 2 of this Quarterly Report on Form 10-Q, our clinical trials for TEPEZZA have been delayed due to the impact of the TEPEZZA supply disruption at Catalent. In addition, clinical site initiation and patient enrollment may be delayed due to prioritization of hospital and healthcare resources toward COVID-19. Current or potential patients in our ongoing or planned clinical trials may also choose to not enroll, not participate in follow-up clinical visits or drop out of the trial as a precaution against contracting ~~COVID-19~~.COVID-19. Further, some patients may not be able or willing to comply with clinical trial protocols if quarantines impede patient movement or interrupt healthcare services. Some clinical sites in the United States have slowed or stopped further enrollment of new patients in clinical trials, denied access to site monitors or otherwise curtailed certain operations. Similarly, our ability to recruit and retain principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19, may be adversely impacted. These events could delay our clinical trials, increase the cost of completing our clinical trials and negatively impact the integrity, reliability or robustness of the data from our clinical trials.

The spread of COVID-19 and actions taken to reduce its spread may also materially affect us economically. As a result of the COVID-19 pandemic and actions taken to slow its spread, the global credit and financial markets have experienced extreme volatility and disruptions, including diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. If the equity and credit markets deteriorate, it may make any additional debt or equity financing more difficult, more costly or more dilutive. While the potential economic impact brought by, and the duration of, COVID-19 may be difficult to assess or predict, there could be a significant disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity and financial position or our business development activities.

COVID-19 continues to rapidly evolve. The extent to which COVID-19 may impact the commercialization of our medicines, our supply chain, our clinical trials, our access to capital and our business development activities, will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of the pandemic, the duration of the pandemic and the efforts by governments and business to contain it, business closures or business disruptions and the impact on the economy and capital markets.

Our ability to generate revenues from our medicines is subject to attaining significant market acceptance among physicians, patients and healthcare payers.*

Our current medicines, and other medicines or medicine candidates that we may develop or acquire, may not attain market acceptance among physicians, patients, healthcare payers or the medical community. Some of our medicines, in particular TEPEZZA and UPLIZNA, have not been on the market for an extended period of time, which subjects us to numerous risks as we attempt to increase our market share. We believe that the degree of market acceptance and our ability to generate revenues from our medicines will depend on a number of factors, including:

With respect to TEPEZZA, sales will depend on market acceptance and adoption by physicians and healthcare payers, as well as the ability and willingness of physicians who do not have in-house infusion capability to refer patients to infusion sites of care. With respect to KRYSTEXXA, our ability to grow sales will be affected by the success of our sales, marketing and clinical strategies, which are intended to expand the patient population and usage of KRYSTEXXA. This includes our marketing efforts in nephrology and our studies designed to improve the response rate to KRYSTEXXA, to evaluate a shorter infusion time, and to evaluate the use of KRYSTEXXA in kidney transplant patients. With respect to RAVICTI, which is approved to treat a very limited patient population, our ability to grow sales will depend in large part on our ability to transition urea cycle disorder, or UCD, patients from BUPHENYL or generic equivalents, which are comparatively much less expensive, to RAVICTI and to ~~encourage~~educate patients and physicians ~~to continue~~on the benefits of continuing RAVICTI therapy once initiated. With respect to PROCYSBI, which is also approved to treat a very limited patient population, our ability to grow sales will depend in large part on our ability to transition patients from the first-generation immediate-release cysteamine therapy to PROCYSBI, to identify additional patients with nephropathic cystinosis and to ~~encourage~~educate patients and physicians ~~to continue~~on the benefits of continuing therapy once initiated. With respect to ACTIMMUNE, while it is the only FDA-approved treatment for chronic granulomatous disease, or CGD, and severe, malignant osteopetrosis, or SMO, they are very rare conditions and, as a result, our ability to grow ACTIMMUNE sales will depend on our ability to identify additional patients with such conditions and ~~encourage~~educate patients and physicians ~~to continue~~on the benefits of continuing treatment once initiated. With respect to UPLIZNA, sales will depend on market acceptance and adoption by physicians and healthcare payers, as well as the ability and willingness of physicians who do not have in-house infusion capability to refer patients to infusion sites of care. With respect to each of PENNSAID 2% w/w, or PENNSAID 2%, ~~RAYOS~~ and ~~DUEXIS,~~RAYOS, their higher cost compared to the generic or branded forms of their active ingredients alone may limit adoption by physicians, patients and healthcare payers. With respect to DUEXIS, studies indicate that physicians do not commonly co-prescribe gastrointestinal, or GI, protective agents to high-risk patients taking nonsteroidal anti-inflammatory drugs, or NSAIDs. We believe this is due in part to a lack of awareness among physicians prescribing NSAIDs regarding the risk of NSAID-induced upper GI ulcers, in addition to the inconvenience of prescribing two separate medications and patient compliance issues associated with multiple prescriptions. If physicians remain unaware of, or do not otherwise believe in, the benefits of combining GI protective agents with NSAIDs, our market opportunity for DUEXIS will be limited. Some physicians may also be reluctant to prescribe DUEXIS due to the inability to vary the dose of ibuprofen and naproxen, respectively, or if they believe treatment with NSAIDs or GI protective agents other than those contained in DUEXIS, including those of its competitors, would be more effective for their patients. If our current medicines or any other medicine that we may seek approval for, or acquire, fail to attain market acceptance, we may not be able to generate significant revenue to sustain profitability, which would have a material adverse effect on our business, results of operations, financial condition and prospects (including, possibly, the value of our ordinary shares).

The COVID-19 pandemic and actions taken to slow its spread has had and will continue to have a negative impact on sales of our medicines. For example, in March 2020 we transitioned our sales force to a virtual model such that they no longer had in-person interactions with healthcare professionals and while we have been working on ways to re-engage patients and physicians as certain U.S. states have started to reduce restrictions, the virtual model is still being used. While we have attempted to maintain the effectiveness of our sales and marketing efforts in the virtual model, it may not be as effective as in-person interactions in terms of conveying key information about our medicines or aiding physicians and their staff in prescribing and helping their patients obtain appropriate reimbursement for our medicines. Many physicians, in particular in primary care practices that prescribe our inflammation segment medicines, have reduced their operations in light of COVID-19, including delaying patient visits and writing new prescriptions, and this has negatively impacted sales in our inflammation segment. Similarly, many patients have deferred non-essential visits to healthcare providers, which has had a negative impact on prescriptions being written and filled. For example, due to reduced willingness of patients to visit physician offices and infusion centers, sales of KRYSTEXXA have been negatively impacted, and we expect this impact to continue in future quarters until healthcare activities and patient visits return to normal levels. It is also possible that a prolonged period of “shelter-in-place” orders and social distancing behaviors and the associated reduction of physician office visits could force various healthcare practices to permanently close or to consolidate with larger practices or healthcare groups, which could cause us to lose previously-established physician relationships. We cannot predict how long the COVID-19 pandemic will continue to negatively impact sales of our medicines and we expect that even after government-mandated restrictions are lifted, our sales force activities, healthcare provider operations and patients’ willingness to visit healthcare facilities will continue to be limited.

Our future prospects are highly dependent on our ability to successfully ~~formulate~~develop and execute commercialization strategies for each of our medicines. Failure to do so would adversely impact our financial condition and prospects.*

A substantial majority of our resources are focused on the commercialization of our current medicines. Our ability to generate significant medicine revenues and to achieve commercial success in the near-term will initially depend almost entirely on our ability to successfully commercialize these medicines in the United States.

With respect to our ~~rare disease medicines, TEPEZZA, KRYSTEXXA, RAVICTI, PROCYSBI and ACTIMMUNE,~~orphan segment, our commercialization strategy includes efforts to increase awareness of the rare conditions that each medicine is designed to treat, enhancing efforts to identify target patients and in certain cases pursue opportunities for label expansion and more effective use through clinical ~~trials.~~trials, as well as opportunities for commercialization outside of the United States. Our comprehensive post-launch commercial strategy for TEPEZZA aims to enable more thyroid eye disease, or TED, patients to benefit from TEPEZZA. We are doing this by: (i) ~~driving~~facilitating continued TEPEZZA uptake in the treatment of ~~acute and chronic~~ TED through continued promotion of TEPEZZA to treating physicians; (ii) continuing to develop the TED market by increasing physician awareness of the disease severity, the urgency to diagnose and treat it, as well as the benefits of treatment with TEPEZZA; (iii) driving accelerated disease identification and time to treatment through our digital ~~broadcast~~ and ~~television~~broadcast marketing campaigns; (iv) enhancing the patient journey with our high-touch, patient-centric model as well as support for the patient and site-of-care referral processes; and (v) expanding more timely access to TEPEZZA for TED patients. Our strategy with respect to KRYSTEXXA includes existing rheumatology account growth, new rheumatology account growth and accelerating nephrology growth, as well as development efforts to enhance response rates through combination treatment with methotrexate and to shorten the infusion time. With respect to RAVICTI and PROCYSBI, our strategy includes accelerating the transition of patients from first-generation therapies, increasing the diagnosis of the associated rare conditions through patient and physician outreach; and increasing compliance rates. Our strategy with respect to ACTIMMUNE, ~~our medicine for the treatment of chronic granulomatous disease,~~ includes increasing awareness and diagnosis of chronic granulomatous disease and increasing compliance rates. With respect to our strategy for UPLIZNA, which leverages the successful strategies we have employed with TEPEZZA and KRYSTEXXA, our aim is to (i) generate greater demand for the medicine by investing in the commercial and clinical support infrastructure; (ii) drive physician awareness of the benefits of UPLIZNA for the treatment of neuromyelitis optica spectrum disorder, or NMOSD, and what differentiates UPLIZNA from other medicines by generating additional trial data analyses and clinical evidence; and (iii) optimize timely access for patients to UPLIZNA with best-in-class patient services, infusion site-of-care referral processes and reimbursement support services. A key component of the strategy is to complete a comprehensive assessment of the current overall commercial and clinical support infrastructure for UPLIZNA to ensure optimal support for the medicine.

We are focusing a significant portion of our commercial activities and resources on TEPEZZA, and we believe our ability to grow our long-term revenues, and a significant portion of the value of our company, relates to our ability to successfully commercialize TEPEZZA in the United States. As a ~~newly-launched~~newly launched medicine for a disease that had no previously-approved treatments, successful commercialization of TEPEZZA is subject to many risks. There are numerous examples of ~~unsuccessful product launches and~~ failures to meet high expectations of market potential, including by pharmaceutical companies with more experience and resources than us. While we have established our commercial team and U.S. sales force, we will need to further train and develop the team in order to continue successfully ~~commercialize~~commercializing TEPEZZA. There are many factors that could cause ~~the launch and~~ commercialization of TEPEZZA to be unsuccessful, including a number of factors that are outside our control. Because no medicine has previously been approved by the FDA for the treatment of TED, it is especially difficult to estimate TEPEZZA’s market potential or the time it will take to increase patient and physician awareness of TED and change current treatment paradigms. For example, shortly after the launch of TEPEZZA, we transitioned our sales force to a virtual model in light of the COVID-19 pandemic, which, combined with physicians generally reducing their own availability, ~~has~~ made it more challenging to execute on our strategy to educate physicians about TEPEZZA and the treatment of TED. In addition, some physicians that are potential prescribers of TEPEZZA do not have the necessary infusion capabilities to administer the medicine and may not otherwise be able or willing to refer their patients to third-party infusion centers, which may discourage them from treating their patients with TEPEZZA. The commercial success of TEPEZZA depends on the extent to which patients and physicians accept and adopt TEPEZZA as a treatment for TED. For example, if the patient population suffering from TED is smaller than we estimate, if it proves difficult to identify TED patients or educate physicians as to the availability and potential benefits of TEPEZZA, or if physicians are unwilling to prescribe or patients are unwilling to take TEPEZZA, the commercial potential of TEPEZZA will be limited. In addition, the prior disruption in TEPEZZA supply resulted in existing patients stopping therapy and an inability of new patients to initiate therapy. We began resupplying TEPEZZA to the market in April 2021. Our ability to continue TEPEZZA supply could be impacted by additional government-mandated COVID-19 vaccine production orders and other risks associated with our reliance on our third-party manufacturers discussed below. We also have limited information regarding how physicians, patients and payers will respond to the pricing of TEPEZZA. Physicians may not prescribe TEPEZZA and patients may be unwilling to use TEPEZZA if coverage is not provided or reimbursement is inadequate to cover a significant portion of the cost. Thus, significant uncertainty remains regarding the commercial potential of TEPEZZA. If the ~~launch or~~continued commercialization of TEPEZZA isbecomes unsuccessful or perceived as disappointing, the price of our ordinary shares could decline significantly and long-term success of the medicine and our company could be harmed.

With respect to ~~our inflammation segment medicines,~~ PENNSAID 2% and ~~DUEXIS,~~RAYOS, our strategy has included entering into rebate agreements with pharmacy benefit managers, or PBMs, ~~for certain of our inflammation segment medicines~~ where we believe the rebates and costs justify expanded formulary access for patients and ensuring patient assistance to ~~these drugs~~this medicine when prescribed through our HorizonCares program. However, we cannot guarantee that we will be able to secure additional rebate agreements on commercially reasonable terms, that expected volume growth will sufficiently offset the rebates and fees paid to PBMs or that our existing agreements with PBMs will have the intended impact on formulary access. In addition, as the terms of our existing agreements with PBMs expire, we may not be able to renew the agreements on commercially favorable terms, or at all. For each of our inflammation segment medicines, we expect that our commercial success will depend on our sales and marketing efforts in the United States, reimbursement decisions by commercial payers, the expense we incur through our patient assistance program for fully bought down contracts and the rebates we pay to PBMs, as well as the impact of numerous efforts at federal, state and local levels to further reduce reimbursement and net pricing of inflammation segment medicines.

~~Our~~In addition, our strategy for RAYOS in the United States is to focus on the rheumatology indications approved for RAYOS, including our collaboration with the Alliance for Lupus Research, to study the effect of RAYOS on the fatigue experienced by systemic lupus erythematosus, or SLE, patients.

If any of our commercial strategies are unsuccessful or we fail to successfully modify our strategies over time due to changing market conditions, our ability to increase market share for our medicines, grow revenues and to sustain profitability will be harmed.

We are dependent on wholesale distributors for distribution of our products in the United States and, accordingly, our results of operations could be adversely affected if they encounter financial difficulties*difficulties.*

~~In 2020,~~During the nine months ended September 30, 2021, four wholesale distributors accounted for substantially all of our sales in the United States. If one of our significant wholesale distributors encounters financial or other difficulties, such distributor may decrease the amount of business that it does with us, and we may be unable to collect all the amounts that the distributor owes on a timely basis or at all, which could negatively impact our business and results of operations.

In order to increase adoption and sales of our medicines, we will need to continue developing our commercial organization as well as recruit and retain qualified sales representatives.*

Part of our strategy is to continue to build a ~~biopharma~~biotech company to successfully execute the commercialization of our medicines in the U.S. market, and in selected markets outside the United States where we have commercial rights. We may not be able to successfully commercialize our medicines in the United States or in any other territories where we have commercial rights. In order to commercialize any approved medicines, we must continue to build our sales, marketing, distribution, managerial and other non-technical capabilities. As of September 30, ~~2020,~~2021, we had approximately ~~445~~485 sales representatives in the field, consisting of approximately ~~200~~280 orphan segment sales representatives ~~(including approximately 50 TEPEZZA sales representatives)~~ and ~~245~~205 inflammation segment sales representatives. We currently have limited resources compared to some of our competitors, and the continued development of our own commercial organization to market our medicines and any additional medicines we may acquire will be expensive and time-consuming. We also cannot be certain that we will be able to continue to successfully develop this capability.

As we continue to add medicines through development efforts and acquisition transactions and execute on our international expansion initiatives, the members of our sales force may have limited experience promoting certain of our medicines. To the extent we employ an acquired entity’s sales forces to promote acquired medicines, we may not be successful in continuing to retain these employees and we otherwise will have limited experience marketing these medicines under our commercial organization. In addition, none of the members of our sales force have promoted TEPEZZA or any other medicine for the treatment of TED prior to the launch of ~~TEPEZZA.~~TEPEZZA and prior to completing the acquisition of Viela Bio, Inc., or Viela, in March 2021, we had no experience as an organization commercializing UPLIZNA. We are required to expend significant time and resources to train our sales force to be credible and able to educate physicians on the benefits of prescribing and pharmacists dispensing our medicines. In addition, we must train our sales force to ensure that a consistent and appropriate message about our medicines is being delivered to our potential customers. Our sales representatives may also experience challenges promoting multiple medicines when we call on physicians and their office staff. We have experienced, and may continue to experience, turnover of the sales representatives that we hired or will hire, requiring us to train new sales representatives. If we are unable to recruit and retain qualified personnel outside of the United States, we may not be able to execute our global expansion strategy successfully. If we are unable to effectively train our sales force and equip them with effective materials, including medical and sales literature to help them inform and educate physicians about the benefits of our medicines and their proper administration and label indication, as well as our patient assistance programs, our efforts to successfully commercialize our medicines could be put in jeopardy, which could have a material adverse effect on our financial condition, share price and operations. For example, we have had to train our sales force to operate in a virtual environment due to the COVID-19 pandemic and are continuing to learn and implement new strategies and techniques to promote our medicines without the benefit of in-person interactions with healthcare providers and their staff. We may not be successful in finding effective ways to promote our medicines remotely or our competitors may be more successful than we are at adapting to virtual marketing.

As a result of the evolving role of various constituents in the prescription decision making process, we focus on hiring sales representatives for our inflammation segment medicines with successful business to business experience. For example, we have faced challenges due to pharmacists switching a patient’s intended prescription from DUEXIS to a generic or over-the-counter brand of their active ingredients, despite such substitution being off-label in the case of DUEXIS. We have faced similar challenges for PENNSAID 2% and RAYOS with respect to generic brands. While we believe the profile of our representatives is suited for this environment, we cannot be certain that our representatives will be able to successfully protect our market for PENNSAID 2%~~, DUEXIS~~ and RAYOS or that we will be able to continue attracting and retaining sales representatives with our desired profile and skills. We will also have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain commercial personnel. To the extent we rely on additional third parties to commercialize any approved medicines, we may receive less revenue than if we commercialized these medicines ourselves. In addition, we may have little or no control over the sales efforts of any third parties involved in our commercialization efforts. In the event we are unable to successfully develop and maintain our own commercial organization or collaborate with a third-party sales and marketing organization, we may not be able to commercialize our medicines and medicine candidates and execute on our business plan.

Coverage and reimbursement may not be available, or reimbursement may be available at only limited levels, for our

medicines, which could make it difficult for us to sell our medicines profitably or to successfully execute planned medicine price increases.*

Market acceptance and sales of our medicines will depend in large part on global coverage and reimbursement policies and may be affected by future healthcare reform measures, both in the United States and other key international markets. Successful commercialization of our medicines will depend in part on the availability of governmental and third-party payer reimbursement for the cost of our medicines. Government health administration authorities, private health insurers and other organizations generally provide reimbursement for healthcare. In particular, in the United States, private health insurers and other third-party payers often provide reimbursement for medicines and services based on the level at which the government (through the Medicare or Medicaid programs) provides reimbursement for such treatments. In the United States, the European Union, or EU, and other significant or potentially significant markets for our medicines and medicine candidates, government authorities and third-party payers are increasingly attempting to limit or regulate the price of medicines and services, particularly for new and innovative medicines and therapies, which has resulted in lower average selling prices. Further, the increased scrutiny of prescription drug pricing practices and emphasis on managed healthcare in the United States and on country and regional pricing and reimbursement controls in the EU and other significant or potentially significant markets will put additional pressure on medicine pricing, reimbursement and usage, which may adversely affect our medicine sales and results of operations. These pressures can arise from rules and practices of managed care groups, judicial decisions and governmental laws and regulations related to Medicare, Medicaid and healthcare reform, pharmaceutical reimbursement policies and pricing in general. These pressures may create negative reactions to any medicine price increases, or limit the amount by which we may be able to increase our medicine prices, which may adversely affect our medicine sales and results of operations.

We expect to experience pricing pressures in connection with the sale of our medicines due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative proposals relating to outcomes and quality. For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively the ACA, increased the mandated Medicaid rebate from 15.1% to 23.1%, expanded the rebate to Medicaid managed care utilization and increased the types of entities eligible for the federal 340B drug discount program. As concerns continue to grow over the need for tighter oversight, there remains the possibility that the Health Resources and Services Administration or another agency under the U.S. Department of Health and Human Services, or HHS, will propose a similar regulation or that Congress will explore changes to the 340B program through legislation. For example, a bill was introduced in 2018 that would require hospitals to report their low-income utilization of the program. Further, the Centers for Medicare & Medicaid Services, or CMS, issued a final rule in 2018 that implemented civil monetary penalties for manufacturers who exceeded the ceiling price methodology for a covered outpatient drug when selling to a 340B covered entity. Pursuant to the final rule, after January 1, 2019, manufacturers must calculate 340B program ceiling prices on a quarterly basis. Moreover, manufacturers could be subject to a $5,000 penalty for each instance where they knowingly and intentionally overcharge a covered entity under the 340B program. With respect to KRYSTEXXA, the “additional rebate” methodology of the 340B pricing rules, as applied to the historical pricing of KRYSTEXXA both before and after we acquired the medicine, have resulted in a 340B ceiling price of one penny. A material portion of KRYSTEXXA prescriptions (normally in the range of ~~15 percent~~low to 20mid-teens percent) are written by healthcare providers that are eligible for 340B drug pricing and therefore the reduction in 340B pricing to a penny has negatively impacted our net sales of KRYSTEXXA. The CMS had also finalized a proposal in calendar years 2018, 2019 and 2020 that would revise the Medicare hospital outpatient prospective payment system by creating a new, significantly reduced reimbursement methodology for drugs purchased under the 340B program for Medicare patients at hospital and other settings. ~~That policy~~These reductions were upheld by the U.S. Court of Appeals for the D.C. Circuit in July 2020, and it is ~~currently~~unclear whether this matter will be subject to further litigation. Further, the ~~subject of on-going litigation.~~CMS final rule for calendar year 2021 continues these reductions for drugs acquired through the 340B program.

Patients are unlikely to use our medicines unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our medicines. Third-party payers may limit coverage to specific medicines on an approved list, also known as a formulary, which might not include all of the FDA-approved medicines for a particular indication. Moreover, a third-party payer’s decision to provide coverage for a medicine does not imply that an adequate reimbursement rate will be approved. Additionally, one third-party payer’s decision to cover a particular medicine does not ensure that other payers will also provide coverage for the medicine, or will provide coverage at an adequate reimbursement rate. Even though we have contracts with some PBMs in the United States, that does not guarantee that they will perform in accordance with the contracts, nor does that preclude them from taking adverse actions against us, which could materially adversely affect our operating results. In addition, the existence of such PBM contracts does not guarantee coverage by such PBM’s contracted health plans or adequate reimbursement to their respective providers for our medicines. For example, some PBMs have placed some of our medicines on their exclusion lists from time to time, which has resulted in a loss of coverage for patients whose healthcare plans have adopted these PBM lists. Additional healthcare plan formularies may also exclude our medicines from coverage due to the actions of certain PBMs, future price increases we may implement, our use of the HorizonCares program or other free medicine programs whereby we assist qualified patients with certain out-of-pocket expenditures for our medicine, including donations to patient assistance programs offered by charitable foundations, or any other co-pay programs, or other reasons. If our strategies to mitigate formulary exclusions are not effective, these events may reduce the likelihood that physicians prescribe our medicines and increase the likelihood that prescriptions for our medicines are not filled.

In light of such policies and the uncertainty surrounding proposed regulations and changes in the coverage and reimbursement policies of governments and third-party payers, we cannot be sure that coverage and reimbursement will be available for any of our medicines in any additional markets or for any other medicine candidates that we may develop. Also, we cannot be sure that reimbursement amounts will not reduce the demand for, or the price of, our medicines. If coverage and reimbursement are not available or are available only at limited levels, we may not be able to successfully commercialize our medicines.

There may be additional pressure by payers, healthcare providers, state governments, federal regulators and Congress, to use generic drugs that contain the active ingredients found in our medicines or any other medicine candidates that we may develop or acquire. If we fail to successfully secure and maintain coverage and adequate reimbursement for our medicines or are significantly delayed in doing so, we will have difficulty achieving market acceptance of our medicines and expected revenue and profitability which would have a material adverse effect on our business, results of operations, financial condition and prospects.

We may also experience pressure from payers as well as state and federal government authorities concerning certain promotional approaches that we may implement such as our HorizonCares program or any other co-pay programs. Certain state and federal enforcement authorities and members of Congress have initiated inquiries about co-pay assistance programs. Some state legislatures have implemented or have been considering implementing laws to restrict or ban co-pay coupons for branded drugs. For example, legislation was signed into law in California that would limit the use of co-pay coupons in cases where a lower cost generic drug is available and if individual ingredients in combination therapies are available over the counter at a lower cost. It is possible that similar legislation could be proposed and enacted in additional states. Additionally, numerous organizations, including pharmaceutical manufacturers, have been subject to ongoing litigation, enforcement actions and settlements related to their patient assistance programs and support. If we are unsuccessful with our HorizonCares program or any other co-pay programs, or we alternatively are unable to secure expanded formulary access through additional arrangements with PBMs or other payers, we would be at a competitive disadvantage in terms of pricing versus preferred branded and generic competitors. We may also experience financial pressure in the future which would make it difficult to support investment levels in areas such as managed care contract rebates, HorizonCares and other access tools.

Our medicines are subject to extensive regulation, and we may not obtain additional regulatory approvals for our medicines.*

The clinical development, manufacturing, labeling, packaging, storage, recordkeeping, advertising, promotion, export, marketing and distribution and other possible activities relating to our medicines and our medicine candidates are, and will be, subject to extensive regulation by the FDA and other regulatory agencies. Failure to comply with FDA and other applicable regulatory requirements may, either before or after medicine approval, subject us to administrative or judicially imposed sanctions.

To market any drugs or biologics outside of the United States, we and current or future collaborators must comply with numerous and varying regulatory and compliance related requirements of other countries. For example, we are pursuing a global expansion strategy, which includes bringing TEPEZZA to patients with TED outside of the United States, including Japan where we are engaging with the Pharmaceuticals and Medical Devices Agency, or PMDA, and the Japanese medical community. Furthermore, we are investing in our European infrastructure to support the potential first-quarter 2022 approval of UPLIZNA by the European Medicines Agency, or EMA, for NMOSD. UPLIZNA has been granted orphan designation by the European Commission, or EC. That designation is subject to additional review by the Committee for Orphan Medicinal Products, or COMP, and may or may not be maintained. In addition, on March 24, 2021, we announced that our strategic partner, Mitsubishi Tanabe Pharma Corporation, or MTPC, had received manufacturing and marketing approval of UPLIZNA for NMOSD in Japan. Approval procedures vary among countries and can involve additional medicine testing and additional administrative review periods, including obtaining reimbursement and pricing approval in select markets. The time required to obtain approval in other countries might differ from that required to obtain FDA approval. The regulatory approval process in other countries may include all of the risks associated with FDA approval as well as additional, presently unanticipated, risks. Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country may negatively impact the regulatory process in others.

