 | ||
EXELIXIS, INC. | ||
| (Exact name of registrant as specified in its charter) | ||
| Delaware | 04-3257395 | ||||
| (State or other jurisdiction of incorporation or organization) | (I.R.S. Employer Identification Number) | ||||
1851 Harbor Bay Parkway
Alameda, CA 94502
(650) 837-7000
(Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices)
Securities Registered Pursuantregistered pursuant to Section 12(b) of the Act:
| Title of | Trading Symbol(s) | Name of | ||||||
| Common Stock $.001 Par Value per Share | EXEL | The Nasdaq Stock Market LLC | ||||||
Securities Registered Pursuantregistered pursuant to Section 12(g) of the Act:
None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ý ☒No ¨☐
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ¨ ☐No ý☒
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 ý ☒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 ý ☒No ¨
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or 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.
| Large accelerated filer | Accelerated filer | |||||||||||||||||||
| Non-accelerated filer | Smaller reporting company | |||||||||||||||||||
| Emerging growth company | ||||||||||||||||||||
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 7(a)(2)(B) of the Securities Act. ¨☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☒
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ¨ ☐No ý☒
State the aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the price at which the common equity was last sold, or the average bid and asked price of such common equity, as of the last business day of the registrant’s most recently completed second fiscal quarter: $5,531.1 million (based on the closing sales price of the registrant’s common stock on June 29, 2018.$5,680,065,864. Excludes an aggregate of approximately 40.9 million shares of the registrant’s common stock held by persons who were directors and/or executive officers of the registrant at June 29, 2018July 2, 2021 on the basis that such persons may be deemed to have been affiliates of the registrant at such date. Exclusion of such shares should not be construed to indicate that any such person possesses the power, direct or indirect, to direct or cause the direction of the management or policies of the registrant or that such person is controlled by or under common control with the registrant.)
DOCUMENTS INCORPORATED BY REFERENCE
Certain portions of the registrant’s definitive proxy statement to be filed with the Securities and Exchange Commission pursuant to Regulation 14A, not later than April 27, 2019,30, 2022, in connection with the registrant’s 20182022 Annual Meeting of Stockholders are incorporated herein by reference into Part III of this Annual Report on Form 10-K.
EXELIXIS, INC.
ANNUAL REPORT ON FORM 10-K
INDEX
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PART I
SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS
Some of the statements under the captions “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and “Business” and elsewhere in this Annual Report on Form 10-K are forward-looking statements. These statements are based on our current expectations, assumptions, estimates and projections about our business and our industry and involve known and unknown risks, uncertainties and other factors that may cause our company’s or our industry’s results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied in, or contemplated by, the forward-looking statements. Our actual results and the timing of events may differ significantly from the results discussed in the forward-looking statements. Factors that might cause such a difference include those discussed inunder the heading “Item 1A. Risk Factors” as well as those discussed elsewhere in this Annual Report on Form 10-K.
These and many other factors could affect our future financial and operating results. We undertake no obligation to update any forward-looking statement to reflect events after the date of this report.
RISK FACTOR SUMMARY
Investing in our securities involves a high degree of risk. Below is a summary of material factors that make an investment in our securities speculative or risky. Importantly, this summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, as well as other risks that we face, can be found under the heading “Item 1A. Risk Factors” below.
•Our ability to grow our company is dependent upon the commercial success of CABOMETYX in its approved indications and the continued clinical development, regulatory approval, clinical acceptance and commercial success of the cabozantinib franchise in additional indications.
•If we are unable to obtain or maintain coverage and reimbursement for our products from third-party payers, our business will suffer.
•Pricing for pharmaceutical products, both in the U.S. and in foreign countries, has come under increasing attention and scrutiny by federal, state and foreign national governments, legislative bodies and enforcement agencies. These activities may result in actions that have the effect of reducing our revenue or harming our business or reputation.
•The entrance of generic competitors and legislative and regulatory action designed to reduce the barriers to the development, approval and adoption of generic drugs in the U.S. could limit the revenue we derive from our products, most notably CABOMETYX, which could have a material adverse impact on our business, financial condition and results of operations.
•We are subject to healthcare laws, regulations and enforcement, as well as laws and regulations relating to privacy, data collection and processing of personal data; our failure to comply with those laws could have a material adverse impact on our business, financial condition and results of operations.
•Clinical testing of cabozantinib for new indications, or of new product candidates, is a lengthy, costly, complex and uncertain process that may fail ultimately to demonstrate safety and efficacy data for those products sufficiently differentiated to compete in our highly competitive market environment.
•The regulatory approval processes of the U.S. Food and Drug Administration and comparable foreign regulatory authorities are lengthy, uncertain and subject to change, and may not result in regulatory approvals for additional cabozantinib indications or for our other product candidates, which could have a material adverse impact on our business, financial condition and results of operations.
•We may be unable to expand our discovery and development pipeline, which could limit our growth and revenue potential.
•Our profitability could be negatively impacted if expenses associated with our extensive clinical development, business development and commercialization activities, both for the cabozantinib franchise and our earlier-stage product candidates, grow more quickly than the revenues we generate.
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•Our clinical, regulatory and commercial collaborations with major companies make us reliant on those companies for their continued performance and investments, which subjects us to a number of risks. For example, we rely on Ipsen and Takeda for the commercial success of CABOMETYX in its approved indications outside of the U.S., and we are unable to control the amount or timing of resources expended by these collaboration partners in the commercialization of CABOMETYX in its approved indications outside of the U.S. In addition, our growth potential is dependent in part upon companies with which we have entered into research collaborations, in-licensing arrangements and similar business development relationships.
•Data breaches, cyber attacks and other failures in our information technology operations and infrastructure could compromise our intellectual property or other sensitive information, damage our operations and cause significant harm to our business and reputation.
•If we are unable to adequately protect our intellectual property, third parties may be able to use our technology, which could adversely affect our ability to compete in the market.