Applications for regulatory approval, including a marketing authorization application, or MAA, for marketing new drugs in ~~Europe,~~the European Economic Area (which consists of the Member States of the EU, Iceland, Liechtenstein and Norway), or EEA, must be supported by extensive clinical and pre-clinical data, as well as extensive information regarding chemistry, manufacturing and controls, or CMC, to demonstrate the safety and effectiveness of the applicable medicine candidate. The number and types of pre-clinical studies and clinical trials that will be required for regulatory approval varies depending on the medicine candidate, the disease or the condition that the medicine candidate is designed to target and the regulations applicable to any particular medicine candidate. Despite the time and expense associated with pre-clinical and clinical studies, failure can occur at any stage, and we could encounter problems that cause us to repeat or perform additional pre-clinical studies, CMC studies or clinical trials. Regulatory authorities could delay, limit or deny approval of a medicine candidate for many reasons, including because they:

Even if we believe that data collected from our pre-clinical studies, CMC studies and clinical trials of our medicine candidates are promising and that our information and procedures regarding CMC are sufficient, our data may not be sufficient to support marketing approval by regulatory authorities, or regulatory interpretation of these data and procedures may be unfavorable. For example, based upon the results of our MIRROR randomized controlled trial evaluating KRYSTEXXA and methotrexate versus KRYSTEXXA alone, we intend to submit a supplemental BLA for KRYSTEXXA, but we cannot guarantee that the FDA will accept our submission for filing or will approve a revised label for KRYSTEXXA. Even if approved, medicine candidates may not be approved for all indications requested and such approval may be subject to limitations on the indicated uses for which the medicine may be marketed, restricted distribution methods or other limitations. Our business and reputation may be harmed by any failure or significant delay in obtaining regulatory approval for the sale of any of our medicine candidates. We cannot predict when or whether regulatory approval will be obtained for any medicine candidate we develop.

The ultimate approval and commercial marketing of any of our medicines in additional indications or geographies is subject to substantial uncertainty. Failure to gain additional regulatory approvals would limit the potential revenues and value of our medicines and could cause our share price to decline.

Since a significant proportion of the regulatory framework in the United Kingdom, or UK, applicable to our business and our products is derived from EU directives and regulations, Brexit has materially impacted the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our products in the UK. The regulatory changes that are a result of Brexit may also materially impact upon the development, manufacture, importation, approval and commercialization of our products in the EEA, should any development or manufacture of these products take place in the UK.

Great Britain is no longer covered by the EU’s procedures for the grant of marketing authorizations (Northern Ireland is still covered by the centralized authorization procedure which leads to a marketing authorization that is valid throughout the EEA and can participate, with certain restrictions, in the other procedures available to market a medicine in the EU). Our medicine candidates require a separate marketing authorization for Great Britain, which involves additional administrative burden. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, could prevent us from or delay us commercializing our medicine candidates in the UK and/or the EEA and restrict our ability to generate revenue and achieve and sustain profitability. If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the UK and/or EEA for our medicine candidates, which could significantly and materially harm our business.

Brexit may influence the attractiveness of the UK as a place to conduct clinical trials. The EU’s regulatory environment for clinical trials is being harmonized as part of the Clinical Trials Regulation, which the EC has confirmed will be applicable from January 31, 2022, but it is currently unclear as to what extent the UK will seek to align its regulations with the EU. Failure of the UK to closely align its regulations with the EU may have an effect on the cost of conducting clinical trials in the UK as opposed to other countries and/or make it harder to seek a marketing authorization for our medicine candidates in the EEA on the basis of clinical trials conducted in the UK.

In the short term there is a risk of disrupted import and export processes due to a lack of administrative processing capacity by the respective UK and EU customs agencies that may delay time-sensitive shipments and may negatively impact our product supply chain.

We may be subject to penalties and litigation and large incremental expenses if we fail to comply with regulatory requirements or experience problems with our medicines.*

Even after we achieve regulatory approvals, we are subject to ongoing obligations and continued regulatory review with respect to many operational aspects including our manufacturing processes, labeling, packaging, distribution, storage, adverse event monitoring and reporting, dispensation, advertising, promotion and recordkeeping. These requirements include submissions of safety and other post-marketing information and reports, ongoing maintenance of medicine registration and continued compliance with current good manufacturing practices, or cGMPs, good clinical practices, or GCPs, good pharmacovigilance practice, good distribution practices and good laboratory practices, or GLPs. If we, our medicines or medicine candidates, or the ~~third-party~~ manufacturing facilities for our medicines or medicine candidates fail to comply with applicable regulatory requirements, a regulatory agency may:

Moreover, existing regulatory approvals and any future regulatory approvals that we obtain will be subject to limitations on the approved indicated uses and patient populations for which our medicines may be marketed, the conditions of approval, requirements for potentially costly, post-market testing and requirements for surveillance to monitor the safety and efficacy of the medicines. Physicians nevertheless may prescribe our medicines to their patients in a manner that is inconsistent with the approved label or that is off-label. Positive clinical trial results in any of our medicine development programs increase the risk that approved pharmaceutical forms of the same active pharmaceutical ingredients, or APIs, may be used off-label in those indications. If we are found to have improperly promoted off-label uses of approved medicines, we may be subject to significant sanctions, civil and criminal fines and injunctions prohibiting us from engaging in specified promotional conduct.

In addition, engaging in improper promotion of our medicines for off-label uses in the United States can subject us to false claims litigation under federal and state statutes. These false claims statutes in the United States include the federal False Claims Act, which allows any individual to bring a lawsuit against a pharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims or causing to present such false or fraudulent claims for payment by a federal program such as Medicare or Medicaid. Growth in false claims litigation has increased the risk that a pharmaceutical company will have to defend a false claim action, pay civil money penalties, settlement fines or restitution, agree to comply with burdensome reporting and compliance obligations and be excluded from Medicare, Medicaid and other federal and state healthcare programs.

The regulations, policies or guidance of regulatory agencies may change and new or additional statutes or government regulations may be enacted that could prevent or delay regulatory approval of our medicine candidates or further restrict or regulate post-approval activities. For example, in January 2014, the FDA released draft guidance on how drug companies can fulfill their regulatory requirements for post-marketing submission of interactive promotional media, and though the guidance provided insight into how the FDA views a company’s responsibility for certain types of social media promotion, there remains a substantial amount of uncertainty regarding internet and social media promotion of regulated medical products. We cannot predict the likelihood, nature or extent of adverse government regulation that may arise from pending or future legislation or administrative action, either in the United States or abroad. If we are unable to achieve and maintain regulatory compliance, we will not be permitted to market our drugs, which would materially adversely affect our business, results of operations and financial condition.

We have rights to medicines in certain jurisdictions but have little or no control over third parties that have rights to commercialize those medicines in other jurisdictions, which could adversely affect our commercialization of these medicines.*

Following our sale of the rights to RAVICTI (i) outside of North America and Japan to Medical Need Europe AB, part of the Immedica Group, or Immedica, in December 2018 and (ii) in Japan to Immedica, Immedica has marketing and distribution rights to RAVICTI in those regions. Following our sale of the rights to PROCYSBI in the Europe, Middle East and Africa, or EMEA, regions to Chiesi Farmaceutici S.p.A., or Chiesi, in June 2017, or the Chiesi divestiture, Chiesi has marketing and distribution rights to PROCYSBI in the EMEA regions. ~~Nuvo Pharmaceuticals Inc.~~MTPC has rights to the development and commercialization of UPLIZNA for NMOSD as well as other potential future indications in Japan and certain other countries in Asia. Hansoh Pharmaceutical Group Company Limited, or Hansoh, has rights to the development and commercialization of UPLIZNA for NMOSD as well as other potential future indications in China, Hong Kong and Macau. Miravo Healthcare (formerly known as Nuvo ~~Research~~Pharmaceuticals Inc.), or ~~Nuvo,~~Miravo, has retained its rights to PENNSAID 2% in territories outside of the United States. In March 2017, ~~Nuvo~~Miravo announced that it had entered into an exclusive license agreement with Sayre Therapeutics PVT Ltd. to distribute, market and sell PENNSAID 2% in India, Sri Lanka, Bangladesh and Nepal, and in December 2017 ~~Nuvo~~Miravo announced that it had entered into a license and distribution agreement with Gebro Pharma AG for the exclusive right to register, distribute, market and sell PENNSAID 2% in Switzerland and Liechtenstein. We have little or no control over Immedica’s activities with respect to RAVICTI outside of North America, ~~and Japan,~~ over Chiesi’s activities with respect to PROCYSBI in the EMEA, over MTPC’s or Hansoh’s activities with respect to UPLIZNA in the certain countries in Asia, or over ~~Nuvo’s~~Miravo’s or its existing and future commercial partners’ activities with respect to PENNSAID 2% outside of the United States even though those activities could impact our ability to successfully commercialize these medicines. For example, Immedica or its assignees, Chiesi or its assignees, MTPC or ~~Nuvo~~Hansoh or their respective assignees or Miravo or its assignees can make statements or use promotional materials with respect to RAVICTI, PROCYSBI, UPLIZNA or PENNSAID 2%, respectively, outside of the United States that are inconsistent with our positioning of the medicines in the United States, and could sell RAVICTI, PROCYSBI, UPLIZNA or PENNSAID 2%, respectively, in foreign countries at prices that are dramatically lower than the prices we charge in the United States. These activities and decisions, while occurring outside of the United States, could harm our commercialization strategy in the United States. In addition, medicine recalls or safety issues with these medicines outside the United States, even if not related to the commercial medicine we sell in the United States, could result in serious damage to the brand in the United States and impair our ability to successfully market them. We also rely on Immedica, Chiesi, MTPC, Hansoh and ~~Nuvo,~~Miravo, or their assignees to provide us with timely and accurate safety information regarding the use of these medicines outside of the United States, as we have or will have limited access to this information ourselves.

We rely on third parties to manufacture commercial supplies of all of our medicines, and we currently intend to rely, in whole or in part, on third parties to manufacture commercial supplies of any other approved medicines. The commercialization of any of our medicines could be stopped, delayed or made less profitable if those third parties fail to provide us with sufficient quantities of medicine or fail to do so at acceptable quality levels or prices or fail to maintain or achieve satisfactory regulatory compliance.*

The facilities used by our third-party manufacturers to manufacture our medicines and medicine candidates must be approved by the applicable regulatory authorities. We do not control the manufacturing processes of third-party manufacturers and are currently completely dependent on our third-party manufacturing partners.

We rely on AGC Biologics A/S (formerly known as CMC Biologics A/S), or AGC Biologics, as our exclusive manufacturer of the TEPEZZA drug substance and Catalent, ~~Indiana, LLC, or Catalent,~~ for TEPEZZA drug product. ~~Following~~On December 17, 2020, we announced that we expected a short-term disruption in TEPEZZA supply as a result of U.S. government-mandated COVID-19 vaccine production orders pursuant to the DPA that dramatically restricted capacity available for the production of TEPEZZA at our drug product contract manufacturer, Catalent. To offset the reduced slots allowed by the DPA and Catalent, we accelerated plans to increase the production scale of TEPEZZA drug product. In March 2021, the FDA approved a prior approval supplement to the TEPEZZA BLA (which was previously approved in January 2020), giving us authorization to manufacture more TEPEZZA drug product resulting in an increased number of vials with each manufacturing slot. We commenced resupply of TEPEZZA to the market in April 2021, but we cannot guarantee that our currently contracted TEPEZZA manufacturing slots at Catalent will not be rescheduled or canceled as a result of additional U.S. government-mandated COVID-19 vaccine production orders, or that they will be completed successfully. During the third quarter of 2021, we were informed that one of our contract manufacturers is manufacturing an adjuvant for a COVID-19 vaccine. The adjuvant is being manufactured on a different line to the line used to manufacture our medicine. We do not expect the manufacturing of this adjuvant to impact the supply of our medicine. While we are not currently aware of any manufacturing facilities, other than Catalent and the other previously mentioned contract manufacturer, that are part of the supply chain for our medicines that are being utilized for the manufacture of vaccines for COVID-19, similar circumstances could arise in the future and could result in supply disruption to our other medicines. Further, following the highly successful launch of TEPEZZA, which ~~has~~ significantly exceeded our expectations, we ~~are in~~began the process of expanding our production capacity in 2020 to meet anticipated future demand for TEPEZZA. If AGC Biologics ~~failed~~fails to supply TEPEZZA drug substance or if Catalent ~~failed~~fails to supply TEPEZZA drug product for a period beyond our current expectation or either manufacturer ~~was~~is otherwise unable to meet our volume requirements due to unexpected market demand for TEPEZZA, it may lead to further TEPEZZA supply constraints. In addition, while we are making progress with our second drug product manufacturer and we are on track to begin shipping TEPEZZA supply from this manufacturer, assuming FDA approval, by the end of 2021, it is possible this timeline could be delayed.

We rely on NOF Corporation, or NOF, as our exclusive supplier of the PEGylation agent that is a critical raw material in the manufacture of KRYSTEXXA. If NOF ~~failed~~fails to supply such PEGylation agent, it may lead to KRYSTEXXA supply constraints. A key excipient used in PENNSAID 2% as a penetration enhancer is dimethyl sulfoxide, or DMSO. We and ~~Nuvo,~~Miravo, our exclusive supplier of PENNSAID 2%, rely on a sole proprietary form of DMSO for which we maintain a substantial safety stock. However, should this supply become inadequate, damaged, destroyed or unusable, we and ~~Nuvo~~Miravo may not be able to qualify a second source. We rely on an exclusive supply agreement with Boehringer Ingelheim Biopharmaceuticals GmbH, or Boehringer Ingelheim Biopharmaceuticals, for manufacturing and supply of ACTIMMUNE. ACTIMMUNE is manufactured by starting with cells from working cell bank samples which are derived from a master cell bank. We and Boehringer Ingelheim Biopharmaceuticals separately store multiple vials of the master cell bank. In the event of catastrophic loss at our or Boehringer Ingelheim Biopharmaceuticals’ storage facility, it is possible that we could lose multiple cell banks and have the manufacturing capacity of ACTIMMUNE severely impacted by the need to substitute or replace the cell banks. In addition, we rely on AstraZeneca UK Limited for the manufacture of the current clinical and commercial supplies of UPLIZNA, and for the current clinical and nonclinical supplies of the other medicine candidates acquired in the Viela acquisition.

In July 2021, we purchased a biologic drug product manufacturing facility in Waterford, Ireland, which is intended to be an additional source of manufacturing to supplement the capabilities of our third-party drug product manufacturers. We are in the process of completing the build-out and validation of this facility and assuming timely receipt of regulatory approvals, we expect that the first medicine manufactured at the facility to be approved for release in 2023. However, we have no experience as a company in developing, validating, obtaining regulatory approval for or running a manufacturing facility and may not be successful in these activities. Even if we are successful in producing medicines at the Waterford facility for commercial sale once we receive the required regulatory approvals, we expect to remain dependent on our third-party manufacturing partners in the near-term and potentially longer.

If we or any of our third-party manufacturers cannot successfully manufacture material that conforms to our specifications and the applicable regulatory authorities’ strict regulatory requirements, or pass regulatory inspection, ~~they~~we or our third-party manufacturers will not be able to secure or maintain regulatory approval for the manufacturing facilities. For example, BASF Corporation, or BASF, our manufacturer of one of the APIs in DUEXIS, ibuprofen in a direct compression blend called DC85, previously notified us that it was not able to supply DC85 due to a technical issue at its manufacturing facility in Bishop, Texas during 2018. BASF has since resolved the technical issue and its manufacturing facility has returned to full operation. BASF is continuing to supply DC85 to us and we consider our DUEXIS inventory on hand to be sufficient to meet current and future commercial requirements. In addition, we have no control over the ability of third-party manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or any other applicable regulatory authorities do not approve these facilities for the manufacture of our medicines or if they withdraw any such approval in the future, or if our suppliers or third-party manufacturers decide they no longer want to supply our primary active ingredients or manufacture our medicines, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our medicines. To the extent our manufacturing facility of that of any third-party manufacturers that we engage with respect to our medicines are different from those currently being used for commercial supply in the United States, the FDA will need to approve ~~the~~such facilities ~~of those third-party manufacturers used in the manufacture of our medicines~~ prior to our sale of any medicine using these facilities.

Although we have entered into supply agreements for the manufacture and packaging of our medicines, our manufacturers may not perform as agreed or may terminate their agreements with us. We currently rely on single source suppliers for certain of our medicines. If our manufacturers terminate their agreements with us, we may have to qualify new back-up manufacturers. We rely on safety stock to mitigate the risk of our current suppliers electing to cease producing bulk drug product or ceasing to do so at acceptable prices and quality. However, we can provide no assurance that such safety stocks would be sufficient to avoid supply shortfalls in the event we have to identify and qualify new contract manufacturers.

The manufacture of medicines requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process controls. Manufacturers of medicines often encounter difficulties in production, particularly in scaling up and validating initial production. These problems include difficulties with production costs and yields, quality control, including stability of the medicine, quality assurance testing, shortages of qualified personnel, as well as compliance with strictly enforced federal, state and foreign regulations. Furthermore, if microbial, viral or other contaminations are discovered in the medicines or in the manufacturing facilities in which our medicines are made, such manufacturing facilities may need to be closed for an extended period of time to investigate and remedy the contamination. We cannot assure that issues relating to the manufacture of any of our medicines will not occur in the future. Additionally, we or our third-party manufacturers may experience manufacturing difficulties due to resource constraints or as a result of labor disputes or unstable political environments. If we or our third-party manufacturers were to encounter any of these difficulties, or our third-party manufacturers otherwise fail to comply with their contractual obligations, our ability to commercialize our medicines or provide any medicine candidates to patients in clinical trials would be jeopardized.

Any delay or interruption in our ability to meet commercial demand for our medicines will result in the loss of potential revenues and could adversely affect our ability to gain market acceptance for these medicines. In addition, any delay or interruption in the supply of clinical trial supplies could delay the completion of clinical trials, increase the costs associated with maintaining clinical trial programs and, depending upon the period of delay, require us to commence new clinical trials at additional expense or terminate clinical trials completely.

Failures or difficulties faced at any level of our supply chain, including any further potential disruption caused by the COVID-19 pandemic, could materially adversely affect our business and delay or impede the development and commercialization of any of our medicines or medicine candidates and could have a material adverse effect on our business, results of operations, financial condition and prospects.

We face significant competition from other biotechnology and pharmaceutical companies, including those marketing generic medicines and our operating results will suffer if we fail to compete effectively.*

The biotechnology and pharmaceutical industries are intensely competitive. We have competitors both in the United States and international markets, including major multinational pharmaceutical companies, biotechnology companies and universities and other research institutions. Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development, or R&D, staff, experienced marketing and manufacturing organizations and well-established sales forces. Additional consolidations in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our competitors and we will have to find new ways to compete and may have to potentially merge with or acquire other businesses to stay competitive. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors may succeed in developing, acquiring or in-licensing on an exclusive basis, medicines that are more effective and/or less costly than our medicines.

Although TEPEZZA does not face direct competition, other therapies, such as corticosteroids, have been used on an off-label basis to alleviate some of the symptoms of TED. While these therapies have not proved effective in treating the underlying disease, and carry with them significant side effects, their off-label use could reduce or delay treatment in the addressable patient population for TEPEZZA. Immunovant Inc., or Immunovant, is ~~also~~ conducting Phase 2 clinical ~~studies~~trials of a ~~medicine~~fully human anti-FcRn monoclonal antibody candidate for the treatment of active TED, also referred to as Graves’ ophthalmopathy. On February 2, 2021, Immunovant announced a voluntary pause in the clinical dosing of the candidate due to elevated total cholesterol and low-density lipoprotein levels in patients treated with the candidate. Immunovant has indicated it intends to continue developing the candidate but did not provide an estimate of when the dosing might resume. Viridian Therapeutics, Inc. is pursuing development of an anti-IGF-1R monoclonal antibody for TED and has announced plans to initiate a Phase 2 trial in the fourth quarter of 2021. While KRYSTEXXA faces limited direct competition, a number of competitors have medicines in clinical trials, including Selecta Biosciences Inc., or Selecta, which has ~~recently~~ initiated a Phase 3 trial of a ~~medicine~~ candidate for the treatment of chronic refractory gout. In September 2020, Selecta announced topline clinical data that did not meet the primary endpoint or demonstrate statistical superiority for ~~their~~its Phase 2 trial that ~~compares their~~compared its candidate, which includes an immunomodulator, to KRYSTEXXA alone. In July 2020, Selecta and Swedish Orphan Biovitrum AB, or Sobi, entered into a strategic licensing agreement under which Sobi will assume responsibility for certain development, regulatory, and commercial activities for this candidate. RAVICTI could face competition from a few medicine candidates that are in ~~early-stage~~ development, including a gene-therapy candidate by Ultragenyx Pharmaceutical Inc., a generic taste-masked formulation option of BUPHENYL by ACER Therapeutics Inc., ~~and~~ an enzyme replacement for a specific UCD subtype (ARG) by Aeglea Bio Therapeutics Inc. and a mRNA-based therapeutic for a specific UCD subtype (OTC) by Arcturus Therapeutics Holdings Inc. PROCYSBI faces competition from Cystagon^® (immediate-release cysteamine bitartrate capsules) for the treatment of cystinosis, Cystadrops^® (cysteamine ophthalmic solution) for the treatment of corneal cystine crystal deposits and Cystaran^TM (cysteamine ophthalmic solution) for treatment of corneal crystal accumulation in patients with cystinosis. Additionally, we are also aware that AVROBIO, Inc. has ~~an early-stage~~a gene therapy candidate in development for the treatment of cystinosis. UPLIZNA faces competition from eculizumab, marketed as Soliris^®by AstraZeneca plc, or AstraZeneca, and satralizumab, marketed as Enspryng^TM by Chugai Pharmaceuticals Co., Ltd., or Chugai, a subsidiary of Roche, each for the treatment of patients with NMOSD. AstraZeneca is also conducting a Phase 3 trial with Ultomiris^® (ravulizumab) in NMOSD and, if approved for this indication, UPLIZNA could face additional competition. UPLIZNA also faces competition from rituximab, an off-label treatment that has been used for years to treat NMOSD given the lack of an approved medicine for this disease prior to 2019. PENNSAID 2% faces competition from generic versions of diclofenac sodium topical solutions that are priced significantly less than the price we charge for PENNSAID 2%. The generic version of Voltaren Gel is the market leader in the topical NSAID category. Legislation enacted in most states in the United States allows, or in some instances mandates, that a pharmacist dispense an available generic equivalent when filling a prescription for a branded medicine, in the absence of specific instructions from the prescribing physician. DUEXIS faces competition from other NSAIDs, including Celebrex®, marketed by Pfizer Inc., and celecoxib, a generic form of the medicine marketed by other pharmaceutical companies. DUEXIS also faces significant competition from the separate use of NSAIDs for pain relief and GI protective medications to reduce the risk of NSAID-induced upper GI ulcers. Both NSAIDs and GI protective medications are available in generic form and may be less expensive to use separately than DUEXIS, despite such substitution being off-label in the case of DUEXIS. Because pharmacists often have economic and other incentives to prescribe lower-cost generics, if physicians prescribe PENNSAID 2% ~~or DUEXIS,~~, those prescriptions may not result in sales. If physicians do not complete prescriptions through our HorizonCares program or otherwise provide prescribing instructions prohibiting generic diclofenac sodium topical solutions as a substitute for PENNSAID 2%, ~~the substitution of generic ibuprofen and famotidine separately as a substitution for DUEXIS,~~ sales of PENNSAID 2% ~~and DUEXIS~~ may suffer despite any success we may have in promoting PENNSAID 2% ~~or DUEXIS~~ to physicians. In addition, other medicine candidates that contain ibuprofen and famotidine in combination or naproxen and esomeprazole in combination, while not currently known or FDA approved, may be developed and compete with DUEXIS in the future.

We have also entered into settlement and license agreements that may allow certain of our competitors to sell generic versions of certain of our medicines in the United States, subject to the terms of such agreements. We granted (i) ~~a non-exclusive license (that is only royalty-bearing in some circumstances) to manufacture and commercialize a generic version of DUEXIS in the United States after January 1, 2023, (ii)~~ non-exclusive licenses to manufacture and commercialize generic versions of PENNSAID 2% in the United States after October 17, 2027, ~~(iii)~~(ii) a non-exclusive license to manufacture and commercialize a generic version of RAYOS tablets in the United States after December 23, 2022, ~~and (iv)~~(iii) non-exclusive licenses to manufacture and commercialize generic versions of RAVICTI in the United States after July 1, 2025, or earlier under certain circumstances and (iv) non-exclusive license to manufacture and commercialize a generic version of PROCYSBI in the United States after March 31, 2030, or earlier under certain circumstances.

~~Patent litigation is currently pending in the United States District Court for the District of New Jersey against~~ ~~Actavis Laboratories UT, Inc., formerly known as Watson Laboratories, Inc., Actavis, Inc. and Actavis plc, or collectively Actavis, who intend to market~~ a generic version of PENNSAID 2% prior to the expiration of certain of our patents listed in the FDA’s Orange Book, or the Orange Book. These cases arise from Paragraph IV Patent Certification notice letters from Actavis advising it had filed an Abbreviated New Drug Application, or ANDA, with the FDA seeking approval to market a generic version of PENNSAID 2% before the expiration of the patents-in-suit.

On February 27, 2020, following a judgment in federal court invalidating certain patents covering VIMOVO, Dr. Reddy’s Laboratories Inc. and Dr. Reddy’s Laboratories Ltd, or collectively, Dr. Reddy’s, launched a generic version of VIMOVO in the United States. While patent litigation against Dr. Reddy’s for infringement continues on additional patents in the New Jersey District Court, we now face generic competition for VIMOVO, which has negatively impacted net sales of ~~VIMOVO in 2020.~~VIMOVO. As a result, we have repositioned our promotional efforts previously directed to VIMOVO to the other inflammation segment medicines and expect that our VIMOVO net sales will continue to decrease in future periods.

~~Patent litigation is currently pending~~On August 4, 2021, following a favorable judgment in the ~~United States~~ District Court, ~~for the District of Delaware and the United States District Court of New Jersey against~~ Alkem Laboratories, Inc., or Alkem, ~~and Teva Pharmaceuticals USA, Inc., or Teva USA, respectively, who each intend to market~~launched a generic version of DUEXIS prior to the expiration of certain of our patents listed in the Orange Book. These cases arise from Paragraph IV Patent Certification notice letters from Alkem and Teva USA advising they had filed an ANDA with the FDA seeking approval to market a generic version of DUEXIS before the expiration of the patents-in-suit.

On June 27, 2020, we received notice from Lupin Limited, or Lupin, that it had filed an ANDA with the FDA seeking approval of a generic version of PROCYSBI. The ANDA contained a Paragraph IV Patent Certification alleging that the patents covering PROCYSBI are invalid and/or will not be infringed by Lupin’s manufacture, use or sale of a generic version of PROCYSBI. Patent litigation is currently pending in the United States District Court of New Jersey against Lupin seeking to prevent Lupin from selling its generic version of PROCYSBI before the expiration of the patents-in-suit.