•If the COVID-19 pandemic is further prolonged or becomes more severe, our business operations and corresponding financial results could suffer, which could have a material adverse impact on our financial condition and prospects for growth.
•The loss of key personnel or the inability to retain and, where necessary, attract additional personnel could impair our ability to operate and expand our operations.
BASIS OF PRESENTATION
We have adopted a 52- or 53-week fiscal year policy that generally ends on the Friday closest to December 31st. Fiscal year 20162021, which was a 52-week year, ended December 31, 2021, fiscal year 2020, which was a 52-week fiscal year, ended on December 30, 2016; fiscal year 2017 ended on December 29, 2017; fiscal year 2018 ended on December 28, 2018;January 1, 2021 and fiscal year 2019, will endwhich was a 53-week fiscal year, ended on January 3, 2020. For convenience, references in this report as of and for the fiscal years ended (or ending, as applicable) December 30, 2016, December 29, 2017, December 28, 2018January 1, 2021 and January 3, 2020 are indicated as being as of and for the years ended (or ending, as applicable) December 31, 2016, 2017, 20182020 and 2019, respectively. The annual period and quarterly period ending January 3, 2020 are a 53-week fiscal year and a 14-week fiscal quarter, respectively; all other annual periods presented are 52-week fiscal years and all interim periods presented are 13-week fiscal quarters.
Item 1. Business
Overview
Exelixis, Inc. (Exelixis, we, our or us) is an oncology-focused biotechnology company that aimsstrives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. OurUsing our considerable drug discovery, and development capabilities and commercialization platform are the foundations upon whichresources and capabilities, we intend to bringhave invented and brought to market novel, effectiveinnovative therapies that appropriately balance patient benefits and tolerable therapiesrisks; we will continue to build on this foundation as we strive to provide cancer patients with additionalnew treatment options.options that improve upon current standards of care.
The other two products resulting from our discovery efforts are: COTELLIC® (cobimetinib), an inhibitor of MEK approved as part of amultiple combination regimenregimens to treat specific forms of advanced melanoma and marketed under a collaboration with Genentech, Inc. (a member of the Roche Group) (Genentech); and MINNEBRO™MINNEBRO® (esaxerenone), an oral, non-steroidal, selective blocker of the mineralocorticoid receptor (MR) approved for the treatment of hypertension in Japan and licensed to Daiichi Sankyo Company, Limited (Daiichi Sankyo). For additional information about these products, see “—Collaborations and Business Development Activities—Other Collaborations.”
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biotherapeutics programs, exploring multiple modalities and mechanisms of action to discover new oncology drugs. So far, these drug discovery and preclinical activities have resulted in four clinical-stage compounds: XL092, a next-generation oral tyrosine kinase inhibitor (TKI); XB002, an antibody drug conjugate (ADC) that targets tissue factor (TF); XL102, a potent, selective and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7); and XL114, a novel anti-cancer compound that inhibits the CARD11-BCL10-MALT1 (CBM) complex.
Exelixis Marketed Products: CABOMETYX and COMETRIQ
As detailed below, CABOMETYX was firstand COMETRIQ have been approved to treat patients with various forms of cancer by the U.S. Food and Drug Administration (FDA) on April 25, 2016,FDA for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy and byU.S. market, the European Commission (EC) on September 9, 2016, similarly for the treatment of advanced RCC in adults in the European Union (EU) following prior VEGF-targeted therapy. On December 19, 2017, the FDA approved the expanded indication for CABOMETYX to include previously untreated patients with advanced RCC,markets and the EC approved CABOMETYX on May 17, 2018Japanese Ministry of Health, Labour and Welfare (MHLW), as a first-line treatment for adults with intermediate- or poor-risk advanced RCC. Most recently, CABOMETYX was approvedwell as by the FDA on comparable regulatory authorities across other markets worldwide.
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| Product | Indication | Approval Date | Regimen | Major Markets | ||||||||||
| CABOMETYX® (cabozantinib) | Renal Cell Carcinoma (RCC) | |||||||||||||
| Patients with advanced RCC who have received prior anti-angiogenic therapy | April 25, 2016 | Monotherapy | U.S. | |||||||||||
| Advanced RCC in adults following prior VEGF-targeted therapy | September 9, 2016 | Monotherapy | EU | |||||||||||
| Patients with advanced RCC | December 19, 2017 | Monotherapy | U.S. | |||||||||||
| First-line treatment of adults with intermediate- or poor-risk advanced RCC | May 17, 2018 | Monotherapy | EU | |||||||||||
| Patients with curatively unresectable or metastatic RCC | March 25, 2020 | Monotherapy | Japan | |||||||||||
| First-line treatment of patients with advanced RCC | January 22, 2021 | Combination with OPDIVO® (nivolumab) | U.S. | |||||||||||
| First-line treatment for patients with advanced RCC | March 31, 2021 | Combination with OPDIVO | EU | |||||||||||
| Patients with unresectable or metastatic RCC | August 25, 2021 | Combination with OPDIVO | Japan | |||||||||||
| Hepatocellular Carcinoma (HCC) | ||||||||||||||
| HCC in adults who have previously been treated with sorafenib | November 15, 2018 | Monotherapy | EU | |||||||||||
| Patients with HCC who have been previously treated with sorafenib | January 14, 2019 | Monotherapy | U.S. | |||||||||||
| Patients with unresectable HCC that has progressed after cancer chemotherapy | November 27, 2020 | Monotherapy | Japan | |||||||||||
| Differentiated Thyroid Cancer (DTC) | ||||||||||||||
| Adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGF receptor-targeted therapy and who are RAI-refractory or ineligible | September 17, 2021 | Monotherapy | U.S. | |||||||||||
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| COMETRIQ® (cabozantinib) | Medullary Thyroid Cancer (MTC) | |||||||||||||
| Patients with progressive, metastatic MTC | November 29, 2012 | Monotherapy | U.S. | |||||||||||
| Adult patients with progressive, unresectable locally advanced or metastatic MTC | March 25, 2014 | Monotherapy | EU | |||||||||||
In 2021, 2020 and 2019, for the treatment of patients with HCC who have been previously treated with sorafenib, which followed the EC’s earlier approval of CABOMETYX on November 15, 2018, for the treatment of HCC in adults previously treated with sorafenib. COMETRIQ, our first marketed product, was approved by the FDA on November 29, 2012, for the treatment of patients with progressive, metastatic MTC, and in March 2014, the EC granted COMETRIQ a conditional marketing authorization for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. In 2018 and 2017, weU.S. commercial organization generated $619.3$1,077.3 million, $741.6 million and $349.0$760.0 million, respectively, in net product revenues from sales of CABOMETYX and COMETRIQ inCOMETRIQ. Outside the U.S.
Renal Cell Carcinoma - CABOMETYX is Now thea Leading Tyrosine Kinase Inhibitor (TKI)TKI Treatment Option for Patients with Advanced RCC
CABOMETYX has become a standard of care for the treatment of patients suffering from advanced RCC, and a growing number of these patients have been or will be treated with CABOMETYX. Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S., with Estimates suggest that approximately 30,00033,000 patients requiring systemic treatment. Globally, approximately 68,000 patientsin the U.S. and over 71,000 worldwide will require systemic treatment for kidney cancer. A growing number of these patientscancer in 2022, with RCC have been or will be treated with CABOMETYX, which has become a new standard of care for the treatment of patients suffering from this difficult-to-treat disease; in fact, as of December 2018, CABOMETYX was the TKI of choice among physicians treating theseover 15,000 patients in termsneed of new prescriptions.a first-line treatment in the U.S.
Since CABOMETYX was first approved, we have deployed our promotional and medical affairs teams have been focused on educatingto educate physicians about CABOMETYX’s unique clinical profile. WeCABOMETYX, and we believe that the product’s success of CABOMETYX is attributable to thisthe strength of the clinical profile, derived fromdata reflected in its FDA-approved labeling for advanced RCC. The CABOMETYX label incorporates the results of ourthe METEOR, CABOSUN and CheckMate -9ER clinical trials,trials. In July 2015, we announced positive results of METEOR, and CABOSUN.a phase 3 pivotal trial comparing CABOMETYX isto everolimus in patients with advanced RCC who have experienced disease progression following treatment with at least one prior VEGF receptor inhibitor. These results formed the basis for the FDA’s approval in April 2016, following which CABOMETYX became the first and only single-agent therapy approved in the U.S. for previously treated advanced RCC to demonstrate statistically significant and clinically meaningful improvements in three key efficacy parameters in a global pivotal trial: overall survival (OS); progression-free survival (PFS); and objective response rate (ORR). In addition,Subsequently, in October 2016, we announced positive results from CABOSUN, a randomized, open-label, active-controlled phase 2 trial conducted by the Alliance for Clinical Trials in Oncology, comparing cabozantinib with sunitinib in patients with previously untreated advanced RCC with intermediate- or poor-risk disease. These results formed the basis for the FDA’s approval in December 2017 of CABOMETYX for previously untreated patients with advanced RCC, and for this patient population, CABOMETYX is the only approved single-agent therapy to improvedemonstrate improved PFS and ORR compared with sunitinib, a first-generation TKI that was the previous standard of care. It is
CABOMETYX has also noteworthydemonstrated positive clinical results in combination with immune checkpoint inhibitors (ICIs), most notably in CheckMate -9ER, an open-label, randomized, multinational phase 3 pivotal trial evaluating OPDIVO, an ICI developed by BMS, in combination with CABOMETYX versus sunitinib in patients with previously untreated, advanced or metastatic RCC. Results from CheckMate -9ER demonstrated that on September 7, 2018, the combination of CABOMETYX and OPDIVO doubled PFS and ORR and reduced the risk of disease progression or death by 40% compared with sunitinib, and formed the basis for the FDA’s approval of the combination in January 2021 as a first-line treatment of patients with advanced RCC. The National Comprehensive Cancer Network (NCCN), the nation’s foremost non-profit alliance of leading cancer centers, updated has included the combination of CABOMETYX with OPDIVO in its Clinical Practice Guidelines to recommendfor Kidney Cancer as a Category 1 option for the first-line treatment of patients with clear cell RCC. The NCCN also lists single-agent CABOMETYX as the only TKIa category 1 preferred regimen in subsequent treatments for patients with preferred status for advancedclear cell RCC, patients who have progressed on prior therapy and for the treatment of advanced RCC regardless of patient risk status (favorable-, intermediate-, and poor risk). These updated recommendations strengthened the differentiation of CABOMETYX from other TKIs approved for this indication, leading many physicians to consider CABOMETYXas a preferred therapeutic option, despite numerous competing products approved to treat advanced RCC. For additional information aboutsystemic therapy regimen for non-clear cell RCC, supporting CABOMETYX’s profile as expressedposition in the METEOR and CABOSUN clinical trial data, see “—Cabozantinib Development Program—Clinical Trials Supporting Regulatory Approvals.”RCC treatment landscape.
In markets outside the U.S. in 2018,2021, we continued to work closely with our collaboration partner Ipsen in support of its regulatory strategy and commercialization efforts for CABOMETYX as a treatment for advanced RCC.RCC, both as a single
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agent and in combination with OPDIVO, as well as in preparation for submission of applications for approvals of CABOMETYX in combination with other therapies, and similarly with our collaboration partner Takeda with respect to the Japanese market. As a result of the approvals of CABOMETYX and/or the combination of CABOMETYX with OPDIVO for RCC indications in more than ten territories61 countries outside of the U.S., including the Member States of the EU, Japan, the U.K., Canada, Brazil, Taiwan, South Korea and Australia, CABOMETYX has continued to grow markedly outside the U.S. both in sales revenue and the number of RCC patients benefiting from its clinical effect. Additionally, with respect to the Japanese market, our partner Takeda is advancing its clinical development activities in Japan support of potential future regulatory filings for CABOMETYX in both RCC and HCC.