If we are unsuccessful in any of the PENNSAID 2% cases, DUEXIS cases or PROCYSBI case, we will likely face generic competition with respect to PENNSAID 2%, DUEXIS, and/or PROCYSBI and sales of PENNSAID 2%, DUEXIS, and/or PROCYSBI will be substantially harmed.

~~On February 27, 2020, following a judgment in federal court invalidating certain patents covering VIMOVO, Dr. Reddy’s launched a generic version of VIMOVO~~ in the United States. While patent litigation against ~~Dr. Reddy’s for infringement~~Alkem continues ~~on additional patents~~ in the ~~New Jersey District~~Federal Circuit Court of Appeals, we now face generic competition for ~~VIMOVO,~~DUEXIS, which has negatively impacted net sales of ~~VIMOVO in 2020.~~DUEXIS. As a result, we have repositioned our promotional efforts previously directed to ~~VIMOVO~~DUEXIS to the other inflammation segment medicines and expect that our ~~VIMOVO~~DUEXIS net sales will continue to decrease in future periods.

ACTIMMUNE is the only medicine currently approved by the FDA specifically for the treatment of CGD and SMO. While there are additional or alternative approaches used to treat patients with CGD and SMO, there are currently no medicines on the market that compete directly with ACTIMMUNE. A widely accepted protocol to treat CGD in the United States is the use of concomitant “triple prophylactic therapy” comprising ACTIMMUNE, an oral antibiotic agent and an oral antifungal agent. However, the FDA-approved labeling for ACTIMMUNE does not discuss this “triple prophylactic therapy,” and physicians may choose to prescribe one or both of the other modalities in the absence of ACTIMMUNE. Because of the immediate and life-threatening nature of SMO, the preferred treatment option for SMO is often to have the patient undergo a bone marrow transplant which, if successful, will likely obviate the need for further use of ACTIMMUNE in that patient. Likewise, the use of bone marrow transplants in the treatment of patients with CGD is becoming more prevalent, which could have a material adverse effect on sales of ACTIMMUNE and its profitability. We are aware of a number of research programs investigating the potential of gene therapy as a possible cure for CGD. Additionally, other companies may be pursuing the development of medicines and treatments that target the same diseases and conditions which ACTIMMUNE is currently approved to treat. As a result, it is possible that our competitors may develop new medicines that manage CGD or SMO more effectively, cost less or possibly even cure CGD or SMO. In addition, U.S. healthcare legislation passed in March 2010 authorized the FDA to approve biological products, known as biosimilars, that are similar to or interchangeable with previously approved biological products, like ACTIMMUNE, based upon potentially abbreviated data packages. Biosimilars are likely to be sold at substantially lower prices than branded medicines because the biosimilar manufacturer would not have to recoup the ~~research and development~~R&D and marketing costs associated with the branded medicine. Though we are not currently aware of any biosimilar under development, the development and commercialization of any competing medicines or the discovery of any new alternative treatment for CGD or SMO could have a material adverse effect on sales of ACTIMMUNE and its profitability. We have licenses to U.S. patents covering ACTIMMUNE. If not otherwise invalidated, those patents expire in August 2022.

BUPHENYL’s composition of matter patent protection and orphan drug exclusivity have expired. Because BUPHENYL has no regulatory exclusivity or listed patents, there is nothing to prevent a competitor from submitting an ANDA for a generic version of BUPHENYL and receiving FDA approval. Generic versions of BUPHENYL to date have been priced at a discount relative to RAVICTI, and physicians, patients, or payers may decide that this less expensive alternative is preferable to RAVICTI. If this occurs, sales of RAVICTI could be materially reduced, but we would nevertheless be required to make royalty payments to Bausch Health Companies Inc. (formerly Ucyclyd Pharma, Inc.), or Bausch, and another external party, at the same royalty rates. While Bausch and its affiliates are generally contractually prohibited from developing or commercializing new medicines, anywhere in the world, for the treatment of UCD or hepatic encephalopathy, or HE, which are chemically similar to RAVICTI, they may still develop and commercialize medicines that compete with RAVICTI. For example, medicines approved for indications other than UCD and HE may still compete with RAVICTI if physicians prescribe such medicines off-label for UCD or HE. We are also aware that Recordati S.p.A (formerly known as Orphan Europe SARL), or Recordati, ~~is conducting clinical trials of~~received FDA approval in January 2021 for carglumic acid ~~to assess~~for the ~~efficacy for~~treatment of acute hyperammonemia ~~in some of~~due to propionic acidemia or methylmalonic acidemia. Carglumic acid, sold under the ~~UCD enzyme deficiencies for which RAVICTI~~name Carbaglu, is also approved for chronic ~~treatment. Carglumic acid is approved for maintenance therapy for chronic~~and acute hyperammonemia ~~and~~due to ~~treat hyperammonemic crises in~~ N-acetylglutamate synthase deficiency, a rare UCD subtype, and is sold under the name Carbaglu. If the results of this trial are successful and Recordati is able to complete development and obtain approval of Carbaglu to treat additional UCD enzyme deficiencies,subtype. RAVICTI may face additional competition from this compound.

The availability and price of our competitors’ medicines could limit the demand, and the price we are able to charge, for our medicines. We will not successfully execute on our business objectives if the market acceptance of our medicines is inhibited by price competition, if physicians are reluctant to switch from existing medicines to our medicines, or if physicians switch to other new medicines or choose to reserve our medicines for use in limited patient populations.

In addition, established pharmaceutical companies may invest heavily to accelerate discovery and development of novel compounds or to acquire novel compounds that could make our medicines obsolete. Our ability to compete successfully with these companies and other potential competitors will depend largely on our ability to leverage our experience in clinical, regulatory and commercial development to:

Our biologic medicines and candidates may face biosimilar competition sooner than anticipated. *

Even if we are successful in achieving regulatory approval to commercialize a biologic medicine candidate ahead of our competitors, our biologic medicines and candidates may face competition from biosimilar products. In the United States, the Biologics Price Competition and Innovation Act of 2009, or BPCIA, created an abbreviated pathway for FDA approval of biosimilar and interchangeable biological products based on a previously licensed reference product. Under the BPCIA, an application for a biosimilar biological product cannot be approved by the FDA until 12 years after the original reference biological product was approved under a BLA. The law is complex and is still being interpreted and implemented by the FDA. As a result, its ultimate impact, implementation, and meaning are subject to uncertainty and any such processes could have a material adverse effect on the future commercial prospects for our biologic medicines and candidates.

68We believe that any of our candidates approved as a biological product under a BLA should qualify for the 12-year period of exclusivity available to reference biological products. However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider our candidates to be reference biological products pursuant to its interpretation of the exclusivity provisions of the BPCIA for competing products, potentially creating the opportunity for biosimilar competition sooner than anticipated. Moreover, the extent to which a biosimilar product, once approved, will be substituted for any one of our reference medicines in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing including whether a future competitor seeks an interchangeability designation for a biosimilar of one of our medicines. Under the BPCIA as well as state pharmacy laws, only interchangeable biosimilar products are considered substitutable for the reference biological product without the intervention of the health care provider who prescribed the original biological product. However, as with all prescribing decisions made in the context of a patient-provider relationship and a patient’s specific medical needs, healthcare providers are not restricted from prescribing biosimilar products in an off-label manner. In addition, a competitor could decide to forego the abbreviated approval pathway available for biosimilar products and to submit a full BLA for product licensure after completing its own preclinical studies and clinical trials. In such a situation, any exclusivity to which we may be eligible under the BPCIA would not prevent the competitor from marketing its biological product as soon as it is approved.

In Europe, the EC has granted marketing authorizations for several biosimilar products pursuant to a set of general and product class-specific guidelines for biosimilar approvals issued over the past few years. In addition, companies may be developing biosimilar products in other countries that could compete with our medicines, if approved.

If competitors are able to obtain marketing approval for biosimilars referencing our medicine candidates, if approved, our future medicines may become subject to competition from such biosimilars, whether or not they are designated as interchangeable, with the attendant competitive pressure and potential adverse consequences. Such competitive products may be able to immediately compete with us in each indication for which our medicine candidates may have received approval.

If we are unable to maintain or realize the benefits of orphan drug exclusivity, we may face increased competition with respect to certain of our medicines.*

Under the Orphan Drug Act of 1983, the FDA may designate a medicine as an orphan drug if it is a drug intended to treat a rare disease or condition affecting fewer than 200,000 people in the United States. A company that first obtains FDA approval for a designated orphan drug for the specified rare disease or condition receives orphan drug marketing exclusivity for that drug for a period of seven years from the date of its approval. PROCYSBI ~~has been granted~~received ten years of market exclusivity, through 2023, as an orphan drug in Europe. PROCYSBI received seven years of market exclusivity, ~~by the FDA, which we expect will provide~~through 2022, for patients two years of age to less than six years of age, and seven years of market exclusivity, through 2024, for patients one year of age to less than two years of age, as an orphan drug ~~marketing exclusivity~~ in the United ~~States until December 2020, with exclusivity for PROCYSBI extending to 2022 for patients ages one to six years. In addition,~~States. TEPEZZA has been granted orphan drug exclusivity for treatment of active (dynamic) phase Graves’ ophthalmopathy, which we expect will provide orphan drug marketing exclusivity in the United States until January 2027. In addition, UPLIZNA was granted orphan drug exclusivity for the treatment of NMOSD, which we expect will provide orphan drug marketing exclusivity in the United States until June 2027. However, despite orphan drug exclusivity, the FDA can still approve another drug containing the same active ingredient and used for the same orphan indication if it determines that a subsequent drug is safer, more effective or makes a major contribution to patient care, and orphan exclusivity can be lost if the orphan drug manufacturer is unable to ensure that a sufficient quantity of the orphan drug is available to meet the needs of patients with the rare disease or condition. Orphan drug exclusivity may also be lost if the FDA later determines that the initial request for designation was materially defective. In addition, orphan drug exclusivity does not prevent the FDA from approving competing drugs for the same or similar indication containing a different active ingredient. If orphan drug exclusivity is lost and we were unable to successfully enforce any remaining patents covering the applicable medicine, we could be subject to generic competition and revenues from the medicine could decrease materially. In addition, if a subsequent drug is approved for marketing for the same or a similar indication as our medicines despite orphan drug exclusivity, we may face increased competition and lose market share with respect to these medicines.

A Breakthrough Therapy Designation by the FDA may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our medicine candidates will receive marketing approval.*

We do not currently have Breakthrough Therapy Designation for any of our medicine candidates, but may seek such designation in the future for other medicine candidates. A Breakthrough Therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For drugs that have been designated as Breakthrough Therapies, interaction and communication between the FDA and the sponsor can help to identify the most efficient path for development. Drugs designated as Breakthrough Therapies are also eligible for accelerated approval.

The FDA has discretion to determine whether the criteria for a Breakthrough Therapy has been met and whether to grant a Breakthrough Therapy Designation to an investigational product. Accordingly, even if we believe, after completing early clinical trials, that one of our medicine candidates meets the criteria for designation as a Breakthrough Therapy, the FDA may disagree and instead determine not to make such designation. In any event, the receipt of a Breakthrough Therapy Designation for a medicine candidate may not result in a faster development process, review or approval compared to medicine candidates considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even after granting Breakthrough Therapy Designation to our medicine candidates, the FDA may later decide that such medicine candidates no longer meet the conditions for qualification and withdraw such designation.

A Fast Track Designation by the FDA, even if granted for any of our medicine candidates, may not lead to a faster development or regulatory review or approval process and does not increase the likelihood that our medicine candidates will receive marketing approval.*

We do not currently have Fast Track Designation for any of our medicine candidates, but may seek such designation in the future. If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA Fast Track Designation. The FDA has broad discretion whether to grant this designation. Even if we believe a particular medicine candidate is eligible for this designation, we cannot assure you that the FDA would decide to grant it. Even if we do receive Fast Track Designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw Fast Track Designation if it believes that the designation is no longer supported by data from our clinical development program. Many drugs that have received Fast Track Designation have failed to obtain regulatory approval.

If we cannot successfully implement our patient assistance programs or increase formulary access and reimbursement for our medicines in the face of increasing pressure to reduce the price of medications, the adoption of our medicines by physicians, patients and payers may decline.*

There continues to be immense pressure from healthcare payers, PBMs and others to use less expensive or generic medicines or over-the-counter brands instead of certain branded medicines. For example, some PBMs have placed certain of our medicines on their exclusion lists from time to time, which has resulted in a loss of coverage for patients whose healthcare plans have adopted these PBM lists. Additional healthcare plans, including those that contract with these PBMs but use different formularies, may also choose to exclude our medicines from their formularies or restrict coverage to situations where a generic or over-the-counter medicine has been tried first. Many payers and PBMs also require patients to make co-payments for branded medicines, including many of our medicines, in order to incentivize the use of generic or other lower-priced alternatives instead. Legislation enacted in most states in the United States allows, or in some instances mandates, that a pharmacist dispenses an available generic equivalent when filling a prescription for a branded medicine, in the absence of specific instructions from the prescribing physician. Because our medicines (other than BUPHENYL, DUEXIS and VIMOVO) do not currently have FDA-approved generic equivalents in the United States, we do not believe our medicines should be subject to mandatory generic substitution laws. We understand that some pharmacies may attempt to obtain physician authorization to switch prescriptions for DUEXIS to prescriptions for multiple generic medicines with similar APIs to ensure payment for the medicine if the physician’s prescription for the branded medicine is not immediately covered by the payer, despite such substitution being off-label in the case of DUEXIS. If ~~these~~ limitations in coverage and other incentives result in patients refusing to fill prescriptions or being dissatisfied with the out-of-pocket costs of their medications, or if pharmacies otherwise seek and receive physician authorization to switch prescriptions, not only would we lose sales on prescriptions that are ultimately not filled, but physicians may be dissuaded from writing prescriptions for our medicines in the first place in order to avoid potential patient non-compliance or dissatisfaction over medication costs, or to avoid spending the time and effort of responding to pharmacy requests to switch prescriptions.

Part of our commercial strategy to increase adoption and access to our medicines in the face of these incentives to use generic alternatives is to offer physicians the opportunity to have eligible patients fill prescriptions through independent pharmacies participating in our HorizonCares patient assistance program, including shipment of prescriptions to patients. We also have contracted with a third-party prescription clearinghouse that offers physicians a single point of contact for processing prescriptions through these independent pharmacies, reducing physician administrative costs, increasing the fill rates for prescriptions and enabling physicians to monitor refill activity. Through HorizonCares, financial assistance may be available to reduce eligible patients’ out-of-pocket costs for prescriptions filled. Because of this assistance, eligible patients’ out-of-pocket cost for our medicines when dispensed through HorizonCares may be significantly lower than such costs when our medicines are dispensed outside of the HorizonCares program. However, to the extent physicians do not direct prescriptions currently filled through traditional pharmacies, including those associated with or controlled by PBMs, to pharmacies participating in our HorizonCares program, we may experience a significant decline in PENNSAID 2% ~~and DUEXIS~~ prescriptions. Our ability to increase utilization of our patient assistance programs will depend on physician and patient awareness and comfort with the programs, and we do not control whether physicians will ultimately use our patient assistance programs to prescribe our medicines or whether patients will agree to receive our medicines through our HorizonCares program. In addition, the HorizonCares program is not available to federal health care program (such as Medicare and Medicaid) beneficiaries. We have also contracted with certain PBMs and other payers to secure formulary status and reimbursement for certain of our inflammation segment medicines, which generally require us to pay administrative fees and rebates to the PBMs and other payers for qualifying prescriptions. While we have business relationships with two of the largest PBMs, Express Scripts, Inc., or Express Scripts, and CVS Caremark, as well as rebate agreements with other PBMs, and we believe these agreements will secure formulary status for certain of our medicines, we cannot guarantee that we will be able to agree to terms with other PBMs and other payers, or that such terms will be commercially reasonable to us. Despite our agreements with PBMs, the extent of formulary status and reimbursement will ultimately depend to a large extent upon individual healthcare plan formulary decisions. If healthcare plans that contract with PBMs with which we have agreements do not adopt formulary changes recommended by the PBMs with respect to our medicines, we may not realize the expected access and reimbursement benefits from these agreements. In addition, we generally pay higher rebates for prescriptions covered under plans that adopt a PBM-chosen formulary than for plans that adopt custom formularies. Consequently, the success of our PBM contracting strategy will depend not only on our ability to expand formulary adoption among healthcare plans, but also upon the relative mix of healthcare plans that have PBM-chosen formularies versus custom formularies. If we are unable to realize the expected benefits of our contractual arrangements with the PBMs we may continue to experience reductions in net sales from our inflammation segment medicines and/or reductions in net pricing for our inflammation segment medicines due to increasing patient assistance costs. If we are unable to increase adoption of HorizonCares for filling prescriptions of our medicines and to secure formulary status and reimbursement through arrangements with PBMs and other payers, particularly with healthcare plans that use custom formularies, our ability to achieve net sales growth for our inflammation segment medicines would be impaired.

There has been negative publicity and inquiries from Congress and enforcement authorities regarding the use of specialty pharmacies and drug pricing. Our patient assistance programs are not involved in the prescribing of medicines and are solely to assist in ensuring that when a physician determines one of our medicines offers a potential clinical benefit to their patients and they prescribe one for an eligible patient, financial assistance may be available to reduce the patient’s out-of-pocket costs. In addition, all pharmacies that fill prescriptions for our medicines are fully independent, including those that participate in HorizonCares. We do not own or possess any option to purchase an ownership stake in any pharmacy that distributes our medicines, and our relationship with each pharmacy is non-exclusive and arm’s length. All of our sales are processed through pharmacies independent of us. Despite this, the negative publicity and interest from Congress and enforcement authorities regarding specialty pharmacies may result in physicians being less willing to participate in our patient assistance programs and thereby limit our ability to increase patient assistance and adoption of our medicines.

We may also encounter difficulty in forming and maintaining relationships with pharmacies that participate in our patient assistance programs. We currently depend on a limited number of pharmacies participating in HorizonCares to fulfill patient prescriptions under the HorizonCares program. If these HorizonCares participating pharmacies are unable to process and fulfill the volume of patient prescriptions directed to them under the HorizonCares program, our ability to maintain or increase prescriptions for our medicines will be impaired. The commercialization of our medicines and our operating results could be affected should any of the HorizonCares participating pharmacies choose not to continue participation in our HorizonCares program or by any adverse events at any of those HorizonCares participating pharmacies. For example, pharmacies that dispense our medicines could lose contracts that they currently maintain with managed care organizations, or MCOs, including PBMs. Pharmacies often enter into agreements with MCOs. They may be required to abide by certain terms and conditions to maintain access to MCO networks, including terms and conditions that could limit their ability to participate in patient assistance programs like ours. Failure to comply with the terms of their agreements with MCOs could result in a variety of penalties, including termination of their agreement, which could negatively impact the ability of those pharmacies to dispense our medicines and collect reimbursement from MCOs for such medicines.

The HorizonCares program may implicate certain federal and state laws related to, among other things, unlawful schemes to defraud, excessive fees for services, healthcare kickbacks, tortious interference with patient contracts and statutory or common law fraud. We have a comprehensive compliance program in place to address adherence with various laws and regulations relating to the selling, marketing and manufacturing of our medicines, as well as certain third-party relationships, including pharmacies. Specifically, with respect to pharmacies, the compliance program utilizes a variety of methods and tools to monitor and audit pharmacies, including those that participate in the HorizonCares program, to confirm their activities, adjudication and practices are consistent with our compliance policies and guidance. Despite our compliance efforts, to the extent the HorizonCares program is found to be inconsistent with applicable laws or the pharmacies that participate in our patient assistance programs do not comply with applicable laws, we may be required to restructure or discontinue such programs, terminate our relationship with certain pharmacies, or be subject to other significant penalties. In November 2015, we received a subpoena from the U.S. Attorney’s Office for the Southern District of New York requesting documents and information related to our patient assistance programs and other aspects of our marketing and commercialization activities. We are unable to predict how long this investigation will continue or its outcome, but we have incurred and anticipate that we may continue to incur significant costs in connection with the investigation, regardless of the outcome. We may also become subject to similar investigations by other governmental agencies or Congress. The investigation by the U.S. Attorney’s Office and any additional investigations of our patient assistance programs and sales and marketing activities may result in significant damages, fines, penalties, exclusion, additional reporting requirements and/or oversight or other administrative sanctions against us.

If the cost of maintaining our patient assistance programs increases relative to our sales revenues, we could be forced to reduce the amount of patient financial assistance that we offer or otherwise scale back or eliminate such programs, which could in turn have a negative impact on physicians’ willingness to prescribe and patients’ willingness to fill prescriptions of our medicines. While we believe that our arrangements with PBMs will result in broader inclusion of certain of our inflammation segment medicines on healthcare plan formularies, and therefore increase payer reimbursement and lower our cost of providing patient assistance programs, these arrangements generally require us to pay administrative and rebate payments to the PBMs and/or other payers and their effectiveness will ultimately depend to a large extent upon individual healthcare plan formulary decisions that are beyond the control of the PBMs. If our arrangements with PBMs and other payers do not result in increased prescriptions and reductions in our costs to provide our patient assistance programs that are sufficient to offset the administrative fees and rebate payments to the PBMs and/or other payers, our financial results may continue to be harmed.

If we are unable to successfully implement our commercial plans and facilitate adoption by patients and physicians of any approved medicines through our sales, marketing and commercialization efforts, then we will not be able to generate sustainable revenues from medicine sales which will have a material adverse effect on our business and prospects.

Our business operations may subject us to numerous commercial disputes, claims and/or lawsuits and such litigation may be costly and time-consuming and could materially and adversely impact our financial position and results of operations.*

Operating in the pharmaceutical industry, particularly the commercialization of medicines, involves numerous commercial relationships, complex contractual arrangements, uncertain intellectual property rights, potential product liability and other aspects that create heightened risks of disputes, claims and lawsuits. In particular, we may face claims related to the safety of our medicines, intellectual property matters, employment matters, tax matters, commercial disputes, competition, sales and marketing practices, environmental matters, personal injury, insurance coverage and acquisition or divestiture-related matters. Any commercial dispute, claim or lawsuit may divert management’s attention away from our business, we may incur significant expenses in addressing or defending any commercial dispute, claim or lawsuit, and we may be required to pay damage awards or settlements or become subject to equitable remedies that could adversely affect our operations and financial results.

We are currently in litigation with multiple generic drug manufacturers regarding intellectual property infringement. For example, we are currently involved in Hatch Waxman litigation with generic drug manufacturers related to DUEXIS ~~PENNSAID 2%, VIMOVO,~~ and ~~PROCYSBI.~~VIMOVO.

Similarly, from time to time we are involved in disputes with distributors, PBMs and licensing partners regarding our rights and performance of obligations under contractual arrangements. For example, we were previously in litigation with Express Scripts related to alleged breach of contract claims.

Litigation related to these disputes may be costly and time-consuming and could materially and adversely impact our financial position and results of operations if resolved against us.

A variety of risks associated with operating our business internationally could adversely affect our business.*

In addition to our U.S. operations, we have operations in Ireland, Bermuda, the Grand Duchy of Luxembourg, or Luxembourg, Switzerland, Germany and in Canada. Furthermore, we are pursuing a global expansion strategy, which includes bringing TEPEZZA to patients with TED outside of the United States, including Japan where we are engaging with the PMDA and the Japanese medical community. Furthermore, we are investing in our European infrastructure to support the potential first-quarter 2022 approval of UPLIZNA by the EMA for NMOSD. UPLIZNA has been granted orphan designation by the EC. That designation is subject to additional review by the COMP and may or may not be maintained.We face risks associated with our international operations, including possible unfavorable political, tax and labor conditions, which could harm our business.

We are subject to numerous risks associated with international business activities, including:

Our business activities outside of the United States are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate. The FCPA and similar anti-corruption laws generally prohibit offering, promising, giving, or authorizing others to give anything of value, either directly or indirectly, to non-U.S. government officials in order to improperly influence any act or decision, secure any other improper advantage, or obtain or retain business. The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect the transactions of the company and to devise and maintain an adequate system of internal accounting controls. As described above, our business is heavily regulated and therefore involves significant interaction with public officials, including officials of non-U.S. governments. Additionally, in many other countries, the health care providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. Recently the SEC and the U.S. Department of Justice, or DOJ, have increased their FCPA enforcement activities with respect to pharmaceutical companies. In addition, under the Dodd–Frank Wall Street Reform and Consumer Protection Act, private individuals who report to the SEC original information that leads to successful enforcement actions may be eligible for a monetary award. We are engaged in ongoing efforts that are designed to ensure our compliance with these laws, including due diligence, training, policies, procedures and internal controls. However, there is no certainty that all employees and third-party business partners (including our distributors, wholesalers, agents, contractors, and other partners) will comply with anti-bribery laws. In particular, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions. Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have a material adverse impact on our business and financial condition.

We are subject to tax audits around the world, and such jurisdictions may assess additional income tax against us. Although we believe our tax positions are reasonable, the final determination of tax audits could be materially different from our recorded income tax provisions and accruals. The ultimate results of an audit could have a material adverse effect on our operating results or cash flows in the period or periods for which that determination is made and could result in increases to our overall tax expense in subsequent periods.

These and other risks associated with our international operations may materially adversely affect our business, financial condition and results of operations.

If we fail to develop or acquire other medicine candidates or medicines, our business and prospects would be limited.*

A key element of our strategy is to develop or acquire and commercialize a portfolio of other medicines or medicine candidates in addition to our current medicines, through business or medicine ~~acquisitions.~~acquisitions such as our acquisition of Viela. Because we do not engage in proprietary drug discovery, the success of this strategy depends in large part upon the combination of our regulatory, development and commercial capabilities and expertise and our ability to identify, select and acquire approved or clinically enabled medicine candidates for therapeutic indications that complement or augment our current medicines, or that otherwise fit into our development or strategic plans on terms that are acceptable to us. Identifying, selecting and acquiring promising medicines or medicine candidates requires substantial technical, financial and human resources expertise. Efforts to do so may not result in the actual acquisition or license of a particular medicine or medicine candidate, potentially resulting in a diversion of our management’s time and the expenditure of our resources with no resulting benefit. If we are unable to identify, select and acquire suitable medicines or medicine candidates from third parties or acquire businesses at valuations and on other terms acceptable to us, or if we are unable to raise capital required to acquire businesses or new medicines, our business and prospects will be limited.

Moreover, any medicine candidate we acquire may require additional, time-consuming development or regulatory efforts prior to commercial sale or prior to expansion into other indications, including pre-clinical studies if applicable, and extensive clinical testing and approval by the FDA and applicable foreign regulatory authorities. All medicine candidates are prone to the risk of failure that is inherent in pharmaceutical medicine development, including the possibility that the medicine candidate will not be shown to be sufficiently safe and/or effective for approval by regulatory authorities. In addition, we cannot assure that any such medicines that are approved will be manufactured or produced economically, successfully commercialized or widely accepted in the marketplace or be more effective or desired than other commercially available alternatives.

In addition, if we fail to successfully commercialize and further develop our medicines, there is a greater likelihood that we will fail to successfully develop a pipeline of other medicine candidates to follow our existing medicines or be able to acquire other medicines to expand our existing portfolio, and our business and prospects would be harmed.