Hepatocellular Carcinoma - the CABOMETYX Label Expanded to IncludeOffers an Important Alternative for Patients with Previously Treated HCC
According to published studies, liver cancer is a leading cause of cancer death worldwide, accounting for more than 700,000800,000 deaths and 800,000900,000 new cases each year. In the U.S., the incidence of liver cancer has more than tripled since 1980. Although HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new
more than 41,000 cases of liver cancer estimated to be diagnosed in the U.S. during 2018,2022, this patient population washas long been underserved. Prior to 2017, there was only one approved systemic therapy for the treatment of HCC. Then, in 2017 and 2018, fourSince that time, multiple new therapies were approved in the U.S. for HCC, oneboth for previously untreated patients and three for patients previously treated with sorafenib. Given the introduction of new and demonstrably more effective therapies, including ICI combination therapies, we believe the second- and later-line market for HCC markettherapies has the potential to grow significantly in coming years, as thethese new treatment options are expected to resultimprove longer-term outcomes, thereby resulting in an increasinga greater number of patients receiving multiple lines of therapy. With the recent approval of CABOMETYX in January 2019 for HCC patients previously treated with sorafenib, we aimexpect to continue to play a key role in the advancement of therapeutic optionstreatment landscape for these patients.
The FDA’s approval of CABOMETYX for thisCABOMETYX’s HCC indication was based on our phase 3 pivotal study, CELESTIAL. The CELESTIAL study met its primary endpoint, demonstrating that cabozantinib significantly improved OS, as compared to placebo. For additional information on CELESTIAL, see “—Cabozantinib Development Program—Clinical Trials Supporting Regulatory Approvals—HCC - CELESTIAL.” Upon FDA approval, we were immediately prepared to offer CABOMETYX to all eligible HCC patients in the U.S. who may benefit from this treatment option. We were able to take action so quickly due to the strength of our existing commercial and medical affairs organizations, in addition to our well-established distribution network and our ability to leverage our RCC commercialization experience. The NCCN’s inclusion ofNCCN has included CABOMETYX in its Clinical Practice Guidelines for Hepatobiliary Cancers as a Category 1 option for the treatment of patients with HCC (Child-Pugh Class A only) who have been previously treated with sorafenib, providing further supportssupport for CABOMETYX as an important new treatment option for eligible HCC patients.
Outside the U.S., the EC’s approval of CABOMETYX provided physicians in the EU with a second approved therapy for the second-line treatment of this aggressive and difficult-to-treat cancer.cancer, and approvals from Health Canada and the Japanese MHLW brought a much-needed therapy to HCC patients in those countries. In addition to the Member States of the EU, Japan, the U.K. and Canada, CABOMETYX is also approved for previously treated HCC indications in Brazil, Taiwan, South Korea, Australia and Hong Kong, among other countries.
Differentiated Thyroid Cancer - a New Opportunity for CABOMETYX to Help an Underserved Patient Population
Published studies indicate that approximately 44,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2022. Differentiated thyroid tumors, which make up about 90% of all thyroid cancers, are typically treated with surgery followed by ablation of the remaining thyroid with radioiodine (RAI). Approximately 5% to 15% of differentiated thyroid tumors are resistant to RAI treatment. With limited treatment options, these patients have a life expectancy of only three to six years from the time metastatic lesions are detected. New treatment options are therefore urgently needed.In December 2020, we announced that COSMIC-311, our phase 3 pivotal trial evaluating cabozantinib in patients with RAI-refractory DTC who have progressed after up to two prior VEGF receptor-targeted therapies, met its co-primary endpoint of demonstrating significant improvement in PFS as compared with placebo. These results formed the basis for the FDA’s approval in September 2021 of CABOMETYX for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGF receptor-targeted therapy and who are RAI-refractory or ineligible. We commenced the commercial launch of CABOMETYX in this patient group upon the FDA’s approval, and we have seen a strong uptake in prescriptions for CABOMETYX in previously treated DTC during the months that followed.
Outside the U.S., our collaboration partner Ipsen submitted a variation application to the European Medicines Agency (EMA) seeking approval of CABOMETYX as a treatment for patients with previously treated, RAI-refractory DTC, with the EMA validating the variation application and beginning its centralized review process in August 2021.
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Medullary Thyroid Cancer - COMETRIQ, the First Commercial Approval of Cabozantinib
Exelixis Development Programs
We have extensive expertise in the clinical development of oncology products, which we leverage when exploring additional clinical uses of cabozantinib in combination with other therapies and advancing that effort to new regulatory approvals. Those activities comprise the broad cabozantinib development program described below. In addition, we also apply that expertise to advancing our company’s next generation of cancer treatments: new, innovative therapies that have the potential to help future cancer patients recover stronger and live longer. Accordingly, we are initiating clinical studies for our small molecule drug candidates—XL092, XL102 and XL114—as well as for our first biotherapeutics product candidate, XB002, and these activities are described under “—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates.”
A summary of our cabozantinib and other development programs is provided below.
Cabozantinib Development Program
Cabozantinib inhibits the activity of tyrosine kinases, including MET, AXL, VEGF receptors, and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance and maintenance of the tumor microenvironment. Objective tumor responses have been observed in patients treated with cabozantinib in more than 20multiple individual tumor types investigated in phase 1, 2 and 23 clinical trials to date, reflecting the medicine’s broad clinical potential. We are currently evaluatingcontinue to evaluate cabozantinib, both as a single agent and in combination with immune checkpoint inhibitors (ICIs),ICIs, in a broad development program comprising over 75100 ongoing or planned clinical trials across multiple indications.tumor types. We, along with our clinical and commercial collaboration partners, sponsor some of those trials, and independent investigators conduct the remaining trials through our Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP) or our investigator sponsored trial (IST) program. In addition to co-sponsoringco-funding select trials with us, our commercial collaboration partners Ipsen and Takeda also conduct trials in their respective territories through similar independently-sponsored programs.