We have experienced growth and expanded the size of our organization substantially in connection with our acquisition transactions, and we may experience difficulties in managing this growth as well as potential additional growth in connection with future medicine, development program or company acquisitions.*

As of December 31, 2013, we employed approximately 300 full-time employees as a consolidated entity. As of September 30, ~~2020,~~2021, we employed approximately ~~1,275~~1,805 full-time employees, including approximately ~~445~~485 sales representatives, representing a substantial change to the size of our organization. We have also experienced, and may continue to experience, turnover of the sales representatives that we hired or will hire in connection with the commercialization of our medicines, requiring us to hire and train new sales representatives. Our management, personnel, systems and facilities currently in place may not be adequate to support anticipated growth, and we may not be able to retain or recruit qualified personnel in the future due to competition for personnel among pharmaceutical businesses.

As our commercialization plans and strategies continue to develop, including as a result of our acquisition of Viela, we will need to continue to recruit and train sales and marketing personnel. In addition, as we build our R&D and manufacturing capabilities, we will need to continue to recruit and train qualified individuals in these areas. Our ability to manage any future growth effectively may require us to, among other things:

Our acquisitions have resulted in many changes, and our acquisition of Viela and our manufacturing facility in Waterford, Ireland, may result in additional changes, including significant changes in the corporate business and legal entity structure, the integration of other companies and their personnel with us, and changes in systems. We may encounter unexpected difficulties or incur unexpected costs, including:

If any of these factors impair our ability to continue to integrate our operations with those of any companies or businesses we acquire, including Viela, we may not be able to realize the business opportunities, growth prospects and anticipated tax synergies from combining the businesses. In addition, we may be required to spend additional time or money on integration that otherwise would be spent on the development and expansion of our business. For example, we will need to spend additional time and money on the integration of Viela’s R&D and sales and marketing functions with our own functions.

We may not be successful in growing our commercial operations outside the United States, and could encounter other challenges in growing our commercial presence, including due to risks associated with political and economic instability, operating under different legal requirements and tax complexities. If we are unable to manage our commercial growth outside of the United States, our opportunities to expand sales in other countries will be limited or we may experience greater costs with respect to our ex-U.S. commercial operations.

We have also broadened our acquisition strategy to include development-stage assets or programs, which entails additional risk to us. For example, if we are unable to identify programs that ultimately result in approved medicines, we may spend material amounts of our capital and other resources evaluating, acquiring and developing medicines that ultimately do not provide a return on our investment. We have less experience evaluating development-stage assets and may be at a disadvantage compared to other entities pursuing similar opportunities. Regardless, development-stage programs generally have a high rate of failure and we cannot guarantee that any such programs will ultimately be successful. While we have significantly enhanced our ~~research and development~~R&D function in recent years, we may need to enhance our clinical development and regulatory functions to properly evaluate and develop earlier-stage opportunities, which may include recruiting personnel that are knowledgeable in therapeutic areas we have not yet pursued. If we are unable to acquire promising development-stage assets or eventually obtain marketing approval for them, we may not be able to create a meaningful pipeline of new medicines and eventually realize a return on our investments. For example, a core strategic rationale for the Viela acquisition was Viela’s pipeline of medicine candidates and R&D capabilities, but if we experience clinical failures with respect to Viela’s medicine candidates and research programs or such candidates and programs do not otherwise result in marketed medicines, we will not realize the expected benefits from our substantial investment in the acquisition and subsequent development of the Viela pipeline. As our R&D plans and strategies continue to develop, including as a result of our acquisition of Viela, we will need to continue to recruit and train R&D personnel.

Our management may also have to divert a disproportionate amount of its attention away from day-to-day activities and toward managing these growth and integration activities. Our future financial performance and our ability to execute on our business plan will depend, in part, on our ability to effectively manage any future growth and our failure to effectively manage growth could have a material adverse effect on our business, results of operations, financial condition and prospects.

Our prior medicine and company acquisitions and any other strategic transactions that we may pursue in the future could have a variety of negative consequences, and we may not realize the benefits of such transactions or attempts to engage in such transactions.*

We have completed multiple medicine and company acquisitions, including most recently Viela, and our strategy is to engage in additional strategic transactions with third parties, such as acquisitions of companies or divisions of companies and asset purchases of medicines, medicine candidates or technologies that we believe will complement or augment our existing business. We may also consider a variety of other business arrangements, including spin-offs, strategic partnerships, joint ventures, restructurings, divestitures, business combinations and other investments. Any such transaction may require us to incur non-recurring and other charges, increase our near and long-term expenditures, pose significant integration challenges, create additional tax, legal, accounting and operational complexities in our business, require additional expertise, result in dilution to our existing shareholders and disrupt our management and business, which could harm our operations and financial results. For example, we assumed responsibility for the patent infringement litigation with respect to RAVICTI upon the closing of our acquisition of Hyperion Therapeutics, Inc., or Hyperion, and we have assumed responsibility for completing post-marketing clinical trials of RAVICTI that are required by the FDA, one of which is ongoing.

We are subject to contractual obligations under an amended and restated license agreement with the Regents of the University of California, San Diego, or UCSD, as amended, with respect to PROCYSBI. To the extent that we fail to perform our obligations under the agreement, UCSD may, with respect to applicable indications, terminate the license or otherwise cause the license to become non-exclusive. If this license was terminated, we would have no further right to use or exploit the related intellectual property, which would limit our ability to develop PROCYSBI in other indications, and could impact our ability to continue commercializing PROCYSBI in its approved indications.

We face significant competition in seeking appropriate strategic transaction opportunities and the negotiation process for any strategic transaction can be time-consuming and complex. In addition, we may not be successful in our efforts to engage in certain strategic transactions because our financial resources may be insufficient and/or third parties may not view our commercial and development capabilities as being adequate. Further, increasing regulatory scrutiny of acquisitions may limit our ability to pursue certain acquisitions where we have potentially competing products or clinical programs. We may not be able to expand our business or realize our strategic goals if we do not have sufficient funding or cannot borrow or raise additional capital. There is no assurance that following any of our recent acquisition transactions or any other strategic transaction, including the acquisition of Viela, we will achieve the anticipated revenues, net income or other benefits that we believe justify such transactions. In addition, any failures or delays in entering into strategic transactions anticipated by analysts or the investment community could seriously harm our consolidated business, financial condition, results of operations or cash flow.

We may not be able to successfully maintain our current advantageous tax status and resulting tax rates, which could adversely affect our business and financial condition, results of operations and growth prospects.

Our parent company is incorporated in Ireland and has subsidiaries maintained in multiple jurisdictions, including Ireland, the United States, Switzerland, Luxembourg, Germany, Canada and Bermuda. We are able to achieve a favorable tax rate through the performance of certain functions and ownership of certain assets in tax-efficient jurisdictions, including Ireland and Bermuda, together with the use of ~~intra-company~~intercompany service and transfer pricing agreements, each on an arm’s length basis. Our effective tax rate may be different than experienced in the past due to numerous factors including, changes to the tax laws of jurisdictions that we operate in, the enactment of new tax treaties or changes to existing tax treaties, changes in the mix of our profitability from jurisdiction to jurisdiction, the implementation of the EU Anti-Tax Avoidance Directive (see further discussion below), the implementation of the Bermuda Economic Substance Act 2018 (effective December 31, 2018) and our inability to secure or sustain acceptable agreements with tax authorities (if applicable). Any of these factors could cause us to experience an effective tax rate significantly different from previous periods or our current expectations. Taxing authorities, such as the U.S. Internal Revenue Service, or IRS, actively audit and otherwise challenge these types of arrangements, and have done so in the pharmaceutical industry. We expect that these challenges will continue as a result of the recent increase in scrutiny and political attention on corporate tax structures. The IRS and/or the Irish tax authorities may challenge our structure and transfer pricing arrangements through an audit or lawsuit. Responding to or defending such a challenge could be expensive and consume time and other resources, and divert management’s time and focus from operating our business. We cannot predict whether taxing authorities will conduct an audit or file a lawsuit challenging this structure, the cost involved in responding to any such audit or lawsuit, or the outcome. If we are unsuccessful in defending such a challenge, we may be required to pay taxes for prior periods, as well as interest, fines or penalties, and may be obligated to pay increased taxes in the future, any of which could require us to reduce our operating expenses, decrease efforts in support of our medicines or seek to raise additional funds, all of which could have a material adverse effect on our business, financial condition, results of operations and growth prospects.

The IRS may not agree with our conclusion that our parent company should be treated as a foreign corporation for U.S. federal income tax purposes following the combination of the businesses of Horizon Pharma, Inc., or HPI, our predecessor, and Vidara Therapeutics International Public Limited Company, or Vidara.

Although our parent company is incorporated in Ireland, the IRS may assert that it should be treated as a U.S. corporation (and, therefore, a U.S. tax resident) for U.S. federal income tax purposes pursuant to Section 7874 of the Internal Revenue Code of 1986, as amended, or the Code. A corporation is generally considered a tax resident in the jurisdiction of its organization or incorporation for U.S. federal income tax purposes. Because our parent company is an Irish incorporated entity, it would generally be classified as a foreign corporation (and, therefore, a non-U.S. tax resident) under these general rules. Section 7874 of the Code provides an exception pursuant to which a foreign incorporated entity may, in certain circumstances, be treated as a U.S. corporation for U.S. federal income tax purposes.

In July 2018, the IRS issued regulations under Section 7874. We do not believe that our classification as a foreign corporation for U.S. federal income tax purposes is affected by Section 7874 or the regulations thereunder, though the IRS may disagree.

Recent and future changes to U.S. and non-U.S. tax laws could materially adversely affect our company.*

Under current law, we expect our parent company to be treated as a foreign corporation for U.S. federal income tax purposes. However, changes to the rules in Section 7874 of the Code or regulations promulgated thereunder or other guidance issued by the U.S. Department of the Treasury, or the U.S. Treasury, or the IRS could adversely affect our parent company’s status as a foreign corporation for U.S. federal income tax purposes or the taxation of transactions between members of our group, and any such changes could have prospective or retroactive application. If our parent company is treated as a domestic corporation, more of our income will be taxed by the United States which may substantially increase our effective tax rate.

In addition, the Organization for Economic ~~Co-operation~~Cooperation and Development, or the OECD, released its Base Erosion and Profit Shifting project final report on October 5, 2015. This report provides the basis for international standards for corporate taxation that are designed to prevent, among other things, the artificial shifting of income to tax havens and low-tax jurisdictions, the erosion of the tax base through interest deductions on ~~intra-company~~intercompany debt and the artificial avoidance of permanent establishments (i.e., tax nexus with a jurisdiction). Legislation to adopt these standards has been enacted or is currently under consideration in a number of jurisdictions. On June 7, 2017, several countries, including many countries that we operate and have subsidiaries in, participated in the signing ceremony adopting the OECD’s Multilateral Convention to Implement Tax Treaty Related Measures to Prevent Base Erosion and Profit Shifting, commonly referred to as the MLI. The MLI came into effect on July 1, 2018. In January 2019, Ireland deposited the instrument of ratification of Ireland’s MLI choices with the OECD. Ireland’s MLI came into force on May 1, 2019, however the provisions in respect of withholding taxes and other taxes levied by Ireland did not come into effect for us until January 1, 2020 (with application also depending on whether the MLI has been ratified in other jurisdictions whose tax treaties with Ireland are affected). The MLI may modify affected tax treaties making it more difficult for us to obtain advantageous tax-treaty benefits. The number of affected tax treaties could eventually be in the thousands. As a result, our income may be taxed in jurisdictions where it is not currently taxed and at higher rates of tax than it is currently taxed, which may increase our effective tax rate.

The Irish Finance Act 2019, or Finance Act 2019, which was signed into law on December 22, 2019, introduced changes to Ireland’s transfer pricing rules, which came into force with effect from January 1, 2020. The changes introduce the 2017 version of the OECD Transfer Pricing Guidelines, or 2017 OECD Guidelines, as the reference guidelines for Ireland’s domestic transfer pricing regime. The 2017 OECD Guidelines were already applicable under Ireland’s international tax treaties and therefore the introduction of these guidelines should only affect transactions with non-tax treaty countries. In addition to updating Irish tax law for the 2017 OECD Guidelines, these changes also extend the transfer pricing rules to certain non-trading transactions and to certain capital transactions. We have restructured certain intercompany arrangements, such that we do not expect there to be a material impact on our effective tax rate as a result of the introduction of these provisions.

On July 12, 2016, the Anti-Tax Avoidance Directive, or ATAD, was formally adopted by the Economic and Financial Affairs Council of the EU. The stated objective of the ATAD is to provide for the effective and swift coordinated implementation of anti-base erosion and profit shifting measures at EU level. Like all directives, the ATAD is binding as to the results it aims to achieve though EU Member States are free to choose the form and method of achieving those results. In addition, the ATAD contains a number of optional provisions that present an element of choice as to how it will be implemented into law. On December 25, 2018, the Finance Act 2018 was signed into Irish law, which introduced certain elements of the ATAD, such as the Controlled Foreign Company, or CFC, regime, into Irish law. The CFC regime became effective as of January 1, 2019. The ATAD also set out a high-level framework for the introduction of Anti-hybrid provisions. Finance Act 2019 introduced Anti-hybrid legislation in Ireland with effect from January 1, 2020. ~~We do not expect these legislative changes to have a material impact on our effective tax rate. The timing of the introduction into Irish tax law of~~It is anticipated that Finance Act 2021 will introduce further ATAD measures, such as the interest limitation rules ~~is unclear.~~and anti-hybrid rules to neutralize reverse-hybrid mismatches into Irish law with effect from January 1, 2022. Although it is difficult at this stage to determine with precision the impact that these remaining provisions will have, their implementation could materially increase our effective tax rate.

On December 22, 2017, U.S. federal income tax legislation was signed into law (H.R. 1, “An Act to provide for reconciliation pursuant to titles II and V of the concurrent resolution on the budget for fiscal year 2018”, informally titled the Tax Cuts and Jobs Act, or the Tax Act) that significantly revised the Code in the United States. The Tax Act, among other things, contained significant changes to corporate taxation, including reduction of the corporate tax rate from a top marginal rate of 35% to a flat rate of 21%, limitation of the tax deduction for interest expense to 30% of adjusted earnings (except for certain small businesses), implementation of a “base erosion anti-abuse tax” which requires U.S. corporations to make an alternative determination of taxable income without regard to tax deductions for certain payments to affiliates, taxation of certain non-U.S. corporations’ earnings considered to be “global intangible low taxed income”, or GILTI, repeal of the alternative minimum tax, or AMT, for corporations and changes to a taxpayer’s ability to either utilize or refund the AMT credits previously generated, changes to the limitation on deductions for certain executive compensation particularly with respect to the removal of the previously allowed performance based compensation exception, changes in the attribution rules relating to shareholders of certain “controlled foreign corporations”, limitation of the deduction for net operating losses to 80% of current year taxable income and elimination of net operating loss carrybacks, one-time taxation of offshore earnings at reduced rates regardless of whether they are repatriated, elimination of U.S. tax on foreign earnings (subject to certain important exceptions), immediate deductions for certain new investments instead of deductions for depreciation expense over time, and modifying or repealing many business deductions and credits. For example, U.S. federal income tax law resulting in additional taxes owed by U.S. shareholders under the GILTI rules, together with the Tax Act’s change to the attribution rules related to “controlled foreign corporations” may discourage U.S. investors from owning or acquiring 10% or greater of our outstanding ordinary shares, which other shareholders may have viewed as beneficial or may otherwise negatively impact the trading price of our ordinary shares.

On March 27, 2020, H.R.748, the Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act, was enacted in the United States, which provides temporary relief from certain aspects of the Tax Act that had imposed limitations on the utilization of certain losses, interest expense deductions, and the timing of refunds of alternative minimum tax credits.

On May 28, 2021, the U.S. Treasury released a 114-page general explanation of tax proposals included in President Joe Biden’s fiscal year 2022 budget submission to Congress, or Green Book. The Green Book includes various U.S. corporate tax proposals such as increasing the corporate U.S. federal tax rate from 21% to 28%, increasing the GILTI tax rate, replacing the Base Erosion and Anti-Abuse Tax, or BEAT, with a Stopping Harmful Inversions and Ending Low-tax Developments, or SHIELD, provision, repealing the deduction for foreign derived intangible income, or FDII, imposing a 15% minimum tax on corporations with book income above $2 billion and restricting deductions of excessive interest of members of financial reporting groups for disproportionate borrowing in the United States. If enacted, some of the proposed measures could materially increase our effective tax rate.

On October 8, 2021, 136 of the 140 members of the OECD/G20 Inclusive Framework on Base Erosion and Profit Shifting approved a statement providing a framework for reform of the international tax rules, or Inclusive Framework Statement. The Inclusive Framework Statement sets out the key terms for an agreement on a two-pillar solution to address the tax challenges arising from the digitalization of the economy. Pillar One focuses on nexus and profit allocation and Pillar Two provides for a global minimum corporate tax rate of 15 percent. The Inclusive Framework Statement provides that Pillar One would apply to multinational enterprises with annual global revenue above 20 billion euros and profitability above 10 percent, with the revenue threshold potentially reduced to 10 billion euros in the future. Based on these thresholds, we would currently be outside the scope of the Pillar One proposals. Although it is difficult at this stage to determine with precision the impact the Pillar Two proposals would have, their implementation could materially increase our effective tax rate.

We are unable to predict what tax laws may be proposed or enacted in the future or what effect such changes would have on our business. To the extent new tax laws are enacted, or new guidance released, this could have an adverse effect on our future effective tax rate. It could also lead to an increase in the complexity and cost of tax compliance. We urge our shareholders to consult with their legal and tax advisors with respect to the potential tax consequences of investing in or holding our ordinary shares.

If a United States person is treated as owning at least 10% of our ordinary shares, such holder may be subject to adverse U.S. federal income tax consequences.*

If a United States person is treated as owning (directly, indirectly, or constructively) at least 10% of the value or voting power of our ordinary shares, such person may be treated as a “United States shareholder” with respect to each “controlled foreign corporation” in our group (if any). Because our group includes one or more U.S. subsidiaries, certain of our non-U.S. subsidiaries could be treated as controlled foreign corporations (regardless of whether or not we are treated as a controlled foreign corporation). A United States shareholder of a controlled foreign corporation may be required to report annually and include in its U.S. taxable income its pro rata share of “Subpart F income,” “global intangible low-taxed income,” and investments in U.S. property by controlled foreign corporations, regardless of whether we make any distributions. An individual that is a United States shareholder with respect to a controlled foreign corporation generally would not be allowed certain tax deductions or foreign tax credits that would be allowed to a U.S. corporation that is a United States shareholder with respect to a controlled foreign corporation. Failure to comply with these reporting and tax paying obligations may subject a United States shareholder to significant monetary penalties and may prevent the statute of limitations from starting with respect to such shareholder’s U.S. federal income tax return for the year for which reporting was due. We cannot provide any assurances that we will assist investors in determining whether any of our non-U.S. subsidiaries is treated as a controlled foreign corporation or whether any investor is treated as a United States shareholder with respect to any such controlled foreign corporation or furnish to any United States shareholders information that may be necessary to comply with the aforementioned reporting and tax paying obligations. A United States investor should consult its advisors regarding the potential application of these rules to an investment in our ordinary shares.

If we are not successful in attracting and retaining highly qualified personnel, we may not be able to successfully implement our business strategy.*

Our ability to compete in the highly competitive biotechnology and pharmaceuticals industries depends upon our ability to attract and retain highly qualified managerial, manufacturing, scientific and medical personnel. We are highly dependent on our management, sales and marketing and scientific and medical personnel, including our executive officers. In order to retain valuable employees at our company, in addition to salary and annual cash incentives, we provide a mix of performance stock units, or PSUs, that vest subject to attainment of specified corporate performance goals and continued services, stock options and restricted stock units, or RSUs, that vest over time subject to continued services. The value to employees of PSUs, stock options and RSUs will be significantly affected by movements in our share price that are beyond our control, and may at any time be insufficient to counteract more lucrative offers from other companies.

Despite our efforts to retain valuable employees, members of our management, sales and marketing, regulatory affairs, clinical development, medical affairs, development and ~~development~~manufacturing teams may terminate their employment with us on short notice. Although we have written employment arrangements with all of our employees, these employment arrangements generally provide for at-will employment, which means that our employees can leave our employment at any time, with or without notice. The loss of the services of any of our executive officers or other key employees and our inability to find suitable replacements could potentially harm our business, financial condition and prospects. We do not maintain “key man” insurance policies on the lives of these individuals or the lives of any of our other employees. Our success also depends on our ability to continue to attract, retain and motivate highly skilled junior, mid-level, and senior managers as well as junior, mid-level, and senior sales and marketing, ~~and~~manufacturing, scientific and medical personnel.

Many of the other biotechnology and pharmaceutical companies with whom we compete for qualified personnel have greater financial and other resources, different risk profiles and longer histories in the industry than we do. They also may provide more diverse opportunities and better chances for career advancement. Some of these characteristics may be more appealing to high quality candidates than that which we have to offer. If we are unable to continue to attract and retain high quality personnel, the rate and success at which we can develop and commercialize medicines and medicine candidates will be limited.

We are ~~with respect to our current medicines, and will be, with respect to any other medicine or medicine candidate for which we obtain FDA or EMA approval or which we acquire,~~ subject to ongoing ~~FDA or EMA~~ obligations and continued regulatory review by the FDA and equivalent foreign regulatory agencies, which may result in significant additional ~~expense. Additionally, any other medicine candidate, if approved by the FDA or EMA, could be subject to labeling~~expense and ~~other restrictions and market withdrawal, and we may be subject to~~ significant penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our medicines.*

Any regulatory approvals that we obtain for our medicine candidates may also be subject to limitations on the approved indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including Phase 4 clinical trials and surveillance to monitor the safety and efficacy of the medicine candidate. In addition, with respect to our current FDA-approved medicines (and with respect to our medicine candidates, if approved), the manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion and recordkeeping for the medicine are subject to extensive and ongoing regulatory requirements. These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with cGMPs, GCPs, International Council for Harmonisation, or ICH, guidelines and GLPs, which are regulations and guidelines enforced by the FDA for all of our medicines in clinical development, for any clinical trials that we conduct post-approval.

In addition, the FDA closely regulates the marketing and promotion of drugs and biologics. The FDA does not regulate the ~~behaviour~~behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturers’ promotional communications. A significant number of pharmaceutical companies have been the target of inquiries and investigations by various U.S. federal and state regulatory, investigative, prosecutorial and administrative entities in connection with the promotion of medicines for off-label uses and other sales practices. These investigations have alleged violations of various U.S. federal and state laws and regulations, including claims asserting antitrust violations, violations of the Food, Drug and Cosmetic Act, or FDCA, false claims laws, the Prescription Drug Marketing Act, anti-kickback laws, and other alleged violations in connection with the promotion of medicines for unapproved uses, pricing and Medicare and/or Medicaid reimbursement.

Later discovery of previously unknown problems with a medicine, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things:

If we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained and we may not sustain profitability, which would have a material adverse effect on our business, results of operations, financial condition and prospects.

We are subject to federal, state and foreign healthcare laws and regulations and implementation or changes to such healthcare laws and regulations could adversely affect our business and results of operations.*

The United States and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals ~~to regulate and to~~that change the healthcare system in ways that could ~~affect our ability to sell our medicines profitably.~~impact profitability. In the United States and ~~elsewhere,~~abroad there is significant interest in ~~promoting changes in healthcare systems~~implementing regulations and legislation with the stated goals of containing healthcare costs, ~~(including a number of proposals pertaining to prescription drugs, specifically),~~ improving quality, and/or expanding access. ~~In the United States, the~~The pharmaceutical industry has been a ~~particular~~ focus of these efforts and has been significantly affected by major legislative ~~initiatives.~~initiatives, particularly in the United States.

The healthcare system is highly regulated in the United States and, as a ~~biopharma~~biotech company that participates in government-regulated healthcare programs, we are subject to complex laws and regulations. ~~If we are found to be in violation of any~~Violation of these laws, or any other federal or state regulations, we may be subject us to significant administrative, civil and/or criminal penalties, damages, disgorgement, fines, exclusion, imprisonment, additional reporting requirements, and/or oversight from federal health care programs ~~and~~that could require the restructuring of our operations. Any of these could have a material adverse effect on our business and financial results. Any action against us for violation of these laws, even if we ultimately are successful in our defense, will cause us to incur significant legal expenses and divert our management’s attention away from the operation of our business.

There ~~remain judicial and Congressional challenges to certain aspects of the ACA, as well as~~were efforts by the Trump administration as well as Congressional and judicial actions taken to ~~repeal~~replace or ~~replace~~weaken certain aspects of the ACA. ~~Since January 2017,~~For example, President Trump ~~has~~ signed several ~~Executive Orders~~executive orders and other directives designed to eliminate, delay or otherwise modify the implementation of certain provisions of the ACA. Concurrently, Congress ~~has~~ considered legislation that would repeal and/or ~~repeal and~~ replace all or part of the ACA. While Congress has not passed comprehensive repeal legislation, it has enacted laws that modify certain provisions of the ~~ACA such as removing penalties, starting~~ACA. For example, the Tax Act included a provision which decreased, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA to $0. Commonly referred to as the “individual mandate,” this provision imposed a fine on certain individuals who fail to maintain qualifying health coverage for ~~not complying with~~all or part of the ~~ACA’s individual mandate to carry health insurance, and eliminating the implementation of certain ACA-mandated fees, and increasing~~year. In addition, Congress increased the manufacturer coverage gap discount that is owed by pharmaceutical manufacturers of branded drugs and biosimilars who participate in Medicare Part ~~D. In particular, the Tax Act included a provision,~~D from 50% to 70%, effective January 1, ~~2019, which decreased~~2019.

Challenges to ~~zero the tax-based shared responsibility payment imposed by~~ the ACA have also taken place in courts, including the U.S. Supreme Court. For example, on ~~certain individuals who fail to maintain qualifying health coverage for all or part of~~June 17, 2021 the U.S. Supreme Court dismissed a ~~year~~challenge on procedural grounds that is commonly referred to as the “individual mandate”. In addition, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminates the health insurer tax. On December 14, 2018, a Texas U.S. District Court Judge ruled thatargued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by ~~Congress as part of~~Congress. Thus, the ~~Tax Act. Additionally, on December 18, 2019,~~ACA will remain in effect in its current form. Further, prior to the U.S. ~~Court of Appeals for the 5th Circuit upheld the District~~Supreme Court ruling on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace, which began on February 15, 2021 and remained open through August 15, 2021. The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. It is possible that the ~~individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the~~ ACA ~~are invalid as well. On March 2, 2020, the United States Supreme Court granted the petitions for writs of certiorari to review this case, which~~ will be ~~heard on November 10, 2020.~~subject to judicial or Congressional challenges in the future. It is unclear how any such ~~litigation~~challenges and ~~other efforts to repeal and replace~~ the ~~ACA~~healthcare reform measures of the Biden administration will impact the ~~ACA~~ACA’s many different provisions affecting the health system, the pharmaceutical sector and our business.

~~Likewise,~~In addition, drug pricing by pharmaceutical companies in the United States has come under increased scrutiny. Specifically, there have been several recent state and U.S. congressional inquiries into pricing practices by pharmaceutical companies.