The following two tables summarize select cabozantinib clinical development activities, one describing studies that evaluate the potential of cabozantinib as a single-agent, and the other describing studies that evaluate the potential of cabozantinib in combination with one or moreother therapies, including ICIs:
| CLINICAL DEVELOPMENT PROGRAM FOR CABOZANTINIB, SINGLE-AGENT | |||||
| Indication | Status Update | ||||
| Thyroid Cancer | |||||
| Progressive, metastatic medullary thyroid cancer | Approved in U.S. and EU (EXAM) | ||||
| Renal Cell Carcinoma (RCC) | |||||
| Advanced RCC | Approved in U.S., EU and | ||||
| First- or second-line papillary RCC | Randomized phase 2† | ||||
| Metastatic variant histology RCC | Phase 2* (CABOSUN II) | ||||
| Locally advanced non-metastatic clear cell RCC | Phase 2* | ||||
| Clear cell or non-clear cell metastatic RCC | Phase 2* | ||||
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| Hepatocellular Carcinoma (HCC) | |||||
| Second- and later-line HCC after prior sorafenib | Approved in U.S. | ||||
| Advanced HCC with Child-Pugh class B cirrhosis after first-line therapy | Phase 2* | ||||
| Non-Small Cell Lung Cancer (NSCLC) | |||||
| Molecular alterations in RET, ROS1, MET, AXL, or NTRK1 | Phase 2* | ||||
| Additional Trials | |||||
| High-risk prostate cancer | Phase 2* (SPARC) | ||||
| Metastatic castration-resistant prostate cancer (mCRPC) with genomic alterations | Phase 2* | ||||
| Metastatic urothelial carcinoma (UC) | Phase 2* (ATLANTIS) | ||||
| Advanced or metastatic UC | Phase 2† | ||||
| Colorectal cancer (CRC) | Phase 2* | ||||
| High-grade uterine sarcomas | Phase 2§ | ||||
| Pancreatic neuroendocrine tumors and carcinoid tumors | Phase 2* and Phase 3† (CABINET) | ||||
| Metastatic adrenocortical carcinoma | Phase 2* | ||||
| Metastatic pheochromocytomas and paragangliomas | Phase 2* | ||||
| Plexiform neurofibromas (pediatric and adult cohorts) | Phase 2* | ||||
| Phase | |||||
| Soft-tissue sarcomas | Phase 2† | ||||
| Refractory germ cell tumors | Phase 2* | ||||
| High-risk pediatric solid tumors | Phase 2* (CaboMain) | ||||
| Pediatric refractory sarcoma, Wilms tumor and other rare tumors | Phase 2† | ||||
| High-grade pediatric glioma | Phase 2* | ||||
____________________
* Trial conducted through our IST program.
† Trial conducted through collaboration with NCI-CTEP.
§ Trial sponsored by the European Organization for Research and Treatment of Cancer.
| CLINICAL DEVELOPMENT PROGRAM FOR CABOZANTINIB, IN COMBINATION WITH | ||||||||
| Indication | Combination Regimen | Status Update | ||||||
| Genitourinary Cancers | ||||||||
| First-line advanced RCC | + nivolumab | Approved in U.S., EU and Japan (CheckMate -9ER) | ||||||
| First-line advanced or metastatic RCC | + nivolumab + ipilimumab | Phase 3 pivotal trial | ||||||
| + | Phase | |||||||
| Advanced RCC that progressed during or following treatment with an immune checkpoint inhibitor (ICI) | + atezolizumab | Phase 3 pivotal trial (CONTACT-03) | ||||||
| First-line metastatic RCC | + nivolumab vs. nivolumab after 4 cycles of nivolumab + ipilimumab | Phase 3† randomized (PDIGREE) | ||||||
| Advanced or metastatic non-clear cell RCC | + nivolumab | Phase 2* | ||||||
| + radium-223 dichloride | Phase 2† (RadiCaL) | |||||||
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| Cisplatin-Ineligible advanced UC | + pembrolizumab | Phase 2* (PemCab) | ||||||||
| Neoadjuvant muscle-invasive UC | + atezolizumab | Phase 2* (ABATE) | ||||||||
| Genitourinary tumors | + nivolumab ± ipilimumab | Phase 1b† | ||||||||
| Genitourinary tumors | + nivolumab + ipilimumab | Phase 2† (ICONIC) | ||||||||
| Advanced non-clear cell RCC | + nivolumab + ipilimumab | Phase 2* | ||||||||
| Metastatic RCC | + nivolumab after cytoreductive surgery | Phase 2* (Cyto-KIK) | ||||||||
| Metastatic RCC | + avelumab | Phase 1b* | ||||||||
| Locally advanced or metastatic UC | + enfortumab vedotin | Phase 1* | ||||||||
| Metastatic hormone-sensitive prostate cancer | + abiraterone + nivolumab | Phase 1* (CABIOS) | ||||||||
| Metastatic RCC | + nivolumab ± CBM 588 | Phase 1* | ||||||||
| Gastrointestinal Cancers | ||||||||||
| First-line advanced HCC | + atezolizumab | Phase 3 pivotal trial (COSMIC-312), including a single-agent cabozantinib | ||||||||
| + nivolumab ± ipilimumab | Phase 1/2 | |||||||||
| Neoadjuvant locally advanced HCC | ± nivolumab | Phase 1b* | ||||||||
| Phase | ||||||||||
| + pembrolizumab | Phase 2* | |||||||||
| +nivolumab | Phase 2* | |||||||||
| Metastatic, refractory pancreatic cancer | + atezolizumab | Phase 2* | ||||||||
| Metastatic pancreatic adenocarcinoma | +pembrolizumab | Phase 2* | ||||||||
| Metastatic colorectal adenocarcinoma | +trifluridine/tipiracil | Phase 1* | ||||||||
| Thyroid Cancers | ||||||||||
| Advanced DTC | + nivolumab | Phase 2† | ||||||||
| Metastatic NSCLC previously treated with an ICI and platinum-containing chemotherapy | + atezolizumab | Phase 3 pivotal trial (CONTACT-01) | ||||||||
| Previously treated non-squamous NSCLC | + nivolumab | Randomized phase 2† | ||||||||
| Gynecologic Cancers | ||||||||||
| Advanced or metastatic endometrial cancer | + nivolumab | Phase 2† | ||||||||
| Phase 2* | ||||||||||