In 2020, the Trump Administration advanced its agenda on drug pricing through a series of executive orders. For example, on July 24, 2020, President Trump announced several executive orders related to prescription drug pricing that attempt to implement several of the Trump Administration proposals, including a policy that would tie both Medicare Part B and Part D drug prices to international drug prices, or the “most favored nation price,” the details of which were released on September 13, 2020; one that directed HHS to finalize the Canadian drug importation proposed rule previously issued by HHS and makes other changes allowing for personal importation of drugs from Canada; one that directed HHS to finalize the rulemaking process on modifying the anti-kickback law safe harbors for plans, pharmacies, and PBMs, commonly known as the “rebate rule”; and one that reduced the cost of insulin and injectable epinephrine to patients acquired through the 340B program. Further, on August 6, 2020, the Trump administration issued another executive order that instructed the federal government to develop a list of “essential” medicines and then buy them and other medical supplies from U.S. manufacturers instead of from companies around the world. The order was meant to reduce regulatory barriers to domestic pharmaceutical manufacturing and catalyze manufacturing technologies needed to keep drug prices low and the production of drug products in the United States. The FDA issued the list of “essential” medicines pursuant to this order on October 30, 2020.

In November 2020, CMS issued an interim final rule, or IFR, implementing the Most Favored Nation, or MFN, Model basing Medicare Part B reimbursement rates for the top fifty drugs covered by Part B based to the lowest price drug manufacturers receive in OECD countries with a similar gross domestic product per capita. The MFN Model mandates participation for providers prescribing drugs included on the list and will apply in all U.S. states and territories for a seven-year period that was scheduled to begin on January 1, 2021 and end December 31, 2027. As a result of litigation challenging the Most Favored Nation model, on August 10, 2021, CMS published a proposed rule that seeks to rescind the MFN Model IFR. The FDA released a final rule implementing a portion of the importation executive order providing guidance for states to build and submit importation plans. Several states have acted to implement importation plans or have introduced legislation to do so. FDA also finalized guidance for manufacturers to obtain an additional National Drug Code for an FDA-approved drug as part of a process to provide a manufacturer a means to import its drugs that were originally intended to be marketed in and authorized for sale in a foreign country. In addition, HHS and FDA are in the process of accepting industry proposals to facilitate personal importation of prescription drugs. On November 20, 2020, HHS also finalized the “rebate rule” regulation by removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through PBMs, unless the price reduction is required by law. The implementation of the rule has been delayed by the Biden Administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between PBMs, the implementation of which have also been delayed until January 1, 2023.

In July 2021, the Biden Administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In the order, the President directed the Federal Trade Commission (FTC) to ban “pay for delay” patent settlement agreements, and to identify and address any efforts that impede generic or biosimilar competition. The executive order also directed the FDA to continue to work with states and Indian Tribes to develop importation programs in accordance with Section 804 of the FDCA and FDA regulations. The order directed HHS to increase support for generic and biosimilar drugs by improving standards for the interchangeability of biologic products, supporting biosimilar adoption by increasing education, and facilitating the approval of biosimilars by updating and clarifying existing requirements and procedures related to biologics licensing. Finally, the executive order directs HHS to submit a report detailing a comprehensive plan within 45 days to fight high prescription drug prices and reduce the amount that the federal government pays for drugs. In response to President Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform. These principles are government drug price negotiations, promoting increased competition including changes to supply chains and promoting biosimilars and generics and supporting public and private research. The plan sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles. No legislation or administrative actions have been finalized to implement the principles.

Congress continued to seek new legislative and/or administrative measures to control drug costs. For example, in April 2021, the U.S. House of Representatives re-introduced the “Elijah E. Cummings Lower Drugs Costs Now Act”, or H.R. 3, that, among other things, empowers HHS to negotiate prices for certain drugs and utilize international price referencing metrics for drugs that are considered high-cost or are reimbursable by both Medicare Part D and Part B, while giving commercial payers, including employer and individual market plans, access to the reference price.

The legislation also contains provisions that would implement a cap on annual price increases for certain drugs covered under Medicare at the rate of inflation or require the respective manufacturers to pay a rebate, and includes a re-design of the Medicare Part D program. Further, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024. Finally, Congress is considering drug pricing as part of legislation to implement the Biden Administration’s Build Back Better initiative. This legislationincludes physical and “human” infrastructure improvement proposals and would use drug pricing reform as a budgetary “pay for.” This legislation is using the budget conciliation process which requires a majority vote to pass the House and Senate. At present, the legislation has not received votes in either chamber. If it were to pass, it could impact the prices of drugs covered by Medicare.

In countries in the EU, legislators, policymakers, and healthcare insurance funds continue to propose and implement cost-containing measures to keep healthcare costs down, due in part to the attention being paid to healthcare cost containment in the EU. Certain of these changes could impose limitations on the prices we will be able to charge for our ~~products~~medicines and any approved ~~product~~medicine candidates or the amounts of reimbursement available for these products from governmental agencies or third-party payers, may increase the tax obligations on pharmaceutical companies such as ours, or may facilitate the introduction of generic competition with respect to our products.

In addition, drug pricing by pharmaceutical companies in the United States has come under increased scrutiny. Specifically, there have been several recent state and U.S. congressional inquiries, proposed federal and state legislation and state laws enacted to, among other things, bring more transparency to drug pricing by requiring drug companies subject to these laws to notify insurers and government regulators of price increases and provide an explanation of the reasons for the increases, reduce the out-of-pocket cost of prescription drugs, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement methodologies. This scrutiny has resulted in several recent congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products. For example, legislation signed into law in 2017 in California requires drug manufactures to provide advance notice and explanation to state regulators, health plans and insurers and PBMs for price increases of more than 16% over two years, or 10% within one year. In addition, a further twelve states have enacted similar drug pricing transparency laws. At the federal level, the President’s budget proposal for the fiscal year 2021 includes a $135 billion allowance to support legislative proposals seeking to reduce drug prices, increase competition, lower out-of-pocket drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs. On March 10, 2020, the Trump administration sent “principles” for drug pricing to Congress, calling for legislation that would, among other things, cap Medicare Part D beneficiary out-of-pocket pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket expenses, and place limits on pharmaceutical price increases. These principles build upon the Trump administration’s previously released “Blueprint to Lower Drug Prices and Reduce Out-of-Pocket Costs”, or Blueprint. The Blueprint contained several potential regulatory actions and legislative recommendations aimed at lowering prescription drug prices including measures to promote innovation and competition for biologics, changes to Medicare Part D to give plan sponsors more leverage when negotiating prices with manufacturers and updating the Medicare drug-pricing dashboard to make price increases and generic competition more transparent. HHS has solicited feedback on some of these measures and has implemented others under its existing authority. For example, in June 2020, the U.S. House of Representatives passed a bill, H.R. 1425, “Patient Protection and Affordable Care Advancement Act”, which proposes to implement a “Fair Price Negotiation Program” to utilize international price referencing metrics for certain drugs that are considered high-cost or are reimbursable by Medicare, while giving commercial payers, including employer and individual market plans, access to the reference price. The California legislature took a similar step in the 2020 budget, directing the California Health and Human Services Agency to develop a process to use international reference pricing for Medicaid drugs. Additionally, on July 24, 2020, President Trump announced four executive orders related to prescription drug pricing that attempt to implement several of the Trump administration proposals, including a policy that would tie Medicare Part B and Part D drug prices to international drug prices, or the price of a “most favored nation”; one that directs HHS to finalize the Canadian drug importation proposed rule previously issued by HHS and makes other changes allowing for personal importation of drugs from Canada; one that directs HHS to finalize the rulemaking process on modifying the anti-kickback law safe harbors for plans, pharmacies, and PBMs, commonly known as the “rebate rule”; and one that reduces costs of insulin and injectable epinephrine to patients of federally qualified health centers. On September 13, 2020, the Trump administration released an executive order revoking the July 24, 2020, “most favored nations” executive order and directing CMS to develop demonstration projects that would apply “most favored nations” pricing to drugs in both Medicare Parts B and D. The FDA released a final rule, effective November 30, 2020, implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs from Canada. Several states have acted to implement importation plans or have introduced legislation to do so. FDA also finalized guidance for manufacturers to obtain an additional National Drug Code, or NDC, for an FDA-approved drug as part of a process to provide a manufacturer a means to import its drugs that were originally intended to be marketed in and authorized for sale in a foreign country. In addition, HHS and FDA are in the process of accepting industry proposals to facilitate personal importation of prescription drugs. The Trump administration has yet to implement or release proposed rules on either the Medicare “most favored nations” policy or the “rebate rule.” Congress and the Trump Administration have both stated that they will continue to seek new legislative and/or administrative measures to control drug costs. In addition, Presidential candidate Biden’s campaign has recently indicated that if candidate Biden is elected, he would direct Medicare to negotiate drug prices using international prices as a reference.

In May 2019, CMS continued to implement proposals from the administration’s Blueprint by issuing a final rule to allow Medicare Advantage plans the option to use step therapy for Part B drugs beginning January 1, 2020. This final rule codified CMS’s policy change that was effective January 1, 2019. In addition, certain governmental initiatives, if enacted by Congress and HHS, could lead to changes to Medicare Parts B and D. Further, the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”. The majority of our medicines are purchased by private payers, and much of the focus of pending legislation is on government program reimbursement. In December 2019, the Further Consolidated Appropriations Act was signed into law which included the Creating and Restoring Equal Access to Equivalent Samples Act, or CREATES Act. The CREATES Act allows generic drug manufacturers to bring suit against a brand name manufacturer to compel the provision of brand samples if the generic manufacturer has made a request for samples and the brand manufacturer fails to deliver sufficient quantities of the sample on commercially reasonable, market-based terms within 31 days of receipt of the request. The United States Senate has also renewed interest in drug pricing legislation that redesigns Medicare Part D and makes changes to Medicare Part B and Medicaid. Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs. Additionally, it is possible that additional governmental action is taken to address the COVID-19 pandemic. For example, on August 6, 2020, the Trump administration issued another executive order that instructs the federal government to develop a list of “essential” medicines and then buy them and other medical supplies from U.S. manufacturers instead of from companies around the world, including China. The order is meant to reduce regulatory barriers to domestic pharmaceutical manufacturing and support manufacturing technologies needed to keep drug prices low and the production of drug products in the United States. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our current medicines and/or those for which we may receive regulatory approval in the future.

We are subject, directly or indirectly, to federal and state healthcare fraud and abuse, transparency laws and false claims laws. Prosecutions under such laws have increased in recent years and we may become subject to such litigation. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties.*

In the United States, we are subject directly, or indirectly or through our customers and other third parties, to various state and federal fraud and abuse and transparency laws, including, without limitation, the federal Anti-Kickback Statute, the federal False Claims Act, ~~civil monetary penalty statutes~~the Civil Monetary Penalties Law prohibiting, among other things, beneficiary inducements, and similar state and local laws, federal and state privacy and security laws, such as the Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act, sunshine laws, government price reporting laws, and other fraud laws. Some states, such as Massachusetts, make certain reported information public. In addition, there are state and local laws that require pharmaceutical representatives to be licensed and comply with codes of conduct, transparency reporting, and other obligations. Collectively, these laws may affect, among other things, our current and proposed research, sales, marketing and educational programs, as well as other possible relationships with customers, pharmacies, physicians, payers, and patients. We are subject to similar laws in the EU/~~European Economic Area,~~EEA, including the EU General Data Protection Regulation (2016/679), or GDPR, under which fines of up to €20.0 million or up to 4% of the annual global ~~turnover~~revenue of the infringer, whichever is greater, could be imposed for significant non-compliance.

Compliance with these laws, including the development of a comprehensive compliance program, is difficult, costly and time consuming. Because of the breadth of these laws and the narrowness of available statutory and regulatory exemptions, it is possible that some of our business activities could be subject to challenge under one or more of such laws. Moreover, state governmental agencies may propose or enact laws and regulations that extend or contradict federal requirements. These risks may be increased where there are evolving interpretations of applicable regulatory requirements, such as those applicable to manufacturer co-pay programs. Pharmaceutical manufacturer co-pay programs, including pharmaceutical manufacturer donations to patient assistance programs offered by charitable foundations, are the subject of ongoing litigation, enforcement actions and settlements (involving other manufacturers and to which we are not a party) and evolving interpretations of applicable regulatory requirements and certain state laws, and any change in the regulatory or enforcement environment regarding such programs could impact our ability to offer such programs. Other recent legislation and regulatory policies contain provisions that disincentivizes the use of co-pay coupons by requiring their value to be included in average sales price or best price calculations, potentially lowering reimbursement for drugs with a high use of copay coupons in Medicare Part B and Medicaid. If we are unsuccessful with our co-pay programs, we would be at a competitive disadvantage in terms of pricing versus preferred branded and generic competitors, or be subject to significant penalties. We are engaged in various business arrangements with current and potential customers, and we can give no assurance that such arrangements would not be subject to scrutiny under such laws, despite our efforts to properly structure such arrangements. Even if we structure our programs with the intent of compliance with such laws, there can be no certainty that we would not need to defend our business activities against enforcement or litigation. Further, we cannot give any assurances that prior business activities or arrangements of other companies that we acquire will not be scrutinized or subject to enforcement or litigation. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have an impact on our business, including the imposition of significant civil, criminal and administrative sanctions, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, imprisonment, integrity oversight and reporting obligations, contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

There has also been a trend of increased federal and state regulation of payments made to physicians and other healthcare providers. The ACA, among other things, imposed reporting requirements on drug manufacturers for payments made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians, ~~as well as~~defined to include doctors, dentists, podiatrists, optometrists and licensed chiropractors, and their immediate family members. Beginning in 2022, applicable manufacturers also will be required to report such information regarding payments and transfers of value provided ~~as well as ownership and investment interests held,~~ during the previous year to include physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives. Failure to submit required information may result in significant civil monetary penalties.

On March 5, 2019, we received a civil investigative demand, or CID, from the DOJ pursuant to the Federal False Claims Act regarding assertions that certain of our payments to PBMs were potentially in violation of the Anti-Kickback Statute. The CID requests certain documents and information related to our payments to PBMs, pricing and our patient assistance program regarding DUEXIS, VIMOVO and PENNSAID 2%. We are cooperating with the investigation. While we believe that our payments and programs are compliant with the Anti-Kickback Statute, no assurance can be given as to the timing or outcome of the DOJ’s investigation, or that it will not result in a material adverse effect on our business.

We are unable to predict whether we could be subject to other actions under any of these or other healthcare laws, or the impact of such actions. If we are found to be in violation of, or to ~~encourage~~have encouraged or ~~assist~~assisted the violation by third parties of any of the laws described above or other applicable state and federal fraud and abuse laws, we may be subject to penalties, including significant administrative, civil and criminal penalties, damages, fines, withdrawal of regulatory approval, imprisonment, exclusion from government healthcare reimbursement programs, contractual damages, reputational harm, diminished profits and future earnings, injunctions and other associated remedies, or private “qui tam” actions brought by individual whistleblowers in the name of the government, and the curtailment or restructuring of our operations, all of which could have a material adverse effect on our business and results of operations. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.

Our medicines or any other medicine candidate that we develop may cause undesirable side effects or have other properties that could delay or prevent regulatory approval or commercialization, result in medicine re-labeling or withdrawal from the market or have a significant impact on customer demand.*

Undesirable side effects caused by any medicine candidate that we develop could result in the denial of regulatory approval by the FDA or other regulatory authorities for any or all targeted indications, or cause us to evaluate the future of our development programs. In our Phase 3 clinical trial evaluating TEPEZZA for the treatment of active TED, the most commonly reported treatment-emergent adverse events were muscle spasms, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dysgeusia, headache and dry skin. With respect to KRYSTEXXA, the most commonly reported serious adverse reactions in the pivotal trial were gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis, exacerbation of pre-existing congestive heart failure and vomiting. With respect to RAVICTI, the most common side effects are diarrhea, nausea, decreased appetite, gas, vomiting, high blood levels of ammonia, headache, tiredness and dizziness. The most common side effects observed in pivotal trials for ACTIMMUNE were “flu-like” or constitutional symptoms such as fever, headache, chills, myalgia and fatigue. With respect to UPLIZNA, the most common adverse reactions across both the randomized and open-label treatment in our N-MOmentum trial for UPLIZNA were urinary tract infection, nasopharyngitis, infusion reaction, arthralgia and headache. The most common infections reported by treated patients in the randomized and open-label periods included urinary tract infection, nasopharyngitis, upper respiratory tract infection and influenza. In addition, two deaths were reported in the ongoing open-label period. One death occurred in a patient experiencing a myelitis attack and was considered unrelated to UPLIZNA by the investigator. The second death was due to complications from mechanical ventilator-associated pneumonia in a patient who developed new neurological symptoms and seizures, the cause of which could not be definitively established. The possibility that the death was treatment-related could not be ruled out, and as a result, under the terms of the protocol for the trial, the death was assessed as treatment-related. There can be no assurance a foreign regulatory authority will agree with the classifications of the deaths made by the investigators or that we will not be required to conduct additional clinical trials of UPLIZNA in order to establish an adequate safety database. With respect to PROCYSBI, the most common side effects include vomiting, nausea, abdominal pain, breath odor, diarrhea, skin odor, fatigue, rash and headache. The most common adverse events reported in a Phase 2 clinical trial of PENNSAID 2% were application site reactions, such as dryness, exfoliation, erythema, pruritus, pain, induration, rash and scabbing. With respect to PROCYSBI, the most common side effects include vomiting, nausea, abdominal pain, breath odor, diarrhea, skin odor, fatigue, rash and headache. In our two Phase 3 clinical trials with DUEXIS, the most commonly reported treatment-emergent adverse events were nausea, dyspepsia, diarrhea, constipation and upper respiratory tract infection. The most common side effects observed in pivotal trials for ACTIMMUNE were “flu-like” or constitutional symptoms such as fever, headache, chills, myalgia and fatigue. The most commonly reported treatment-emergent adverse events in the Phase 3 clinical trials with RAYOS included flare in rheumatoid arthritis related symptoms, abdominal pain, nasopharyngitis, headache, flushing, upper respiratory tract infection, back pain and weight gain.

The FDA or other regulatory authorities may also require, or we may undertake, additional clinical trials to support the safety profile of our medicines or medicine candidates.

In addition, if we or others identify undesirable side effects caused by our medicines or any other medicine candidate that we may develop that receives marketing approval, or if there is a perception that the medicine is associated with undesirable side effects:

If any of these events occurred with respect to our medicines, our ability to generate significant revenues from the sale of these medicines would be significantly harmed.

We rely on third parties to conduct our pre-clinical and clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines or if they experience regulatory compliance issues, we may not be able to obtain regulatory approval for or commercialize our medicine candidates and our business could be substantially harmed.*

We have agreements with third-party contract research organizations, or CROs, to conduct our clinical programs, including those required for post-marketing commitments, and we expect to continue to rely on CROs for the completion of on-going and planned clinical trials. We may also have the need to enter into other such agreements in the future if we were to develop other medicine candidates or conduct clinical trials in additional indications for our existing medicines. We also rely heavily on these parties for the execution of our clinical studies and control only certain aspects of their activities. Nevertheless, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol. We, our CROs and our academic research organizations are required to comply with current GCP or ICH regulations. The FDA, ~~enforces~~and regulatory authorities in other jurisdictions, enforce these GCP or ICH regulations through periodic inspections of trial sponsors, principal investigators and trial sites. If we or our CROs or collaborators fail to comply with applicable GCP or ICH regulations, the data generated in our clinical trials may be deemed unreliable and our submission of marketing applications may be delayed or the FDA, or such other regulatory authorities, may require us to perform additional clinical trials before approving our marketing applications. We cannot assure that, upon inspection, the FDA, or such other regulatory authorities, will determine that any of our clinical trials comply or complied with GCP or ICH regulations. In addition, our clinical trials must be conducted with medicine produced under cGMP regulations, and may require a large number of test subjects. Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process. Moreover, our business may be implicated if any of our CROs or collaborators violates federal or state fraud and abuse or false claims laws and regulations or privacy and security laws. We must also obtain certain third-party institutional review board, or IRB, and ethics committee approvals in order to conduct our clinical trials. Delays by IRBs and ethics committees in providing such approvals may delay our clinical trials.

If any of our relationships with these third-party CROs or collaborators terminate, we may not be able to enter into similar arrangements on commercially reasonable terms, or at all. If CROs or collaborators do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements or for other reasons, our clinical trials may be extended, delayed or terminated and we may not be able to obtain regulatory approval for or successfully commercialize our medicines and medicine candidates. As a result, our results of operations and the commercial prospects for our medicines and medicine candidates would be harmed, our costs could increase and our ability to generate revenues could be delayed.

Switching or adding additional CROs or collaborators can involve substantial cost and require extensive management time and focus. In addition, there is a natural transition period when a new CRO or collaborator commences work. As a result, delays may occur, which can materially impact our ability to meet our desired clinical development timelines. Though we carefully manage our relationships with our CROs and collaborators, there can be no assurance that we will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition or prospects. In particular, the ability of our CROs to conduct certain of their operations, including monitoring of clinical sites, has been limited by the COVID-19 pandemic, and to the extent that our CROs are unable to fulfil their contractual obligations as a result of the COVID-19 pandemic or government orders in response to the pandemic, we may have limited or no recourse under the terms of our contractual agreements with our CROs.

Clinical development of drugs and biologics involves a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results.*

Clinical testing is expensive and can take many years to complete, and its outcome is uncertain. Failure can occur at any time during the clinical trial process. The results of pre-clinical studies and early clinical trials of potential medicine candidates may not be predictive of the results of later-stage clinical trials. Medicine candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through pre-clinical studies and initial clinical testing. For example, in December 2016, we announced that the Phase 3 trial, Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s ataxia, evaluating ACTIMMUNE for the treatment of Friedreich’s ataxia did not meet its primary endpoint. Additionally, we discontinued our ACTIMMUNE investigator-initiated trials in oncology to focus on our strategic pipeline where we see more promise and long-term intellectual ~~property.~~property protection.

In some instances, there can be significant variability in safety and efficacy results between different clinical trials of the same medicine candidate due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, differences in and adherence to the dosing regimen and other trial protocols and the rate of dropout among clinical trial participants. Various pipeline programs among our current pipeline are subject to this risk; for example, in a Phase 1b clinical trial, Viela observed that dazodalibep (HZN-4920) decreased disease activity in patients with rheumatoid arthritis. Viela subsequently initiated a Phase 2 clinical trial for dazodalibep (HZN-4920) in patients with rheumatoid arthritis, a separate Phase 2b clinical trial for dazodalibep (HZN-4920) in Sjögren’s syndrome and a separate Phase 2 clinical trial for dazodalibep (HZN-4920) in kidney transplant rejection, which clinical trials we have assumed and are conducting. There is no assurance that dazodalibep (HZN-4920) will have a similar impact on disease activity in such clinical trials.

We may experience delays in clinical trials or investigator-initiated studies. We do not know whether any additional clinical trials will be initiated in the future, begin on time, need to be redesigned, enroll patients on time or be completed on schedule, if at all. Clinical trials can be delayed for a variety of reasons, including delays related to:

Our clinical trials may also be affected by COVID-19. ~~Clinical~~For example, our post-marketing clinical trials for TEPEZZA have been delayed due to the impact of the TEPEZZA supply disruption at Catalent. In addition, clinical site initiation and patient enrollment may be delayed due to prioritization of hospital and healthcare resources toward ~~COVID-19.~~ COVID-19 or its variants. Current or potential patients in our ongoing or planned clinical trials may also choose to not enroll, not participate in follow-up clinical visits or drop out of the trial as a precaution against contracting ~~COVID-19~~.COVID-19. Further, some patients may not be able or willing to comply with clinical trial protocols if quarantines impede patient movement or interrupt healthcare services. Some clinical sites in the United States have slowed or stopped further enrollment of new patients in clinical trials, denied access to site monitors or otherwise curtailed certain operations. Similarly, our ability to recruit and retain principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19, may be adversely impacted. The availability of supplies needed for the conduct of clinical trials may be impacted by COVID-19 supply disruptions, including laboratory tubes needed for lab testing. These events could delay our clinical trials, increase the cost of completing our clinical trials and negatively impact the integrity, reliability or robustness of the data from our clinical trials.

Patient enrollment, a significant factor in the timing of clinical trials, is affected by many factors including the size and nature of the patient population, the proximity of patients to clinical sites, the eligibility criteria for the trial, the design of the clinical trial, competing clinical trials and clinicians’ and patients’ perceptions as to the potential advantages of the medicine candidate being studied in relation to other available therapies, including any new drugs or biologics that may be approved for the indications we are investigating. In addition, if patients drop out of our trials, miss scheduled doses or follow-up visits or otherwise fail to follow trial protocols, or if our trials are otherwise disputed due to COVID-19 or actions taken to slow its spread, the integrity of data from our trials may be compromised or not accepted by the FDA or other regulatory authorities, which would represent a significant setback for the applicable program.

We could encounter delays if prescribing physicians encounter unresolved ethical issues associated with enrolling patients in clinical trials of our medicine candidates in lieu of prescribing existing treatments that have established safety and efficacy profiles. Further, a clinical trial may be suspended or terminated by us, our collaborators, the FDA or other regulatory authorities due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a medicine candidate, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. If we experience delays in the completion of, or if we terminate, any clinical trial of our medicine candidates, the commercial prospects of our medicine candidates will be harmed, and our ability to generate medicine revenues from any of these medicine candidates will be ~~delayed.~~delayed or reduced. In addition, any delays in completing our clinical trials will increase our costs, slow down our medicine development and approval process and jeopardize our ability to commence medicine sales and generate revenues.

Moreover, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services. Under certain circumstances, we may be required to report some of these relationships to the FDA. The FDA may conclude that a financial relationship between us and a principal investigator has created a conflict of interest or otherwise affected interpretation of the study. The FDA may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA and may ultimately lead to the denial of marketing approval of one or more of our medicine candidates.

Any of these occurrences may harm our business, financial condition, results of operations and prospects significantly. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our medicine candidates.

The sizes of the patient populations suffering from some of the diseases we are targeting are small and based on estimates that may not be accurate.*

Because certain of our clinical trials are focused on indications with small patient populations, our ability to enroll eligible patients may be limited or may result in slower enrollment than we anticipate. In addition, our projections of both the number of people who have some of the diseases we are targeting, as well as the subset of people with these diseases who have the potential to benefit from treatment with our medicines and any of our future medicine candidates, are estimates. These estimates have been derived from a variety of sources, including scientific literature, surveys of clinics, physician interviews, patient foundations and market research, and may prove to be incorrect. Further, new studies may change the estimated incidence or prevalence of these diseases. The number of patients may turn out to be lower than expected. Additionally, the potentially addressable patient population for our medicines and any future medicine candidates may be limited or may not be amenable to treatment with our medicines and any of our medicine candidates, if and when approved. Even if we obtain significant market share for our medicines and any of our medicine candidates (if and when they are approved), small potential target populations for certain indications means we may never achieve profitability without obtaining market approval for additional indications.