| Poorly differentiated neuroendocrine carcinomas | + nivolumab + ipilimumab | Phase 2† | ||||||||
| Head and Neck Cancers | ||||||||||
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| Recurrent, metastatic squamous cell carcinoma | + cetuximab | Phase 1* | ||||||
| Recurrent, metastatic squamous cell carcinoma | + pembrolizumab | Phase 2* | ||||||
| Melanoma | ||||||||
| Unresectable, advanced melanoma | + nivolumab + ipilimumab | Phase 2* | ||||||
| Advanced, metastatic melanoma | + pembrolizumab | Phase 2* | ||||||
| Sarcoma | ||||||||
| Unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas | + temozolomide | Phase 2* | ||||||
| Sarcomas of the extremities | + radiation therapy | Phase 2* | ||||||
| Metastatic soft tissue sarcomas | + PD-1 + CTLA-4 inhibition | Phase 2* | ||||||
| Angiosarcoma pre-treated with taxane | + nivolumab | Phase 2† | ||||||
| Additional Trials in Multiple Tumor Types | ||||||||
| Advanced solid tumors | + atezolizumab | Phase 1b (COSMIC-012) with | ||||||
| Advanced CRC, HCC, gastric, gastroesophageal or esophageal adenocarcinoma | + durvalumab | Phase 1* (CAMILLA) | ||||||
| Metastatic or recurrent gastric or gastro-esophageal adenocarcinoma | + pembrolizumab | Phase 2* | ||||||
| Advanced non-squamous NSCLC, UC and advanced malignant mesothelioma | + pemetrexed | Phase 1* | ||||||
| Multiple solid tumor types and HIV | + nivolumab | Phase 1† | ||||||
| Advanced solid tumors | + pamiparib | Phase 1* | ||||||
| Pediatric multiple tumor types | + retinoic acid | Phase 1* | ||||||
____________________
* Trial conducted through our IST program. † Trial conducted through collaboration with NCI-CTEP. § Trial sponsored by the European Organization for Research and Treatment of Cancer. |
Trials Conducted Under our Clinical Collaboration Agreements
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Combination Studies with Bristol-Myers Squibb Company (BMS)BMS
RCC - CheckMate 9ER
charge.
Combination Studies with the Roche Group (Roche)
Diversifying our exploration of cabozantinib combinations with ICIs, in February 2017, we entered into a master clinical supply agreement with F. Hoffmann-La Roche Ltd. (Roche) for the purpose of evaluating cabozantinib and Roche’s anti-PD-L1 ICI, atezolizumab, in locally advanced or metastatic solid tumors. As part of the collaboration,clinical supply agreement, we are evaluating this combination in a phase 1b trial in locally advanced or metastatic tumors, COSMIC-021, and a phase 3 pivotal trial in previously untreated advanced HCC. Depending on resultsInformed by the data generated from the phase 1b trial, COSMIC-021, we may also evaluateentered into a joint clinical research agreement with Roche in December 2019, pursuant to which we are evaluating this combination in various other tumor types, including NSCLC.three late-stage clinical trials: the first, CONTACT-01, focuses on patients with metastatic non-small cell lung cancer (NSCLC) who have been previously treated with an ICI and platinum-containing chemotherapy; the second, CONTACT-02, focuses on patients with metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with one novel hormonal therapy (NHT); and the third, CONTACT-03, focuses on patients with inoperable, locally advanced or metastatic RCC who have progressed during or following treatment with an ICI as the immediate preceding therapy. For additional information on the terms of the masterjoint clinical supplyresearch agreement, see “—Collaborations—Collaborations and Business Development Activities—Cabozantinib Development Collaborations—Roche.”
Locally Advanced or Metastatic Solid Tumors - COSMIC-021
. In June 2017, we initiated COSMIC-021, a phase 1b dose escalation study that is evaluating the safety and tolerability of cabozantinib in combination with Roche’s atezolizumab in patients with locally advanced or metastatic solid tumors. We are the trial sponsor of COSMIC-021, and Roche is providing atezolizumab free of charge.
The study is divided into two parts: a dose-escalation phase, which was completed in 2018; and an expansion cohort phase, which is ongoing. The dose-escalation phase of the trial enrolled 12 patients with advanced RCC, and results were presented at the ESMO 2018 Congress. The primary objective was to determine the optimal dose and schedule of daily oral administration of cabozantinib when given in combination with atezolizumab to inform the trial’s subsequent expansion stage. Cabozantinib doses of 40 mg daily and 60 mg daily were evaluated. All patients received the standard atezolizumab dosing regimen of 1200 mg infusion once every 3 weeks. The dose-escalation phase of the study determined the optimal dose of cabozantinib as 40 mg daily when given in combination with the standard atezolizumab dosing regimen of 1200 mg infusion once every 3 weeks. No dose-limiting toxicities or serious adverse events (AEs) were noted. Dose reductions and higher grade AEs were less frequent with the 40 mg cabozantinib dosing cohort. Encouraging clinical activity was also observed. The safety profile for the combination in the dose-escalation phase of the trial was consistent with the established profile of each combination agent, and no new safety signals have emerged.