Business interruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.*

Our operations could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics or health pandemics, such as the current COVID-19 pandemic, and other natural or man-made disasters or business interruptions. While we carry insurance for certain of these events and have implemented disaster management plans and contingencies, the occurrence of any of these business interruptions could seriously harm our business and financial condition and increase our costs and expenses. We conduct significant management operations at both our global headquarters located in Dublin, Ireland and our U.S. office located in ~~Lake Forest,~~Deerfield, Illinois. If our Dublin or ~~Lake Forest~~Deerfield offices were affected by a natural or man-made disaster or other business interruption, our ability to manage our domestic and foreign operations could be impaired, which could materially and adversely affect our results of operations and financial condition. We currently rely, and intend to rely in the future, on third-party manufacturers and suppliers to produce our medicines and third-party logistics partners to ship our medicines. Our ability to obtain commercial supplies of our medicines could be disrupted and our results of operations and financial condition could be materially and adversely affected if the operations of these third-party suppliers or logistics partners were affected by a man-made or natural disaster or other business interruption. The ultimate impact of such events on us, our significant suppliers and our general infrastructure is unknown.

We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.*

We generate and store sensitive data, including research data, intellectual property, personal data, and proprietary business information owned or controlled by ourselves or our employees, partners and other parties. We manage and maintain our applications and data utilizing a combination of our own on-site systems and third-party information technology systems, including cloud-based data ~~centers.~~centers and mobile technology infrastructure, both operated by third parties. We are dependent upon such systems, infrastructure and data ~~including mobile technologies,~~ to operate our business. The multitude and complexity of our computer systems ~~may make~~and those of our third-party service providers makes them vulnerable to service interruption or destruction, disruption of data integrity, inadvertent ~~errors~~actions or inactions that expose our data or systems, malicious intrusion, or random attacks. Likewise, data privacy or security incidents or breaches caused by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized persons or to the public. ~~Cyberattacks~~Cyber incidents that cause such incidents are increasing in their frequency, sophistication and intensity.

~~Cyberattacks~~Cyber incidents could include the deployment of harmful malware, ransomware, denial-of-service, supply chain attacks, social engineering and other means to exploit our systems and affect service reliability and threaten data confidentiality, integrity and availability. Changes in how our employees work and access our systems during the ~~current~~ COVID-19 pandemic could lead to additional opportunities for bad actors to launch cyberattacks or for employees to cause inadvertent security risks or incidents. Our business partners, particularly our third-party service providers, face similar risks and any security breach of their systems could adversely affect our security and business posture. A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, compel us to comply with federal and/or state breach notification laws and foreign law equivalents, subject us to mandatory corrective action, require us to verify the correctness of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and/or result in increased costs or loss of revenue. The effects of a security breach or privacy violation could be further amplified during the ~~current~~ COVID-19 pandemic. Moreover, the prevalent use of mobile devices that access confidential information increases the risk of data security breaches, which could lead to the loss of confidential information, trade secrets or other intellectual property.

Despite significant efforts to create security barriers to the above described threats, it is impossible for us to entirely mitigate these risks. We may be unable to anticipate or prevent techniques used to obtain unauthorized access or to compromise our systems because they change frequently and are generally not detected until after an incident has occurred. In addition, an accidental or intentional cybersecurity event could result in significant increases in costs, including costs for remediating the effects of such an event, fines imposed by regulators, lost revenues due to decrease in customer trust and network downtime, increases in insurance premiums due to cybersecurity incidents and damages to our reputation because of any such incident. While we have invested, and continue to invest, in the protection of our data and information technology infrastructure, there can be no assurance that our efforts will prevent service interruptions, or identify vulnerabilities or breaches in our systems, that could adversely affect our business and operations and/or result in the loss of critical, sensitive, or ~~sensitive~~personal information, which could result in financial, legal, business or reputational harm to us. In addition, we cannot be certain that (a) our liability insurance will be sufficient in type or amount to cover us against claims related to security ~~breaches,~~incidents, cyberattacks and other related breaches; (b) such coverage will cover any indemnification claims against us relating to any incident, will continue to be available to us on economically reasonable terms, or at all; or (c) any insurer will not deny coverage as to any future claim. The successful assertion of one or more large claims against us that exceed available insurance coverage, or the occurrence of changes in our insurance policies, including premium increases or the imposition of large deductible or co-insurance requirements, could adversely affect our reputation, business, financial condition and results of operations.

We are subject to extensive worldwide laws and regulations related to data privacy and cybersecurity, and our failure to comply with these laws and regulations could harm our business.*

We are subject to laws and regulations governing data privacy and the protection of personal information. These laws and regulations govern our processing of personal data, including the collection, access, use, processing, analysis, modification, storage, transfer, security breach notification, destruction and disposal of personal data. There are foreign and state law versions of these laws and regulations to which we are currently and/or may in the future, be subject. For example, the collection and use of personal health data in the EU is governed by the GDPR. The GDPR, which is wide-ranging in scope, imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information disclosed to the individuals about our privacy practices, the security and confidentiality of the personal data, data breach notification and the use of third-party processors in connection with the processing of personal data. The GDPR also imposes strict rules on the transfer of personal data out of the EU to the United States or other jurisdictions deemed not to have adequate controls, provides an enforcement authority and imposes potentially large monetary penalties for noncompliance. The GDPR requirements apply not only to third-party transactions, but also to transfers of information within our company, including employee information. The GDPR and similar data privacy laws of other jurisdictions place significant responsibilities on us and create potential liability in relation to personal data that we or our third-party service providers process, including in clinical trials conducted in the United States and EU. In addition, we expect that there will continue to be new proposed laws, regulations and industry standards relating to privacy and data protection in the United States, the EU and other jurisdictions, and we cannot determine the impact such future laws, regulations and standards may have on our business.

~~Further,~~The UK’s vote in favor of exiting the EU, often referred to as Brexit, ~~has~~and ongoing developments in the UK have created uncertainty with regard to data protection regulation in the ~~United Kingdom. In particular, while~~UK. As of January 1, 2021, and the expiry of transitional arrangements agreed to between the UK and EU, data processing in the UK is governed by a UK version of the GDPR (combining the GDPR and the Data Protection Act 2018), exposing us to two parallel regimes, each of ~~2018, that “implements”~~which potentially authorizes similar fines and ~~complements~~other potentially divergent enforcement actions for certain violations. As a result of the expiration of the period specified by the Trade and Cooperation Agreement, or TCA, the UK has become an ‘inadequate third country’ under the GDPR ~~achieved Royal Assent on May 23, 2018~~ and ~~is now effective in the United Kingdom, it is still unclear whether transfer~~transfers of data from the ~~European Economic Area~~ EEA to the ~~United Kingdom will remain lawful under GDPR. During~~UK now require an ‘transfer mechanism,’ such as the standard contractual clauses. Furthermore, with the expiration of the TCA-specified period, there may be an increasing scope for divergence in application, interpretation and enforcement of ~~“transition” (i.e., until December 31, 2020), EU~~the data protection law ~~will continue to apply in~~as between the ~~United Kingdom, including the GDPR, after which the GDPR will be converted into United Kingdom law. Beginning in 2021, the United Kingdom will be~~UK and EEA. As a ~~“third country” under the GDPR. We~~result, we may ~~however,~~ incur liabilities, expenses, costs, and other operational losses under GDPR and applicable EU Member States and the ~~United Kingdom~~UK privacy laws in connection with any measures we take to comply with them. On June 28, 2021, the EC announced a decision of “adequacy” concluding that the UK ensures an equivalent level of data protection to the GDPR, which provides some relief regarding the legality of continued personal data flows from the EEA to the UK. Some uncertainty remains, however, as this adequacy determination must be renewed after four years and may be modified or revoked in the interim. We cannot fully predict how the Data Protection Act, the UK GDPR, and other UK data protection laws or regulations may develop in the medium to longer term nor the effects of divergent laws and guidance regarding how data transfers to and from the UK will be regulated.

Recent legal developments in Europe have created further complexity and uncertainty regarding transfers of personal data from the EU and ~~United Kingdom~~UK to the United States. On July 16, 2020, the Court of Justice of the European Union, or CJEU, invalidated the EU-US Privacy Shield Framework, or Privacy Shield, under which personal data could be transferred from the EU and ~~United Kingdom~~UK to United States entities who had self-certified under the Privacy Shield scheme. Nine of our United States entities have self-certified under the ~~scheme to facilitate~~Privacy Shield framework and we have entered into the ~~transfer~~standard contractual clauses within our group for transfers of ~~personal~~ data from the EU and ~~United Kingdom~~UK to the United States. ~~The United Kingdom’s supervisory authority may similarly invalidate use of the Privacy Shield as a vehicle for lawful data transfers from the United Kingdom to the United States. As such,~~Based on current EEA and UK law, our transfers of personal data to the United States may not comply with European data protection law and may increase our exposure to the GDPR’s heightened sanctions for violations of its cross-border data transfer restrictions, including fines of up to the greater of 4% of annual global revenue or €20.0 million and injunctions against transfers. While the CJEU upheld the adequacy of the standard contractual clauses (a standard form of contract approved by the ~~European Commission~~EC as an adequate personal data transfer mechanism, and potential alternative to the Privacy Shield), it made clear that reliance on them alone may not necessarily be sufficient in all circumstances. Use of the standard contractual clauses must now be assessed on a case-by-case basis taking into account the legal regime applicable in the destination country, in particular applicable surveillance laws and rights of individuals and additional measures and/or contractual provisions may need to be put in ~~place, however, the~~place. The nature of these additional measures, ~~is currently~~however, remains uncertain. As supervisory authorities issue further guidance on personal data export mechanisms, including circumstances where the standard contractual clauses cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints and/or regulatory investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we provide our services, the geographical location or segregation of our relevant systems and operations, and could adversely affect our financial results. On June 4, 2021, the EC adopted new standard contractual clauses under the GDPR for personal data transfers outside the EEA, which may require us to expend significant resources to update our contractual arrangements and to comply with such obligations.

Additionally, the California Consumer Privacy Act, or CCPA, went into effect on January 1, 2020. The CCPA has been dubbed the first “GDPR-like” law in the United States since it creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households. The CCPA requires covered companies to provide new disclosures to California consumers (as that word is broadly defined in the CCPA), provide such consumers new ways to opt-out of certain sales of personal information, and allow for a new private right of action for data breaches. ~~Despite amendments and multiple revisions of draft regulations (which have now been finalized), it~~It remains unclear how the CCPA will be interpreted, but as currently written, it will likely impact our business activities and exemplifies the vulnerability of our business to not only cyber threats but also the evolving regulatory environment related to personal data and protected health information. Further, California voters approved a new privacy law, the California Privacy Rights Act, or CPRA, in the November 3, 2020 election. Effective starting on January 1, 2023, the CPRA will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information. The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA. New legislation proposed or enacted in various other states will continue to shape the data privacy environment nationally. Certain state laws, including new laws fashioned after the CCPA and CPRA, may be more stringent or broader in scope, or offer greater individual rights, with respect to confidential, sensitive and personal information than federal, international or other state laws, and such laws may differ from each other, which may complicate compliance efforts. As we expand our operations and trials (both preclinical or clinical), the CCPA and CPRA may increase our compliance costs and potential liability. Some observers have noted that the CCPA and CPRA could mark the beginning of a trend toward more stringent privacy legislation in the United States. Other states are beginning to pass similar ~~laws.~~laws, including Virginia (which passed the Consumer Data Protection Act on March 2, 2021) Colorado (which enacted the Colorado Privacy Act that takes effect on July 1, 2023), and pending bills in Washington, New York, and Minnesota.

Compliance with these and any other applicable privacy and data security laws and regulations is a rigorous and time-intensive process, and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules. Any actual or perceived failure by us to comply with any applicable federal, state or similar foreign laws and regulations relating to data privacy and security could result in damage to our reputation, as well as proceedings or litigation by governmental agencies or other third parties, including class action privacy litigation in certain jurisdictions, which would subject us to significant fines, sanctions, awards, penalties or judgments, all of which could have a material adverse effect on our business, financial condition, results of operations and prospects. Furthermore, the laws are not consistent, and compliance in the event of a widespread data breach is costly.

If product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization of our medicines.

We face an inherent risk of product liability claims as a result of the commercial sales of our medicines and the clinical testing of our medicine candidates. For example, we may be sued if any of our medicines or medicine candidates allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the medicine, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of our medicines and medicine candidates. Even a successful defense would require significant financial and management resources. Regardless of the merits or eventual outcome, liability claims may result in:

Our inability to obtain and retain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of medicines we develop. We currently carry product liability insurance covering our clinical studies and commercial medicine sales in the amount of $125.0 million in the aggregate. Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that is in excess of the limits of our insurance coverage. If we determine that it is prudent to increase our product liability coverage due to the on-going commercialization of our current medicines in the United States, and/or the potential commercial launches of any of our medicines in additional markets or for additional indications, we may be unable to obtain such increased coverage on acceptable terms or at all. Our insurance policies also have various exclusions, and we may be subject to a product liability claim for which we have no coverage. We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts.

Our business involves the use of hazardous materials, and we and our third-party manufacturers must comply with environmental laws and regulations, which can be expensive and restrict how we do business.*

Our third-party manufacturers’ activities involve the controlled storage, use and disposal of hazardous materials owned by us, including the components of our medicine candidates and other hazardous compounds. We and our manufacturers are subject to federal, state and local as well as foreign laws and regulations governing the use, manufacture, storage, handling and disposal of these hazardous materials. Although we believe that the safety procedures utilized by our third-party manufacturers for handling and disposing of these materials comply with the standards prescribed by these laws and regulations, we cannot eliminate the risk of accidental contamination or injury from these materials. In the event of an accident, state, federal or foreign authorities may curtail the use of these materials and interrupt our business operations. We currently only maintain hazardous materials insurance coverage related to our South San Francisco facility and our Rockville, Maryland facility. If we are subject to any liability as a result of our third-party manufacturers’ activities involving hazardous materials, our business and financial condition may be adversely affected. In the future we may seek to establish longer-term third-party manufacturing arrangements, pursuant to which we would seek to obtain contractual indemnification protection from such third-party manufacturers potentially limiting this liability exposure.

Our employees, independent contractors, principal investigators, consultants, vendors, distributors and CROs may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

We are exposed to the risk that our employees, independent contractors, principal investigators, consultants, vendors, distributors and CROs may engage in fraudulent or other illegal activity. Misconduct by these parties could include intentional, reckless and/or negligent conduct or unauthorized activities that violate FDA regulations, including those laws that require the reporting of true, complete and accurate information to the FDA, manufacturing standards, federal and state healthcare fraud and abuse laws and regulations, and laws that require the true, complete and accurate reporting of financial information or data. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Misconduct by our employees and other third parties may also include the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. We have adopted a Code of Business Conduct and Ethics, but it is not always possible to identify and deter misconduct by our employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, the exclusion from participation in federal and state healthcare programs and imprisonment.

We ~~have incurred significant operating losses.~~may not remain profitable in future periods.*

~~We have financed our operations primarily through equity and debt financings and have incurred significant operating losses. We~~Although we recorded operating income ~~of $250.0 million~~and net income for the nine months ended September 30, ~~2020~~2021 and ~~operating income of $126.6 million and $37.9 million~~ for the years ended December 31, 2020 and 2019, ~~and 2018, respectively~~. ~~We recorded net income of $199.2 million for~~we may incur operating losses in the nine months ended September 30, 2020, net income of $573.0 million for the year ended December 31, 2019, and a net loss of $38.4 million for the year ended December 31, 2018. As of September 30, 2020, we had an accumulated deficit of $406.4 million. Ourfuture. Losses in prior ~~losses have~~periods resulted principally from costs incurred in our development activities for our medicines and medicine candidates, commercialization activities related to our medicines and costs associated with our acquisition ~~transactions and costs associated with derivative liability accounting.~~transactions. Our prior losses, combined with possible future losses, have had and ~~will~~may continue to have an adverse effect on our shareholders’ equity and working capital. ~~While we anticipate that we will generate operating profits in the future, whether we can accomplish this~~Our ability to maintain profitability will depend on the revenues we generate from the sale of our medicines being sufficient to cover our operating expenses. We also expect our operating expenses to increase substantially as a result of continuing to develop Viela’s pipeline of medicine candidates, which will negatively impact our future profitability until such time, if ever, that these potential medicine candidates are approved and successfully commercialized, as well as developing our manufacturing and international sales and marketing capabilities.

We have limited sources of revenues and significant expenses. We cannot be certain that we will sustain profitability, which would depress the market price of our ordinary shares and could cause our investors to lose all or a part of their investment.*

Our ability to sustain profitability depends upon our ability to generate sales of our medicines. The commercialization of our medicines has been primarily in the United States. We may never be able to successfully commercialize our medicines or develop or commercialize other medicines in the United States, which we believe represents our most significant commercial opportunity. Our ability to generate future revenues depends heavily on our success in:

Even if we do generate additional medicine sales, we may not be able to sustain profitability on a quarterly or annual basis. Our failure to become and remain profitable would depress the market price of our ordinary shares and could impair our ability to raise capital, expand our business, diversify our medicine offerings or continue our operations.

Our operations have consumed substantial amounts of cash since inception. We expect to continue to spend substantial amounts to:

While we believe that our existing cash and cash equivalents, ~~will be sufficient to fund our operations~~along with future cash flows based on our current expectations of continued revenue growth, will be sufficient to fund our operations, we may need to raise additional funds if we choose to expand our commercialization or development efforts more rapidly than presently anticipated, if we develop or acquire additional medicines or acquire companies, or if our revenue does not meet expectations.

We cannot be certain that additional funding will be available on acceptable terms, or at all. As a result of the COVID-19 pandemic and actions taken to slow its spread, the global credit and financial markets have at times experienced extreme volatility and disruptions, including diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. If the equity and credit markets deteriorate, it may make any additional debt or equity financing more difficult, more costly and more dilutive. If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back or discontinue the development or commercialization of one or more of our medicines or medicine candidates or one or more of our other ~~research and development~~R&D initiatives, or delay, cut back or abandon our plans to grow the business through acquisitions. We also could be required to:

In addition, if we are unable to secure financing to support future acquisitions, our ability to execute on a key aspect of our overall growth strategy would be impaired.

Any of the above events could significantly harm our business, financial condition and prospects.

We have incurred a substantial amount of debt, which could adversely affect our business, including by restricting our ability to engage in additional transactions or incur additional indebtedness, and prevent us from meeting our debt obligations.*

As of September 30, ~~2020,~~2021, we had $~~1,002.8~~$2,557.8 million book value, or ~~$1,018.0~~$2,610.0 million aggregate principal amount of indebtedness, including ~~$418.0~~$2,010.0 million in secured indebtedness.

This substantial level of debt could have important consequences to our business, including, but not limited to:

~~The~~Our credit agreement and the indenture governing our 5.5% Senior Notes due 2027, or 2027 Senior Notes, impose, and the terms of any future indebtedness may impose, various covenants that limit our ability and/or the ability of our restricted subsidiaries’ (as designated under such agreements) to, among other things, pay dividends or distributions, repurchase equity, prepay junior debt and make certain investments, incur additional debt and issue certain preferred stock, incur liens on assets, engage in certain asset sales, consolidate with or merge or sell all or substantially all of our assets, enter into transactions with affiliates, designate subsidiaries as unrestricted subsidiaries, and allow to exist certain restrictions on the ability of restricted subsidiaries to pay dividends or make other payments to us.

Our ability to obtain future financing and engage in other transactions may be restricted by these covenants. In addition, any credit ratings will impact the cost and availability of future borrowings and our cost of capital. Our ratings at any time will reflect each rating organization’s then opinion of our financial strength, operating performance and ability to meet our debt obligations. There can be no assurance that we will achieve a particular rating or maintain a particular rating in the future. A reduction in our credit ratings may limit our ability to borrow at acceptable interest rates. If our credit ratings were downgraded or put on watch for a potential downgrade, we may not be able to sell additional debt securities or borrow money in the amounts, at the times or interest rates or upon the more favorable terms and conditions that might otherwise be available. Any impairment of our ability to obtain future financing on favorable terms could have an adverse effect on our ability to refinance any of our then-existing debt and may severely restrict our ability to execute on our business strategy, which includes the continued acquisition of additional medicines or businesses.

As a result of the COVID-19 pandemic and actions taken to slow its spread, the global credit and financial markets have experienced extreme volatility and disruptions, including diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. In addition, government efforts to stimulate economic activity in the face of the COVID-19 pandemic have caused interest rates to fluctuate and created uncertainty as to future fluctuations. If the equity and credit markets deteriorate, it may make any additional debt or equity financing more difficult, more costly or more dilutive.

We may not be able to generate sufficient cash to service all of our indebtedness and may be forced to take other actions to satisfy our obligations under our indebtedness, which may not be successful.*

Our ability to make scheduled payments under or to refinance our debt obligations depends on our financial condition and operating performance, which is subject to prevailing economic, industry and competitive conditions and to certain financial, business and other factors beyond our control. For example, we expect that the COVID-19 pandemic and actions taken to slow its spread will continue to have a negative impact on net sales of our medicines, which will in turn negatively impact our cash flows. Our ability to generate cash flow to meet our payment obligations under our debt may also depend on the successful implementation of our operating and growth strategies. Any refinancing of our debt could be at higher interest rates and may require us to comply with more onerous covenants, which could further restrict our business operations. We cannot assure that we will maintain a level of cash flows from operating activities sufficient to pay the principal, premium, if any, and interest on our indebtedness.

If our cash flows and capital resources are insufficient to fund our debt service obligations, we may be forced to reduce or delay capital expenditures, sell assets or business operations, seek additional capital or restructure or refinance our indebtedness. We cannot ensure that we would be able to take any of these actions, that these actions would be successful and permit us to meet our scheduled debt service obligations or that these actions would be permitted under the terms of existing or future debt agreements, including the indenture that governs the 2027 Senior Notes and ~~the~~our credit agreement. In addition, any failure to make payments of interest and principal on our outstanding indebtedness on a timely basis would likely result in a reduction of our credit rating, which could harm our ability to incur additional indebtedness.

If we cannot make scheduled payments on our debt, we will be in default and, as a result:

We generally have broad discretion in the use of our cash and may not use it effectively.

Our management has broad discretion in the application of our cash, and investors will be relying on the judgment of our management regarding the use of our cash. Our management may not apply our cash in ways that ultimately increase the value of any investment in our securities. We expect to use our existing cash to fund commercialization activities for our medicines, to potentially fund additional medicine, medicine candidate or business acquisitions, to potentially fund additional regulatory approvals of certain of our medicines, to potentially fund development, life cycle management or manufacturing activities of our medicines and medicine candidates, to potentially fund share repurchases, and for working capital, milestone payments, capital expenditures and general corporate purposes. We may also invest our cash in short-term, investment-grade, interest-bearing securities. These investments may not yield a favorable return to our shareholders. If we do not invest or apply our cash in ways that enhance shareholder value, we may fail to achieve expected financial results, which could cause the price of our ordinary shares to decline.

Our ability to use net operating loss carryforwards and certain other tax attributes to offset U.S. income taxes may be limited.*

Under Sections 382 and 383 of the Code, if a corporation undergoes an “ownership change” (generally defined as a greater than 50 percent change (by value) in its equity ownership over a three-year period), the corporation’s ability to use pre-change net operating loss carryforwards and other pre-change tax attributes to offset post-change income may be limited. For example, we continue to carry forward our annual limitation resulting from an ownership change date of August 2, 2012. The limitation on pre-change net operating losses incurred prior to the August 2, 2012 change date is approximately $7.7 million for ~~2020~~2021 through 2028. In addition, we recognized $32.2 million of federal net operating losses, $2.2 million of state net operating losses and $9.5 million of federal tax credits following our acquisition of River Vision Development Corp. These acquired federal net operating losses and tax credits are subject to an annual limitation of $2.6 million. The net operating loss carryforward and tax credit carryforward limitations are cumulative such that any use of the carryforwards below the limitations in one year will result in a corresponding increase in the limitations for the subsequent tax year. Under the Tax Act, as modified by the CARES Act, U.S. federal net operating losses incurred in taxable years beginning after December 31, 2017 may be carried forward indefinitely, but the deductibility of federal net operating losses generated in taxable years beginning after December 31, 2017, to the extent such net operating losses are carried forward into taxable years beginning after December 31, 2020, is limited to 80 percent of the then current year’s taxable income. Under the CARES Act, U.S. federal net operating losses arising in a tax year beginning after December 31, 2017, and before January 1, 2021, can be carried back five years. ~~It remains uncertain if and~~We continue to ~~what extent various U.S. states will conform~~monitor legislation regarding the states’ conformity to the Tax Act and the CARES Act.

Following certain acquisitions of a U.S. corporation by a foreign corporation, Section 7874 of the Code limits the ability of the acquired U.S. corporation and its U.S. affiliates to utilize U.S. tax attributes such as net operating losses to offset U.S. taxable income resulting from certain transactions. Based on the limited guidance available, we expect this limitation is applicable for approximately ten years following our merger transaction with Vidara with respect to certain ~~intra-company~~intercompany transactions. As a result, we or our other U.S. affiliates may not be able to utilize U.S. tax attributes to offset U.S. taxable income or U.S. tax liability respectively, if any, resulting from certain ~~intra-company~~intercompany taxable transactions during such period. Notwithstanding this limitation, we expect that we will be able to fully use our U.S. net operating losses and tax credits prior to their expiration. As a result of this limitation, however, it may take Horizon Therapeutics USA, Inc. (formerly known as Horizon Pharma USA, Inc. and as the successor to HPI) longer to use its net operating losses and tax credits. Moreover, contrary to these expectations, it is possible that the limitation under Section 7874 of the Code on the utilization of U.S. tax attributes could prevent us from fully utilizing our U.S. tax attributes prior to their expiration if we do not generate sufficient taxable income or tax obligations.

Any limitation on our ability to use our net operating loss and tax credit carryforwards, including the carryforwards of companies that we acquire, will likely increase the taxes we would otherwise pay in future years if we were not subject to such limitations.

Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and share price.*

From time to time, including recently as a result of the COVID-19 pandemic and actions taken to slow its spread, global credit and financial markets have experienced extreme volatility and disruptions, including severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, and uncertainty about economic stability. Our general business strategy may be adversely affected by any such economic downturn, volatile business environment and continued unpredictable and unstable market conditions. If the equity and credit markets deteriorate, it may make any necessary debt or equity financing more difficult to complete, more costly, and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our growth strategy, financial performance and share price and could require us to delay or abandon commercialization or development plans. There is a risk that one or more of our current service providers, manufacturers and other partners may not survive an economic down-turn, which could directly affect our ability to attain our operating goals on schedule and on budget.

At September 30, 2021, we had $1,068.5 million of cash and cash equivalents consisting of cash, money market funds, time deposits and U.S. federal government securities. While we are not aware of any downgrades, material losses, or other significant deterioration in the fair value of our cash equivalents since September 30, 2021, no assurance can be given that deterioration in conditions of the global credit and financial markets would not negatively impact our current portfolio of cash equivalents or our ability to meet our financing objectives. Dislocations in the credit market may adversely impact the value and/or liquidity of marketable securities owned by us.