Enrollment in the expansion stagephase of this study which is currently ongoing, includes the following eighteen20 combination therapy tumor expansion cohorts:
cohorts in NSCLC, mCRPC, RCC and various other tumor types. Encouraging efficacy and safety data has emerged from the trial and has been instrumental in guiding our clinical development strategy for cabozantinib in combination with ICIs, including supporting the initiation of COSMIC-312, CONTACT-01, CONTACT-02 and CONTACT-03. Moreover, certain cohorts have been expanded, including a cohort of patients with advanced non-squamous NSCLC without a defined tumor genetic alteration (EGFR, ALK, ROS1, or BRAF)mCRPC who have not received prior therapybeen previously treated with an ICI;
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solely on the Cohort 6 results; however, we will continue to 1,000 patients. In addition, there are two exploratory cohorts that will evaluate cabozantinib as a single-agent therapythe combination regimen in patients with NSCLC without a defined tumor genetic alteration andpreviously treated mCRPC in patients with UC, in each case who have progressed following treatment with an ICI.the CONTACT-02 phase 3 pivotal trial.
HCC - COSMIC-312
COSMIC-312. In December 2018, we initiated COSMIC-312, a multicenter, randomized, controlled phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC. The co-primary endpoints of the trial are PFS and OS. An exploratoryalso includes a third arm will also evaluateevaluating cabozantinib monotherapy in this first-line setting. The study aimssetting in order to enroll approximately 640 patients at up to 200 sites globally. Patients will be randomized to oneaddress the contribution of three arms: cabozantinib and atezolizumab (40 mg); sorafenib; or cabozantinib (60 mg). The co-primary endpointscomponents for the trial are PFS and OS.
combination therapy. We are sponsoring COSMIC-312, and Ipsen will co-fundis co-funding the trial. Ipsen will have access to the results to support potential future regulatory submissions outside of the U.S. and Japan. Roche is providing atezolizumab free of charge. In August 2020, we announced the completion of patient enrollment in COSMIC-312, providing the requisite patient population to conduct the event-driven analyses of the trial’s two primary endpoints of PFS and OS. Separately, patient enrollment remains open in mainland China in order to enroll a sufficient number of patients to enable local registration, if supported by the clinical data. Patients are being randomized to one of three arms: cabozantinib (40 mg) in combination with atezolizumab; sorafenib; or cabozantinib monotherapy (60 mg). In June and November 2021, we announced results from COSMIC-312, which were presented at the ESMO Asia Virtual Oncology Week in November 2021. The trial met one of the primary endpoints, demonstrating significant improvement in BIRC assessed PFS at the planned primary analysis, reducing the risk of disease progression or death by 37% compared with sorafenib (hazard ration [HR]: 0.63; 99% confidence interval [CI]: 0.44-0.91; P=0.0012; pre-specified critical P-value of 0.01). Median PFS was 6.8 months for cabozantinib in combination with atezolizumab versus 4.2 months for sorafenib. The interim OS analysis performed at the same time did not reach statistical significance (HR: 0.90; 96% CI: 0.69-1.18; P=0.438). Median OS was 15.4 months for cabozantinib in combination with atezolizumab versus 15.5 months for sorafenib. The trial is continuing as planned to the final analysis of OS, anticipated during the first quarter of 2022, and we intend to submit an sNDA to the FDA for the combination regimen if supported by the final OS analysis.
NSCLC - CONTACT-01. Lung cancer is the second most common type of cancer in the U.S., with more than 236,000 new cases expected to be diagnosed in 2022. The disease is the leading cause of cancer-related mortality in both men and women, causing 25% of all cancer-related deaths. The majority (84%) of lung cancer cases are NSCLC, which mainly comprise adenocarcinoma, squamous cell carcinoma and large cell carcinoma. The five-year survival rate for patients with NSCLC is 25%, but that rate falls to just 7% for those with advanced or metastatic disease. Due to the urgent need for treatment options for patients with NSCLC and based on positive early-stage results from COSMIC-021, in June 2020, we and Roche initiated CONTACT-01, a global, multicenter, randomized, open-label phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab versus docetaxel in patients with metastatic NSCLC who have been previously treated with an ICI and platinum-containing chemotherapy. Patients are randomized 1:1 to the experimental arm of cabozantinib in combination with atezolizumab or to the control arm of docetaxel. The primary endpoint for the trial is OS, and secondary endpoints include PFS, ORR and DOR, in each case per RECIST v. 1.1. In November 2021, we announced the completion of enrollment of 366 patients at 117 sites globally. Based on current event rates, we anticipate announcing results of the interim OS analysis in the second half of 2022. CONTACT-01 is sponsored by Roche and co-funded by us. In addition, both Ipsen and Takeda have opted into and are co-funding the trial, and both companies will have access to the results to support potential future regulatory submissions in their respective territories outside of the U.S.
mCRPC - CONTACT-02. According to the American Cancer Society, in 2022, approximately 268,500 new cases of prostate cancer will be diagnosed, and 34,500 people will die from the disease. Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies—a common treatment for prostate cancer—is known as mCRPC. Researchers estimate that in 2020, 43,000 men were diagnosed with mCRPC, which has a median survival of less than two years. In response to this significant unmet need and based on positive early-stage results from Cohort 6 of COSMIC-021, in June 2020, we and Roche initiated CONTACT-02, a global, multicenter, randomized, open-label phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab in patients with mCRPC who have been previously treated with one NHT. The trial aims to enroll approximately 580 patients at approximately 280 sites globally, and we expect to complete enrollment in the second half of 2022. Patients are being randomized 1:1 to the experimental arm of cabozantinib in combination with atezolizumab or to the control arm of a second NHT (either abiraterone and prednisone or enzalutamide). The two primary endpoints for the trial are PFS per RECIST v. 1.1 as assessed by BIRC and OS, and secondary endpoints include ORR, prostate-specific antigen response rate and DOR. CONTACT-02 is sponsored by us and co-funded by Roche. In addition, both Ipsen and Takeda have opted into and are co-funding the trial, and both companies will have access to the results to support potential future regulatory submissions in their respective territories outside of the U.S.