The ~~United Kingdom’s~~UK’s referendum to leave the EU and the ~~United Kingdom’s~~UK’s exit from the EU on January 31, 2020, or “Brexit,” has caused and may continue to cause disruptions to capital and currency markets worldwide. The full impact of Brexit, however, remains uncertain. Pursuant to the formal withdrawal arrangements agreed to between the ~~United Kingdom~~UK and the EU, the ~~United Kingdom will be~~UK was subject to a transition period, or Transition Period, until December 31, 2020, during which EU rules ~~will continue~~continued to apply. ~~Negotiations between~~The TCA, which outlines the ~~United Kingdom and the EU are expected to continue in relation to the customs and~~future trading relationship between the ~~United Kingdom~~UK and the EU was agreed in December 2020, entered into force provisionally on January 1, 2021, and has been permanently applicable since May 1, 2021 following its ratification by the ~~expiry~~EU Parliament.

There remains uncertainty as to the practical impacts of Brexit and, especially in the early stages of the ~~Transition Period. During this period of negotiation~~UK and ~~afterwards,~~the EU operating under different legislation, our results of operations and access to capital may be negatively affected by interest rate, exchange rate and other market and economic volatility, as well as political uncertainty. Brexit may also have a detrimental effect on our customers, distributors and suppliers, which would, in turn, adversely affect our revenues and financial condition.

~~At September 30, 2020, we had $1,725.4 million~~While the TCA provides for the tariff-free trade of ~~cash~~medicinal products between the UK and ~~cash equivalents consisting~~the EU there may be additional non-tariff costs to such trade which did not exist prior to the end of ~~cash~~the Transition Period. Further, should the UK diverge from the EU from a regulatory perspective in relation to medicinal products, tariffs could be put into place in the future. Any further changes in international trade, tariff and ~~money market funds. While we are not aware~~import/export regulations as a result of ~~any downgrades, material losses,~~Brexit or otherwise may impose unexpected duty costs or other ~~significant deterioration~~non-tariff barriers on us.

We could therefore, both now and in the ~~fair value of our cash equivalents since September 30, 2020, no assurance can be given that deterioration in conditions~~future, face additional expenses (when compared to the position prior to the end of the Transition Period) to operate our business, which could harm or delay our business. These developments, or the perception that any of them could occur, may significantly reduce global ~~credit~~trade and, ~~financial markets would not negatively impact our current portfolio of cash equivalents or our ability to meet our financing objectives. Dislocations~~ in particular, trade between the ~~credit market may adversely impact~~impacted nations and the ~~value and/or liquidity of marketable securities owned by us.~~UK.

If the London Inter-Bank Offered Rate, or LIBOR, is discontinued, interest payments under our credit agreement may be calculated using another reference rate.*

In July 2017, the Chief Executive of the United Kingdom Financial Conduct Authority, or FCA, which regulates LIBOR, announced that the FCA intends to phase out the use of LIBOR by the end of 2021. In addition, the U.S. Federal Reserve, in conjunction with the Alternative Reference Rates Committee, a steering committee ~~comprised~~composed of large U.S. financial institutions, is considering replacing U.S. dollar LIBOR with the Secured Overnight Financing Rate, or SOFR, a new index calculated by short-term repurchase agreements, backed by Treasury securities. Although there have been certain issuances utilizing SOFR, it is unknown whether this or any other alternative reference rate will attain market acceptance as a replacement for LIBOR. LIBOR is used as a benchmark rate throughout our credit agreement, and our credit agreement does not address all circumstances in which LIBOR ceases to be published. There remains uncertainty regarding the future utilization of LIBOR and the nature of any replacement rate, and any potential effects of the transition away from LIBOR on us are not known. The transition process may involve, among other things, increased volatility and illiquidity in markets for instruments that currently rely on LIBOR and may result in increased borrowing costs, the effectiveness of related transactions such as hedges, uncertainty under applicable documentation, including the credit agreement, or difficult and costly processes to amend such documentation. As a result, our ability to refinance our credit agreement or other indebtedness or to hedge our exposure to floating rate instruments may be impaired, which would adversely affect the operations of our business.

Changes in accounting rules or policies may affect our financial position and results of operations.

Accounting principles generally accepted in the United States, or GAAP, and related implementation guidelines and interpretations can be highly complex and involve subjective judgments. Changes in these rules or their interpretation, the adoption of new guidance or the application of existing guidance to changes in our business could significantly affect our financial position and results of operations. In addition, our operation as an Irish company with multiple subsidiaries in different jurisdictions adds additional complexity to the application of GAAP and this complexity will be exacerbated further if we complete additional strategic transactions. Changes in the application of existing rules or guidance applicable to us or our ~~wholly owned~~wholly-owned subsidiaries could significantly affect our consolidated financial position and results of operations.

Covenants under the indenture governing our 2027 Senior Notes and our credit agreement may restrict our business and operations in many ways, and if we do not effectively manage our covenants, our financial conditions and results of operations could be adversely affected.*

The indenture governing the 2027 Senior Notes and the credit agreement impose various covenants that limit our ability and/or our restricted subsidiaries’ ability to, among other things:

If we are unable to successfully manage the limitations and decreased flexibility on our business due to our significant debt obligations, we may not be able to capitalize on strategic opportunities or grow our business to the extent we would be able to without these limitations.

Our failure to comply with any of the covenants could result in a default under the credit agreement or the indenture governing the 2027 Senior Notes, which could permit the administrative agent or the trustee, as applicable, or permit the lenders or the holders of the 2027 Senior Notes to cause the administrative agent or the trustee, as applicable, to declare all or part of any outstanding senior secured term loans or revolving loans, or the 2027 Senior Notes to be immediately due and payable or to exercise any remedies provided to the administrative agent or the trustee, including, in the case of the credit agreement proceeding against the collateral granted to secure our obligations under the credit agreement. An event of default under the credit agreement or the indenture governing the 2027 Senior Notes could also lead to an event of default under the terms of the other agreement. Any such event of default or any exercise of rights and remedies by our creditors could seriously harm our business.

If intangible assets that we have recorded in connection with our acquisition transactions become impaired, we could have to take significant charges against earnings.

In connection with the accounting for our various acquisition transactions, we have recorded significant amounts of intangible assets. Under GAAP, we must assess, at least annually and potentially more frequently, whether the value of goodwill has been impaired. Amortizing intangible assets will be assessed for impairment in the event of an impairment indicator. For example, during the year ended December 31, 2018, we recorded an impairment of $33.6 million to fully write off the book value of developed technology related to PROCYSBI in Canada and Latin America. Such impairment and any reduction or other impairment of the value of goodwill or other intangible assets will result in a charge against earnings, which could materially adversely affect our results of operations and shareholders’ equity in future periods.

If we are unable to obtain or protect intellectual property rights related to our medicines and medicine candidates, we may not be able to compete effectively in our markets.*

We rely upon a combination of patents, trade secret protection and confidentiality agreements to protect the intellectual property related to our medicines and medicine candidates. The strength of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain. The patent applications that we own may fail to result in issued patents with claims that cover our medicines in the United States or in other foreign countries. If this were to occur, early generic competition could be expected against our current medicines and other medicine candidates in development. There is no assurance that all potentially relevant prior art relating to our patents and patent applications has been found, which prior art can invalidate a patent or prevent a patent from issuing based on a pending patent application. In particular, because the APIs in RAYOS ~~DUEXIS~~ and PENNSAID 2% have been on the market as separate medicines for many years, it is possible that these medicines have previously been used off-label in such a manner that such prior usage would affect the validity of our patents or our ability to obtain patents based on our patent applications. In addition, claims directed to dosing and dose adjustment may be substantially less likely to issue in light of the Supreme Court decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc., where the court held that claims directed to methods of determining whether to adjust drug dosing levels based on drug metabolite levels in the red blood cells were not patent eligible because they were directed to a law of nature. This decision may have wide-ranging implications on the validity and scope of pharmaceutical method claims.

Even if patents do successfully issue, third parties may challenge their validity, enforceability or scope, which may result in such patents being narrowed or invalidated.

Patent litigation is currently pending in the ~~United States District Court for the District of New Jersey against~~ ~~Actavis, who intend to market~~ a generic version of PENNSAID 2% prior to the expiration of certain of our patents listed in the Orange Book. These cases arise from Paragraph IV Patent Certification notice letters from Actavis advising they had filed an ANDA with the FDA seeking approval to market a generic version of PENNSAID 2% before the expiration of the patents-in-suit. For a more detailed description of the PENNSAID 2% litigation, see Note 16, ~~Legal Proceedings, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.~~

Patent litigation is currently pending in the United States District Court for the District of New Jersey and the Court of Appeals for the Federal Circuit against Dr. Reddy’s for marketing a generic version of VIMOVO before the expiration of certain of our patents listed in the Orange Book. The cases arise from Paragraph IV Patent Certification notice letters from Dr. Reddy’s, advising that it had filed an ANDA with the FDA seeking approval to market generic versions of VIMOVO before the expiration of the patents-in-suit. On July 30, 2019, the Federal Circuit Court of Appeals denied our request for a rehearing of the Court’s invalidity ruling against the 6,926,907 and 8,557,285 patents for VIMOVO coordinated-release tablets. As a result, the District Court entered judgment in September 2019 invalidating the ‘907 and ‘285 patents, which ended any restriction against the FDA from granting final approval to Dr. Reddy’s generic version of VIMOVO. On February 18, 2020, the FDA granted final approval for Dr. Reddy’s generic version of VIMOVO. On February 27, 2020, Dr. Reddy’s launched its generic version of VIMOVO in the United States. Patent litigation against Dr. Reddy’s for infringement continues with respect to certain patents in the New Jersey District Court. We have repositioned our promotional efforts previously directed to VIMOVO to the other inflammation segment medicines and expect that our VIMOVO net sales will continue to decrease in future periods. For a more detailed description of the VIMOVO litigation, see Note 16, ~~Legal Proceedings, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.~~

~~Patent litigation is currently pending in the United States District Court for the District of Delaware~~ and the United States District Court of New Jersey against Alkem, ~~and~~Teva Pharmaceuticals USA, Inc., or Teva USA, and Torrent Pharmaceuticals Limited, or Torrent, respectively, who ~~each~~either have or intend to market a generic version of DUEXIS prior to the expiration of certain of our patents listed in the FDA’s Orange Book. These cases arise from Paragraph IV Patent Certification notice letters from Alkem, ~~and~~ Teva USA and Torrent advising they had filed an ANDA with the FDA seeking approval to market a generic version of DUEXIS before the expiration of the patents-in-suit. For a more detailed description of the DUEXIS litigation, ~~see~~refer to Note 16, Legal Proceedings, of the ~~Notes~~notes to Unaudited Condensed Consolidated Financial ~~Statements,~~statements, included in Item 1 of this Quarterly Report on Form 10-Q.

Patent litigation is currently pending in the United States District Court of New Jersey against Lupin, who intends to market a generic version of PROCYSBI prior to the expiration of certain of our patents listed in the Orange Book. The case arises from Paragraph IV Patent Certification notice letter from Lupin advising it has filed an ANDA with the FDA seeking approval to market a generic version of PROCYSBI before the expiration of the patents-in-suit. For a more detailed description of the PROCYSBI litigation, see Note 16, ~~Legal Proceedings, of the Notes to Unaudited Condensed Consolidated Financial Statements, included in Item 1 of this Quarterly Report on Form 10-Q.~~

~~We intend to vigorously defend our intellectual property rights relating to our medicines, but we cannot predict the outcome of the DUEXIS cases, the PENNSAID 2% cases, and the PROCYSBI case.~~ Any adverse outcome in these matters or any new generic challenges that may arise could result in one or more generic versions of our medicines being launched before the expiration of the listed patents, which could adversely affect our ability to successfully execute our business strategy to increase sales of our medicines, and would negatively impact our financial condition and results of operations, including causing a significant decrease in our revenues and cash flows.

Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property or prevent others from designing around our claims. If the patent applications we hold with respect to our medicines fail to issue or if their breadth or strength of protection is threatened, it could dissuade companies from collaborating with us to develop them and threaten our ability to commercialize our medicines. We cannot offer any assurances about which, if any, patents will issue or whether any issued patents will be found not invalid and not unenforceable or will go unthreatened by third parties. Since patent applications in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued, we cannot be certain that we were the first to file any patent application related to our medicines or any other medicine candidates. Furthermore, if third parties have filed such patent applications, an interference proceeding in the United States can be provoked by a third-party or instituted by us to determine which party was the first to invent any of the subject matter covered by the patent claims of our applications.

In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable, processes for which patents are difficult to enforce and any other elements of our drug discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents. Although we expect all of our employees to assign their inventions to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information or technology to enter into confidentiality agreements, we cannot provide any assurances that all such agreements have been duly executed or that our trade secrets and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques.

Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result, we may encounter significant problems in protecting and defending our intellectual property both in the United States and abroad. For example, if the issuance, in a given country, of a patent to us, covering an invention, is not followed by the issuance, in other countries, of patents covering the same invention, or if any judicial interpretation of the validity, enforceability, or scope of the claims in, or the written description or enablement in, a patent issued in one country is not similar to the interpretation given to the corresponding patent issued in another country, our ability to protect our intellectual property in those countries may be limited. Changes in either patent laws or in interpretations of patent laws in the United States and other countries may materially diminish the value of our intellectual property or narrow the scope of our patent protection. If we are unable to prevent material disclosure of the non-patented intellectual property related to our technologies to third parties, and there is no guarantee that we will have any such enforceable trade secret protection, we may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business, results of operations and financial condition.

If we fail to comply with our obligations in the agreements under which we license rights to technology from third parties, we could lose license rights that are important to our business.*

We are party to a number of technology licenses that are important to our business and expect to enter into additional licenses in the future. For example, we rely on a license from Bausch with respect to technology developed by Bausch in connection with the manufacturing of RAVICTI. The purchase agreement under which Hyperion purchased the rights to RAVICTI contains obligations to pay Bausch regulatory and sales milestone payments relating to RAVICTI, as well as royalties on the net sales of RAVICTI. On May 31, 2013, when Hyperion acquired BUPHENYL under a restated collaboration agreement with Bausch, Hyperion received a license to use some of the manufacturing technology developed by Bausch in connection with the manufacturing of BUPHENYL. The restated collaboration agreement also contains obligations to pay Bausch regulatory and sales milestone payments, as well as royalties on net sales of BUPHENYL. If we fail to make a required payment to Bausch and do not cure the failure within the required time period, Bausch may be able to terminate the license to use its manufacturing technology for RAVICTI and BUPHENYL. If we lose access to the Bausch manufacturing technology, we cannot guarantee that an acceptable alternative method of manufacture could be developed or acquired. Even if alternative technology could be developed or acquired, the loss of the Bausch technology could still result in substantial costs and potential periods where we would not be able to market and sell RAVICTI and/or BUPHENYL. We also license intellectual property necessary for commercialization of RAVICTI from an external party. This party may be entitled to terminate the license if we breach the agreement, including failure to pay required royalties on net sales of RAVICTI, or we do not meet specified diligence obligations in our development and commercialization of RAVICTI, and we do not cure the failure within the required time period. If the license is terminated, it may be difficult or impossible for us to continue to commercialize RAVICTI, which would have a material adverse effect on our business, financial condition and results of operations.

We hold an exclusive, worldwide license from F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., or Roche, to patents and know-how for TEPEZZA. We also have exclusive sub-licenses for rights licensed to Roche for TEPEZZA by certain third-party licensors. Roche may have the right to terminate the license upon our breach, if not cured within a specified period of time. Roche may also terminate the license in the event of our bankruptcy or insolvency, or if we challenge the validity of Roche’s patents. If the license is terminated for our breach or based on our challenging the validity of Roche’s patents, then all rights and licenses granted to us by Roche would also terminate, and we may be required to assign and transfer to Roche certain filings and approvals, trademarks, and data in our possession necessary for the development and commercialization of TEPEZZA, and assign clinical trial agreements to the extent permitted. We may also be required to grant Roche an exclusive license under our patents and know-how for TEPEZZA, and to manufacture and supply TEPEZZA to Roche for a transitional period. We also have a license of patent rights to TEPEZZA under a license agreement with Lundquist Institute (formerly known as Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center), or Lundquist. Lundquist has the right to terminate the license agreement upon our material breach, if not cured within a specified period of time, or in the event of our bankruptcy or insolvency. If one or more of these licenses is terminated, it may be impossible for us to continue to commercialize TEPEZZA, which would have a material adverse effect on our business, financial condition and results of operations.

96We also hold an exclusive license to patents and technology from Duke University, or Duke, and Mountain View Pharmaceuticals, Inc., or MVP, covering KRYSTEXXA. Duke and MVP may terminate the license if we commit fraud or for our willful misconduct or illegal conduct. Duke and MVP may also terminate the license upon our material breach of the agreement, if not cured within a specified period of time, or upon written notice if we have committed two or more material breaches under the agreement. Duke and MVP may also terminate the license in the event of our bankruptcy or insolvency. If the license is terminated, it may be impossible for us to continue to commercialize KRYSTEXXA, which would have a material adverse effect on our business, financial condition and results of operations.

We are subject to contractual obligations under our amended and restated license agreement with UCSD, as amended, with respect to PROCYSBI. If one or more of these licenses was terminated, we would have no further right to use or exploit the related intellectual property, which would limit our ability to develop PROCYSBI in other indications, and could impact our ability to continue commercializing PROCYSBI in its approved indications.

We also license rights to know-how and trademarks for ACTIMMUNE from Genentech Inc., or Genentech. Genentech may terminate the agreement upon our material default, if not cured within a specified period of time. Genentech may also terminate the agreement in the event of our bankruptcy or insolvency. Upon such a termination of the agreement, all intellectual property rights conveyed to us under the agreement, including the rights to the ACTIMMUNE trademark, revert to Genentech. If we fail to comply with our obligations under this agreement, we could lose the ability to market and distribute ACTIMMUNE, which would have a material adverse effect on our business, financial condition and results of operations.

Following our acquisition of Viela on March 15, 2021, we are a party to a number of intellectual property license agreements including (i) our licenses with Duke University and Dana-Farber Cancer Institute related to UPLIZNA, (ii) our license with SBI Biotech Co. Ltd related to daxdilimab (HZN-7734), (iii) our license with MedImmune, LLC, or MedImmune, related to dazodalibep (HZN-4920), (iv) our sublicense with MedImmune for its license with Lonza Sales AG, or Lonza, related to UPLIZNA and daxdilimab (HZN-7734), (v) our sublicense with MedImmune for its license with BioWa, Inc., or BioWa, related to UPLIZNA, and (vi) our sublicense with MedImmune for its license with BioWa and Lonza related to daxdilimab (HZN-7734). If we fail to comply with our obligations under these agreements, or we are subject to a bankruptcy, we may be required to make certain payments to the licensor, we may lose the exclusivity of our license, or the licensor may have the right to terminate the license, in which event we would not be able to develop or market products covered by the license.

We hold an exclusive license to Vectura Group plc’s, or Vectura, proprietary technology and know-how covering the delayed release of corticosteroids relating to RAYOS. If we fail to comply with our obligations under our agreement with Vectura or our other license agreements, or if we are subject to a bankruptcy, the licensor may have the right to terminate the license, in which event we would not be able to market medicines covered by the license, including RAYOS.

Some intellectual property has been discovered through government-funded programs and thus may be subject to federal regulations such as “march-in” rights, certain reporting requirements and a preference for U.S.-based companies. Compliance with such regulations may limit our exclusive rights, and limit our ability to contract with non-U.S. manufacturers.*

Some of our intellectual property rights, specifically, intellectual property rights related to UPLIZNA that are in-licensed from Duke University, were generated through the use of U.S. government funding and are therefore subject to certain federal regulations. As a result, the U.S. government may have certain rights to intellectual property embodied in certain of our current or future medicine candidates pursuant to the Bayh-Dole Act of 1980, or the Bayh-Dole Act. These U.S. government rights in certain inventions developed under a government-funded program include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, the U.S. government has the right, under certain limited circumstances, to require us to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (i) adequate steps have not been taken to commercialize the invention; (ii) government action is necessary to meet public health or safety needs; or (iii) government action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”). To our knowledge, however, the U.S. government has, to date, not exercised any march-in rights on any patented technology that was generated using U.S. government funds. The U.S. government also has the right to take title to these inventions if we or the applicable grantee fail to disclose the invention to the government and fail to file an application to register the intellectual property within specified time limits. Intellectual property generated under a government funded program is also subject to certain reporting requirements, compliance with which may require us to expend substantial resources. In addition, the U.S. government requires that any products embodying the subject invention or produced through the use of the subject invention be manufactured substantially in the United States. The manufacturing preference requirement can be waived if the owner of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the United States or that under the circumstances domestic manufacture is not commercially feasible. This preference for U.S. manufacturers may limit our ability to contract with non-U.S. product manufacturers for products covered by such intellectual property. To the extent any of our current or future intellectual property is generated through the use of U.S. government funding, the provisions of the Bayh-Dole Act may similarly apply.

The patent protection and patent prosecution for some of our medicine candidates is dependent on third parties.*

While we normally seek and gain the right to fully prosecute the patents relating to our medicine candidates, there may be times when patents relating to our medicine candidates are controlled by our licensors. This is the case with current patents and patent applications licensed from MedImmune related to dazodalibep (HZN-4920), and those licensed from Duke University related to inebilizumab. If we, or any of our future licensing partners fail to appropriately file, prosecute and maintain patent protection for patents covering any of our medicine candidates, our ability to develop and commercialize those medicine candidates may be adversely affected and we may not be able to prevent competitors from making, using, and selling competing products. In addition, even where we now have the right to control patent prosecution of patents and patent applications we have licensed from third parties, we may still be adversely affected or prejudiced by actions or inactions of our licensors.

The market price of our ordinary shares historically has been volatile and is likely to continue to be volatile, and you could lose all or part of any investment in our ordinary shares.

The trading price of our ordinary shares has been volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond our control. In addition to the factors discussed in this “Risk Factors” section and elsewhere in this report, these factors include:

In addition, the stock market in general, and The Nasdaq Global Select Market and the stock of biotechnology companies in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Broad market and industry factors may adversely affect the market price of our ordinary shares, regardless of our actual operating performance.

We have never declared or paid dividends on our share capital and we do not anticipate paying dividends in the foreseeable future.

We have never declared or paid any cash dividends on our ordinary shares. We currently anticipate that we will retain future earnings for the development, operation and expansion of our business and do not anticipate declaring or paying any cash dividends for the foreseeable future, including due to limitations that are currently imposed by our credit agreement and the indenture governing the 2027 Senior Notes. Any return to shareholders will therefore be limited to the increase, if any, of our ordinary share price.

Future sales and issuances of our ordinary shares, securities convertible into our ordinary shares or rights to purchase ordinary shares or convertible securities could result in additional dilution of the percentage ownership of our shareholders and could cause our share price to decline.*

Additional capital may be needed in the future to continue our planned operations. To the extent we raise additional capital by issuing equity securities or securities convertible into or exchangeable for ordinary shares, our shareholders may experience substantial dilution. We may sell ordinary shares, and we may sell convertible or exchangeable securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time. If we sell such ordinary shares, convertible or exchangeable securities or other equity securities in subsequent transactions, existing shareholders may be materially diluted. New investors in such subsequent transactions could gain rights, preferences and privileges senior to those of holders of ordinary shares. We also maintain equity incentive plans, including our Amended and Restated 2020 Equity Incentive Plan, as amended, Amended and Restated 2018 Equity Incentive Plan, as amended, 2014 Non-Employee Equity Plan, as amended, and 2020 Employee Share Purchase Plan, and intend to grant additional ordinary share awards under these and future plans, which will result in additional dilution to our existing shareholders.

Irish law differs from the laws in effect in the United States and may afford less protection to holders of our securities.

It may not be possible to enforce court judgments obtained in the United States against us in Ireland based on the civil liability provisions of the U.S. federal or state securities laws. In addition, there is some uncertainty as to whether the courts of Ireland would recognize or enforce judgments of U.S. courts obtained against us or our directors or officers based on the civil liabilities provisions of the U.S. federal or state securities laws or hear actions against us or those persons based on those laws. We have been advised that the United States currently does not have a treaty with Ireland providing for the reciprocal recognition and enforcement of judgments in civil and commercial matters. Therefore, a final judgment for the payment of money rendered by any U.S. federal or state court based on civil liability, whether or not based solely on U.S. federal or state securities laws, would not automatically or necessarily be enforceable in Ireland.

As an Irish company, we are governed by the Irish Companies Act 2014 (as amended), which differs in some material respects from laws generally applicable to U.S. corporations and shareholders, including, among others, differences relating to interested director and officer transactions and shareholder lawsuits. Likewise, the duties of directors and officers of an Irish company generally are owed to the company only. Shareholders of Irish companies generally do not have a personal right of action against directors or officers of the company and may exercise such rights of action on behalf of the company only in limited circumstances. Accordingly, holders of our securities may have more difficulty protecting their interests than would holders of securities of a corporation incorporated in a jurisdiction of the United States.

Provisions of our articles of association, and Irish law could delay or prevent a takeover of us by a third party.

Our articles of association could delay, defer or prevent a third-party from acquiring us, despite the possible benefit to our shareholders, or otherwise adversely affect the price of our ordinary shares. For example, our articles of association:

In addition, several mandatory provisions of Irish law could prevent or delay an acquisition of us. For example, Irish law does not permit shareholders of an Irish public limited company to take action by written consent with less than unanimous consent. We are also subject to various provisions of Irish law relating to mandatory bids, voluntary bids, requirements to make a cash offer and minimum price requirements, as well as substantial acquisition rules and rules requiring the disclosure of interests in our ordinary shares in certain circumstances.

These provisions may discourage potential takeover attempts, discourage bids for our ordinary shares at a premium over the market price or adversely affect the market price of, and the voting and other rights of the holders of, our ordinary shares. These provisions could also discourage proxy contests and make it more difficult for you and our other shareholders to elect directors other than the candidates nominated by our board of directors, and could depress the market price of our ordinary shares.

Any attempts to take us over will be subject to Irish Takeover Rules and subject to review by the Irish Takeover Panel.

We are subject to the Irish Takeover Rules, under which our board of directors will not be permitted to take any action which might frustrate an offer for our ordinary shares once it has received an approach which may lead to an offer or has reason to believe an offer is imminent.

In certain circumstances, the transfer of shares in an Irish incorporated company will be subject to Irish stamp duty, which is a legal obligation of the buyer. This duty is currently charged at the rate of 1.0 percent of the price paid or the market value of the shares acquired, if higher. Because our ordinary shares are traded on a recognized stock exchange in the United States, an exemption from this stamp duty is available to transfers by shareholders who hold ordinary shares beneficially through brokers, which in turn hold those shares through the Depositary Trust Company, or DTC, to holders who also hold through DTC. However, a transfer by or to a record holder who holds ordinary shares directly in his, her or its own name could be subject to this stamp duty. We, in our absolute discretion and insofar as the Irish Companies Act 2014 (as amended) or any other applicable law permit, may, or may provide that one of our subsidiaries will pay Irish stamp duty arising on a transfer of our ordinary shares on behalf of the transferee of such ordinary shares. If stamp duty resulting from the transfer of ordinary shares which would otherwise be payable by the transferee is paid by us or any of our subsidiaries on behalf of the transferee, then in those circumstances, we will, on our behalf or on behalf of such subsidiary (as the case may be), be entitled to (i) seek reimbursement of the stamp duty from the transferee, (ii) set-off the stamp duty against any dividends payable to the transferee of those ordinary shares and (iii) claim a first and permanent lien on the ordinary shares on which stamp duty has been paid by us or such subsidiary for the amount of stamp duty paid. Our lien shall extend to all dividends paid on those ordinary shares.

In certain circumstances, as an Irish tax resident company, we will be required to deduct Irish dividend withholding tax (currently at the rate of 25%) from dividends paid to our shareholders. Shareholders that are resident in the United States, EU countries (other than Ireland) or other countries with which Ireland has signed a tax treaty (whether the treaty has been ratified or not) generally should not be subject to Irish withholding tax so long as the shareholder has provided its broker, for onward transmission to our qualifying intermediary or other designated agent (in the case of shares held beneficially), or our or its transfer agent (in the case of shares held directly), with all the necessary documentation by the appropriate due date prior to payment of the dividend. However, some shareholders may be subject to withholding tax, which could adversely affect the price of our ordinary shares.

We have incurred and will continue to incur significant increased costs as a result of operating as a public company and our management will be required to devote substantial time to compliance initiatives.*

As a public company, we have incurred and will continue to incur significant legal, accounting and other expenses that we did not incur as a private company. In particular, the Sarbanes-Oxley Act of 2000, or the Sarbanes-Oxley Act, as well as rules subsequently implemented by the SEC and the Nasdaq Stock Market, Inc., or Nasdaq, impose significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices. These rules and regulations have substantially increased our legal and financial compliance costs and have made some activities more time-consuming and costly. These effects are exacerbated by our transition to an Irish company and the integration of numerous acquired businesses and operations into our historical business and operating structure. If these requirements divert the attention of our management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition and results of operations. The increased costs will continue to decrease our net income or increase our net income, and may require us to reduce costs in other areas of our business or increase the prices of our medicines or services. For example, these rules and regulations make it more difficult and more expensive for us to obtain and maintain director and officer liability insurance. We cannot predict or estimate the amount or timing of additional costs that we may incur to respond to these requirements. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our board of directors, our board committees or as executive officers. If we fail to comply with the continued listing requirements of Nasdaq, our ordinary shares could be delisted from The Nasdaq Global Select Market, which would adversely affect the liquidity of our ordinary shares and our ability to obtain future financing.

The Sarbanes-Oxley Act requires, among other things, that we maintain effective internal controls for financial reporting and disclosure controls and procedures. In particular, we are required to perform annual system and process evaluation and testing of our internal controls over financial reporting to allow management to report on the effectiveness of our internal controls over financial reporting, as required by Section 404 of the Sarbanes-Oxley Act, or Section 404. Our independent registered public accounting firm is also required to deliver a report on the effectiveness of our internal control over financial reporting. Our testing, or the testing by our independent registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses. Our compliance with Section 404 requires that we incur substantial expense and expend significant management efforts, particularly because of our Irish parent company structure and international operations. If we are not able to comply with the requirements of Section 404 or if we or our independent registered public accounting firm identify deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses, the market price of our ordinary shares could decline and we could be subject to sanctions or investigations by Nasdaq, the SEC or other regulatory authorities, which would require additional financial and management resources.

New laws and regulations as well as changes to existing laws and regulations affecting public companies, including the provisions of the Sarbanes-Oxley Act and rules adopted by the SEC and by Nasdaq, would likely result in increased costs as we respond to their requirements.

Securities class action litigation could divert our management’s attention and harm our business and could subject us to significant liabilities.

The stock markets have from time to time experienced significant price and volume fluctuations that have affected the market prices for the equity securities of pharmaceutical companies. These broad market fluctuations may cause the market price of our ordinary shares to decline. In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for us because biotechnology and biopharma companies have experienced significant stock price volatility in recent years. For example, following declines in our stock price, two federal securities class action lawsuits were filed in March 2016 against us and certain of our current and former officers alleging violations of the Securities Exchange Act of 1934, as amended, which lawsuits were dismissed by the plaintiffs in June 2018. Even if we are successful in defending any similar claims that may be brought in the future, such litigation could result in substantial costs and may be a distraction to our management and may lead to an unfavorable outcome that could adversely impact our financial condition and prospects.

We are exposed to the risk that our employees, independent contractors, principal investigators, consultants, vendors, distributors and CROs may engage in fraudulent or other illegal activity. Misconduct by these parties could include intentional, reckless and/or negligent conduct or unauthorized activities that violate FDA regulations, including those laws that require the reporting of true, complete and accurate information to the FDA, manufacturing standards, federal and state healthcare fraud and abuse laws and regulations, and laws that require the true, complete and accurate reporting of financial information or data. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Misconduct by our employees and other third parties may also include the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. We have adopted a Code of Conduct and Ethics, but it is not always possible to identify and deter misconduct by our employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, the exclusion from participation in federal and state healthcare programs and imprisonment.

Third-party claims of intellectual property infringement may prevent or delay our development and commercialization efforts.

Our commercial success depends in part on us avoiding infringement of the patents and proprietary rights of third parties. There is a substantial amount of litigation, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries, including patent infringement lawsuits, interferences, oppositions and inter party reexamination proceedings before the United States Patent and Trademark Office, or the U.S. PTO. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which our collaborators are developing medicine candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our medicine candidates may be subject to claims of infringement of the patent rights of third parties.

Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents or patent applications with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our medicines and/or any other medicine candidates. Because patent applications can take many years to issue, there may be currently pending patent applications, which may later result in issued patents that our medicine candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing process of any of our medicine candidates, any molecules formed during the manufacturing process or any final medicine itself, the holders of any such patents may be able to block our ability to commercialize such medicine candidate unless we obtained a license under the applicable patents, or until such patents expire. Similarly, if any third-party patent were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, including combination therapy, the holders of any such patent may be able to block our ability to develop and commercialize the applicable medicine candidate unless we obtained a license or until such patent expires. In either case, such a license may not be available on commercially reasonable terms or at all.

Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize one or more of our medicine candidates. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business. In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing medicines, which may be impossible or require substantial time and monetary expenditure. We cannot predict whether any such license would be available at all or whether it would be available on commercially reasonable terms. Furthermore, even in the absence of litigation, we may need to obtain licenses from third parties to advance our research or allow commercialization of our medicine candidates, and we have done so from time to time. We may fail to obtain any of these licenses at a reasonable cost or on reasonable terms, if at all. In that event, we would be unable to further develop and commercialize one or more of our medicine candidates, which could harm our business significantly. We cannot provide any assurances that third-party patents do not exist which might be enforced against our medicines, resulting in either an injunction prohibiting our sales, or, with respect to our sales, an obligation on our part to pay royalties and/or other forms of compensation to third parties.

~~If we fail to comply with our obligations in the agreements under which we license rights to technology from third parties, we could lose license rights that are important to our business.~~

We also hold an exclusive license to patents and technology from Duke University, or Duke, and Mountain View Pharmaceuticals, Inc., or MVP, covering KRYSTEXXA. Duke and MVP may terminate the license if we commit fraud or for our willful misconduct or illegal conduct. Duke and MVP may also terminate the license upon our material breach of the agreement, if not cured within a specified period of time, or upon written notice if we have committed two or more material breaches under the agreement. Duke and MVP may also terminate the license in the event of our bankruptcy or insolvency. If the license is terminated, it may be impossible for us to continue to commercialize KRYSTEXXA, which would have a material adverse effect on our business, financial condition and results of operations.

We hold an exclusive license to Vectura Group plc’s, or Vectura, proprietary technology and know-how covering the delayed-release of corticosteroids relating to RAYOS. If we fail to comply with our obligations under our agreement with Vectura or our other license agreements, or if we are subject to a bankruptcy, the licensor may have the right to terminate the license, in which event we would not be able to market medicines covered by the license, including RAYOS.

We hold an exclusive, worldwide license from F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., or Roche, to patents and know-how for TEPEZZA. We also have exclusive sub-licenses for rights licensed to Roche for TEPEZZA by certain third-party licensors. Roche may have the right to terminate the license upon our breach, if not cured within a specified period of time. Roche may also terminate the license in the event of our bankruptcy or insolvency, or if we challenge the validity of Roche’s patents. If the license is terminated for our breach or based on our challenging the validity of Roche’s patents,then all rights and licenses granted to us by Roche would also terminate, and we may be required to assign and transfer to Roche certain filings and approvals, trademarks, and data in our possession necessary for the development and commercialization of TEPEZZA, and assign clinical trial agreements to the extent permitted. We may also be required to grant Roche an exclusive license under our patents and know-how for TEPEZZA, and to manufacture and supply TEPEZZA to Roche for a transitional period. We also have a license of patent rights to TEPEZZA under a license agreement with Lundquist Institute (formerly known as ~~Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center), or Lundquist~~. Lundquist has the right to terminate the license agreement upon our material breach, if not cured within a specified period of time, or in the event of our bankruptcy or insolvency. If one or more of these licenses is terminated, it may be impossible for us to continue to commercialize TEPEZZA, which would have a material adverse effect on our business, financial condition and results of operations.

We may be involved in lawsuits to protect or enforce our patents or the patents of our licensors, which could be expensive, time consuming and unsuccessful.

Competitors may infringe our patents or the patents of our licensors. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time-consuming. In addition, in an infringement proceeding, a court may decide that one of our patents, or a patent of one of our licensors, is not valid or is unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation or defense proceedings could put one or more of our patents at risk of being invalidated or interpreted narrowly and could put our patent applications at risk of not issuing.

There are numerous post grant review proceedings available at the U.S. PTO (including inter partes review, post-grant review and ex-parte reexamination) and similar proceedings in other countries of the world that could be initiated by a third-party that could potentially negatively impact our issued patents.

Interference proceedings provoked by third parties or brought by us may be necessary to determine the priority of inventions with respect to our patents or patent applications or those of our collaborators or licensors. An unfavorable outcome could require us to cease using the related technology or to attempt to license rights to it from the prevailing party. Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable terms. Our defense of litigation or interference proceedings may fail and, even if successful, may result in substantial costs and distract our management and other employees. We may not be able to prevent, alone or with our licensors, misappropriation of our intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of our ordinary shares.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these ~~requirements.~~requirements.

Periodic maintenance fees on any issued patent are due to be paid to the U.S. PTO and foreign patent agencies in several stages over the lifetime of the patent. The U.S. PTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. If we or licensors that control the prosecution and maintenance of our licensed patents fail to maintain the patents and patent applications covering our medicine candidates, our competitors might be able to enter the market, which would have a material adverse effect on our business.

We may be subject to claims that our employees, consultants or independent contractors have wrongfully used or disclosed confidential information of third parties.

We employ individuals who were previously employed at other biotechnology or pharmaceutical companies. We may be subject to claims that we or our employees, consultants or independent contractors have inadvertently or otherwise used or disclosed confidential information of our employees’ former employers or other third parties. We may also be subject to claims that former employers or other third parties have an ownership interest in our patents. Litigation may be necessary to defend against these claims. There is no guarantee of success in defending these claims, and even if we are successful, litigation could result in substantial cost and be a distraction to our management and other employees.

The market price of our ordinary shares historically has been volatile and is likely to continue to be volatile, and you could lose all or part of any investment in our ordinary shares.*

~~We have never declared or paid dividends on our share capital and we do not anticipate paying dividends in the foreseeable future.~~

As a public company, we have incurred and will continue to incur significant legal, accounting and other expenses that we did not incur as a private company. In particular, the Sarbanes-Oxley Act of 2000, or the Sarbanes-Oxley Act, as well as rules subsequently implemented by the SEC and the Nasdaq Stock Market, Inc., or Nasdaq, impose significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices. These rules and regulations have substantially increased our legal and financial compliance costs and have made some activities more time-consuming and costly. These effects are exacerbated by our transition to an Irish company and the integration of numerous acquired businesses and operations into our historical business and operating structure. If these requirements divert the attention of our management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition and results of operations. The increased costs will continue to decrease our net income or increase our net income (loss), and may require us to reduce costs in other areas of our business or increase the prices of our medicines or services. For example, these rules and regulations make it more difficult and more expensive for us to obtain and maintain director and officer liability insurance. We cannot predict or estimate the amount or timing of additional costs that we may incur to respond to these requirements. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our board of directors, our board committees or as executive officers. If we fail to comply with the continued listing requirements of Nasdaq, our ordinary shares could be delisted from The Nasdaq Global Select Market, which would adversely affect the liquidity of our ordinary shares and our ability to obtain future financing.

Sales of a substantial number of our ordinary shares in the public market could cause our share price to decline.*

If our existing shareholders sell, or indicate an intention to sell, substantial amounts of our ordinary shares in the public market, the trading price of such ordinary shares could decline. In addition, our ordinary shares that are either subject to outstanding options and restricted stock units or reserved for future issuance under our employee benefit plans are or may become eligible for sale in the public market to the extent permitted by the provisions of various vesting schedules and the Securities Act of 1933, as ~~amended, or the Securities Act.~~amended. If these additional ordinary shares are sold, or if it is perceived that they will be sold, in the public market, the trading price of our ordinary shares could decline.

Additional capital may be needed in the future to continue our planned operations. To the extent we raise additional capital by issuing equity securities or securities convertible into or exchangeable for ordinary shares, our shareholders may experience substantial dilution. We may sell ordinary shares, and we may sell convertible or exchangeable securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time. If we sell such ordinary shares, convertible or exchangeable securities or other equity securities in subsequent transactions, existing shareholders may be materially diluted. New investors in such subsequent transactions could gain rights, preferences and privileges senior to those of holders of ordinary shares. We also maintain equity incentive plans, including our 2020 Equity Incentive Plan, 2014 Non-Employee Equity Plan, as amended, and 2020 Employee Share Purchase Plan, and intend to grant additional ordinary share awards under these and future plans, which will result in additional dilution to our existing shareholders.

~~Irish law differs from the laws in effect in the United States and may afford less protection to holders of our securities.~~

~~Provisions of our articles of association, and Irish law could delay or prevent a takeover of us by a third party.~~

~~Any attempts to take us over will be subject to Irish Takeover Rules and subject to review by the Irish Takeover Panel.~~

If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.

The trading market for our ordinary shares will depend in part on the research and reports that securities or industry analysts publish about us or our business. If one or more of the analysts who cover us downgrade our rating or publish inaccurate or unfavorable research about our business, our share price could decline. If one or more of these analysts cease coverage of our company or fail to publish reports on our company regularly, demand for our ordinary shares could decrease, which might cause our share price and trading volume to decline.

~~Securities class action litigation could divert our management’s attention and harm our business and could subject us to significant liabilities.~~

The stock markets have from time to time experienced significant price and volume fluctuations that have affected the market prices for the equity securities of pharmaceutical companies. These broad market fluctuations may cause the market price of our ordinary shares to decline. In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for us because biotechnology and biopharma companies have experienced significant stock price volatility in recent years. For example, following declines in our stock price, two federal securities class action lawsuits were filed in March 2016 against us and certain of our current and former officers alleging violations of the Securities Exchange Act of 1934, as amended, which lawsuits were dismissed by the plaintiffs in June 2018. Even if we are successful in defending any similar claims that may be brought in the future, such litigation could result in substantial costs and may be a distraction to our management, and may lead to an unfavorable outcome that could adversely impact our financial condition and prospects.

During the three months ended September 30, 2020, we issued an aggregate of 6,673,046 ordinary shares to certain holders of our 2.5% Exchangeable Senior Notes due 2022, or Exchangeable Senior Notes. The shares were issued as a result of such holders exercising their rights to exchange an aggregate principal amount of $191.2 million of the Exchangeable Senior Notes.

~~The offers, sales and issuances of the securities described above were deemed to be exempt from registration under the Securities Act in reliance on Section~~ ~~4(a)(2) and 3(a)(9) of the Securities Act. No underwriters were involved in these transactions.~~

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.

Ireland		Not Applicable
(State or other jurisdiction of incorporation or organization)		(I.R.S. Employer Identification No.)

~~Connaught House, 1st Floor~~70 Saint Stephen’s Green ~~1 Burlington Road,~~ Dublin ~~4, D04 C5Y6,~~2, D02 E2X4, Ireland		Not Applicable
(Address of principal executive offices)		(Zip Code)


Title of each class	Trading Symbol	Name of each exchange on which registered
Ordinary shares, nominal value $0.0001 per share	HZNP	The Nasdaq Global Select Market

		Page
		No.
PART I. FINANCIAL INFORMATION
Item 1.	Financial Statements	1
	Condensed Consolidated Balance Sheets as of September 30, ~~2020~~2021 and as of December 31, ~~2019~~2020 (Unaudited)	1
	Condensed Consolidated Statements of Comprehensive Income ~~(Loss)~~ for the Three and Nine Months Ended September 30, ~~2020~~2021 and ~~2019~~2020 (Unaudited)	2
	Condensed Consolidated Statements of Shareholders’ Equity for the Three and Nine Months Ended September 30, ~~2020~~2021 and ~~2019~~2020 (Unaudited)	3
	Condensed Consolidated Statements of Cash Flows for the Nine Months Ended September 30, ~~2020~~2021 and ~~2019~~2020 (Unaudited)	5
	Notes to Unaudited Condensed Consolidated Financial Statements	7
Item 2.	Management’s Discussion and Analysis of Financial Condition and Results of Operations	3335
Item 3.	Quantitative and Qualitative Disclosures About Market Risk	5557
Item 4.	Controls and Procedures	5558
PART II. OTHER INFORMATION
Item 1.	Legal Proceedings	5659
Item 1A.	Risk Factors	56
~~Item 2.~~	~~Unregistered Sales of Equity Securities and Use of Proceeds~~	~~103~~59
Item 6.	Exhibits	~~104~~115
	Signatures	~~106~~117

~~Buildings~~		~~40 years~~
~~Land improvements~~		~~10 years~~
~~Machinery and equipment~~		~~5 to 7 years~~
~~Furniture and fixtures~~		~~3 to 5 years~~
~~Computer equipment~~		~~3 years~~
~~Software~~		~~3 years~~
~~Trade show equipment~~		~~3 years~~

Construction in process	$	22,736
Buildings		21,550
Furniture and fixtures		1,089
Definite-lived intangible assets		21,794
Other		775
Total consideration	$	67,944

Large accelerated filer	☒	Accelerated filer	☐

Non-accelerated filer	☐	Smaller reporting company	☐

Emerging growth company	☐

Equity value (54,988,820 shares at $53.00 per share)	$	2,914,407
Net settlements on the exercise of stock options		78,554
Consideration for exchange of Viela stock options		1,130
Total consideration	$	2,994,091

	Before			Adjustments			After
Deferred tax liabilities, net	$	(457,928	)	$	6,869		$	(451,059	)
Accrued expenses and other current liabilities		(73,401	)		(335	)		(73,736	)
Other long-term liabilities		(22,631	)		—			(22,631	)
Accounts payable		(4,768	)		—			(4,768	)
Accrued trade discounts and rebates		(1,492	)		(373	)		(1,865	)
Marketable securities		400			—			400
Property, plant and equipment		1,747			—			1,747
Other assets		3,253			—			3,253
Accounts receivable		8,053			(267	)		7,786
Prepaid expenses and other current assets		16,444			(837	)		15,607
Inventories		149,348			2,300			151,648
Cash and cash equivalents		342,347			—			342,347
In-process research and development		910,000			—			910,000
Developed technology		1,460,000			—			1,460,000
(Liabilities assumed) and assets acquired		2,331,372			7,357			2,338,729
Goodwill		662,719			(7,357	)		655,362
Fair value of consideration paid	$	2,994,091		$	—		$	2,994,091

Cash proceeds	$	6,000
Less net assets sold:
Developed technology		(16,999	)
Inventory		(236	)
Release of contingent consideration liability	272
Loss on sale of assets	$	(10,963	)

	Wholesaler Fees			Co-Pay and			Government
	and Commercial			Other Patient			Rebates and
	Rebates			Assistance			Chargebacks			Total
Balance at December 31, 2019	$	138,761		$	163,641		$	164,508		$	466,910
Current provisions relating to sales during the nine months ended September 30, 2020		239,788			665,575			432,755			1,338,118
Adjustments relating to prior-year sales		(16,279	)		(3,059	)		(7,796	)		(27,134	)
Payments relating to sales during the nine months ended September 30, 2020		(158,996	)		(587,936	)		(268,302	)		(1,015,234	)
Payments relating to prior-year sales		(118,302	)		(160,501	)		(155,976	)		(434,779	)
Balance at September 30, 2020	$	84,972		$	77,720		$	165,189		$	327,881

Location	Approximate Square Feet		Lease Expiry Date
Dublin, Ireland (St. Stephen’s Green) ⁽¹⁾		63,000	May 4, 2041
Dublin, Ireland (Connaught House) ⁽¹⁾		18,900	November 4, 2029
Lake Forest, Illinois		160,000	March 31, 2031
~~Novato, California~~		~~61,000~~	~~August 31, 2021~~
South San Francisco, California		20,000	January 31, 2030
Rockville, Maryland ⁽²⁾		24,500	August 31, 2023 to April 30, 2026
Chicago, Illinois		9,200	December 31, 2028
Gaithersburg, Maryland ⁽²⁾		7,200	June 30, 2022
Washington, D.C.		6,000	September 15, 2022
Mannheim, Germany		4,800	December 31, 2022


TEPEZZA Worldwide Net Sales Threshold	Milestone Payment
>$250 million	$50 million
>$375 million	$75 million
>$500 million	$100 million

Exhibit Number		Description of Document

2.1#		Agreement and Plan of Merger, dated January 31, 2021, by and among Horizon Therapeutics USA, Inc., Teiripic Merger Sub, Inc., Viela Bio, Inc. and solely for purposes of Sections 6.7 and 9.12 of the Merger Agreement, Horizon Therapeutics plc (incorporated by reference to Exhibit 2.1 to Horizon Therapeutics Public Limited Company’s Current Report on Form 8-K, filed on February 1, 2021).

3.1		Memorandum and Articles of Association of Horizon Therapeutics Public Limited Company, as amended (incorporated by reference to Exhibit 3.1 to Horizon Therapeutics Public Limited Company’s Quarterly Report on Form 10-Q, filed on May 8, 2019).

4.1		Indenture dated as of July 16, 2019 by and between Horizon Therapeutics USA, Inc., the guarantors party thereto and U.S. Bank National Association, as trustee (incorporated by reference to Exhibit 4.1 to Horizon Therapeutics Public Limited Company’s Current Report on Form 8-K, filed on July 16, 2019).

4.2		Form of ~~5.5%~~5.500% Senior Note due 2027 (incorporated by reference to Exhibit 4.1 to Horizon Therapeutics Public Limited Company’s Current Report on Form 8-K, filed on July 16, 2019).

4.3		First Supplemental Indenture, dated November 19, 2019, by and between HZNP Finance Limited and U.S. Bank National Association (incorporated by reference to Exhibit 4.5 to Horizon Therapeutics Public Limited Company’s Quarterly Report on Form 10-Q, filed on May 6, 2020).

4.4		Second Supplemental Indenture, dated April 23, 2020, by and among Horizon Properties Holding LLC, Curzion Pharmaceuticals, Inc. and U.S. Bank National Association (incorporated by reference to Exhibit 4.6 to Horizon Therapeutics Public Limited Company’s Quarterly Report on Form 10-Q, filed on May 6, 2020).

10.1*4.5		~~Amendment No. 3 to Commercial Supply Agreement,~~Third Supplemental Indenture, dated ~~July 30, 2020,~~March 15, 2021, by and between ~~AGC Biologics A/S (formerly known as CMC Biologics A/S)~~Viela Bio, Inc. and U.S. Bank National Association (incorporated by reference to Exhibit 4.5 to Horizon Therapeutics ~~Ireland DAC.~~
10.2*		Development and Manufacturing Services Agreement, dated June 10, 2015, by and between AGC Biologics A/S (formerly known as CMC Biologics A/S) and Horizon Therapeutics Ireland DAC (as successor in interest to River Vision Development Corp)Public Limited Company’s Quarterly Report on Form 10-Q, filed on May 5, 2021).
~~10.3~~		Incremental Amendment and Lender Joinder Agreement, dated August 17, 2020, by and among JP Morgan Chase Bank, N.A., as an incremental revolving lender and as an issuing bank, Horizon Therapeutics USA, Inc. and Citibank, N.A., as administrative agent.

10.4*10.1+		~~API Supply Agreement, dated November 3, 2010, by and between Cambrex Profarmaco Milano and~~ Horizon Therapeutics ~~Ireland DAC (as successor in interest to Raptor Therapeutics Inc.~~Public Limited Company Amended and ~~Raptor Pharmaceuticals Europe B.V.), as amended April 9, 2013.~~Restated 2020 Equity Incentive Plan and Form of Option Agreement, Form of Stock Option Grant Notice, Forms of Restricted Stock Unit Agreement and Forms of Restricted Stock Unit Grant Notice thereunder.

10.2+		Horizon Therapeutics Public Limited Company Amended and Restated 2018 Equity Incentive Plan (assumed from Viela Bio, Inc.) and Form of RSU Award Grant Notice and Form of Award Agreement (RSU Award) thereunder.

10.3+		Horizon Therapeutics Public Limited Company 2014 Non-Employee Equity Plan, as amended, and Form of Option Agreement, Form of Stock Option Grant Notice, Forms of Restricted Stock Unit Agreement and Forms of Restricted Stock Unit Grant Notice thereunder.

31.1		Certification of Principal Executive Officer pursuant to Rule 13a-14(a) or 15d-14(a) of the Exchange Act.

31.2		Certification of Principal Financial Officer pursuant to Rule 13a-14(a) or 15d-14(a) of the Exchange Act.

32.1		Certification of Principal Executive Officer pursuant to Rule 13a-14(b) or 15d-14(b) of the Exchange Act and 18 U.S.C. Section 1350.

32.2		Certification of Principal Financial Officer pursuant to Rule 13a-14(b) or 15d-14(b) of the Exchange Act and 18 U.S.C. Section 1350.

Exhibit Number		Description of Document

101. INS		Inline XBRL Instance Document – the instance document does not appear in the Interactive Data File because its XBRL tags are embedded within the Inline XBRL document

101.SCH		Inline XBRL Taxonomy Extension Schema Document

101.CAL		Inline XBRL Taxonomy Extension Calculation Linkbase Document

101.DEF		Inline XBRL Taxonomy Extension Definition Linkbase Document

101.LAB		Inline XBRL Taxonomy Extension Label Linkbase Document

101.PRE		Inline XBRL Taxonomy Extension Presentation Linkbase Document

104		Cover Page Interactive Data File (formatted as Inline XBRL and contained in Exhibit 101)

	HORIZON THERAPEUTICS PLC

Date: November ~~2, 2020~~3, 2021	By:	/s/ Timothy P. Walbert
		Timothy P. Walbert
		Chairman, President and Chief Executive Officer (Principal Executive Officer)

Date: November ~~2, 2020~~3, 2021	By:	/s/ Paul W. Hoelscher
		Paul W. Hoelscher
		Executive Vice President, Chief Financial Officer (Principal Financial Officer)