RCC - CONTACT-03. Taking into account the rapidly evolving treatment landscape for RCC and based on positive early-stage results from COSMIC-021, in July 2020, we and Roche initiated CONTACT-03, a global, multicenter, randomized, open-label phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab versus cabozantinib alone in
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patients with inoperable, locally advanced or metastatic RCC who progressed during or following treatment with an ICI as the immediate preceding therapy. Patients are randomized 1:1 to the experimental arm of cabozantinib in combination with atezolizumab or to the control arm of cabozantinib alone. The two primary endpoints for the trial are PFS per RECIST v. 1.1 as assessed by BIRC and OS, and secondary endpoints include PFS, ORR and DOR as assessed by the investigators. CONTACT-03 is sponsored by Roche and co-funded by us. In addition, both Ipsen and Takeda have the right to opt in and co-fund the trial and if doing so, they will have access to the results to support potential future regulatory submissions in their respective territories outside of the U.S. In January 2022, we announced the completion of enrollment of 523 patients at 168 sites globally. Based on current event rates, we anticipate announcing results of PFS and the first interim OS analysis in the second half of 2022. We intend to use the data from CONTACT-03 to further study the therapeutic potential of cabozantinib in this patient population, both as a single agent and in combination with ICIs.
Other Trials Evaluating Cabozantinib in Combination with other Therapies
RCC - CANTATA: In January 2021 Calithera Biosciences, Inc. (Calithera) announced that the CANTATA trial did not meet its primary endpoint of improving PFS per independent review for Calithera’s teleaglenastat (also known as CB-839) plus cabozantinib as compared with cabozantinib alone in previously treated advanced or metastatic RCC. The HR was 0.94 (p=0.65), and median PFS was 9.2 months among patients treated with telaglenastat and cabozantinib as compared to 9.3 months for patients treated with cabozantinib and placebo. We provided cabozantinib for the trial through a material supply agreement with Calithera.
Trials Conducted through our CRADA with NCI-CTEP and our IST Program
In October 2011, we entered into a CRADA with NCI-CTEP for the clinical development of cabozantinib. Through ourThe CRADA with NCI-CTEP and our IST program we have been able to expandenabled further expansion of the cabozantinib development program while avoiding over-burdeningwith less burden on our internal development resources. OurThis CRADA reflects a major commitment by NCI-CTEP to support the broad exploration of cabozantinib’s potential in a wide variety of cancers, each representing a substantial unmet medical need. Through this mechanism, NCI-CTEP provides funding for as many as 20 active clinical trials of cabozantinib each year for a five-year period. TheWe and NCI-CTEP have extended the term of the CRADA was extended in October 2016 for an additional five-year period through October 2021,2026, provided that both parties maintain the right to terminate the CRADA for any reason upon sixty days’ notice, for an uncured material breach upon thirty days’ notice and immediately for safety concerns. Investigational New Drug (IND) applications for trials under the CRADA are held by NCI-CTEP. NCI-CTEP also retains rights to any inventions made in whole or in part by NCI-CTEP investigators. However, for inventions that claim the use and/or the composition of cabozantinib, we have an automatic option to elect a worldwide, non-exclusive license to cabozantinib inventions for commercial purposes, with the right to sublicense to affiliates or collaborators working on our behalf, as well as an additional, separate option to negotiate an exclusive license to cabozantinib inventions. Further, before any trial proposed under the CRADA may commence, the protocol is subject to our review and approval, and the satisfaction of certain other conditions. WeAs reflected by the results from completed trials and given the numerous ongoing and planned clinical trials, we believe our CRADA with NCI-CTEP has and will enable us to continue to expand the cabozantinib development program broadly in a cost-efficient manner. A summary of key trials under this collaboration is provided below.
Advanced Genitourinary Tumors
In February 2021, positive initial results were announced from PAPMET (also known as SWOG S1500), a randomized phase 2 trial conducted by the Southwest Oncology Group evaluating cabozantinib versus sunitinib in patients with previously treated genitourinary tumors being conducted under our CRADAmetastatic papillary RCC. PAPMET met its primary endpoint, demonstrating a statistically significant and clinically meaningful prolongation of PFS, with NCI-CTEPa median PFS of 9.0 months for cabozantinib (95% CI: 6-12) versus 5.6 months for sunitinib (95% CI: 3-7) (HR: 0.60; 95% CI: 0.37-0.97; P=0.019). Detailed results from PAPMET were first presented at the ESMO 2016 Congress in October 2016 and most recently updated at the 2018 ASCOvirtual American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in February 2018. 2021 and published in The updated data reported results from 78 patients treated with either cabozantinib and nivolumab with or without ipilimumab. Forty-nine patients were treated with the doublet combination of cabozantinib and nivolumab and 29 patients were treated with the triplet combination of cabozantinib, nivolumab and ipilimumab. Among the nineteen patients with metastatic UC who were evaluable for response, the ORR across all treatment groups was 42% (2 complete responses (CRs) and 6 PRs of 19 patients) and the DCR (DCR = CR, PR and SD) was 84%. Seven of eight (88%) metastatic UC patients with an objective response had not progressed at the time of the data cut-off. Median PFS in this patient population was 12.8 months and the OS rate at 12 months was 77%. Among the 13 patients with metastatic RCC who were evaluable for response, ORR was 54 percent (7 PRs of 13 patients) and the DCR was 100%. In the overall study the ORR in 64 evaluable patients was 36% (3 CRs and 20 PRs) with a median DOR of 24 months. 78 patients were included in the safety analysis. No dose-limitingLancet.
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Neuroendocrine Tumors
The Alliance is leading the CABINET study that treats patients with stage IV EGFR wild-type NSCLC. This trial (Study E1512) was sponsored through our CRADAwell- or moderately-differentiated neuroendocrine tumors (NETs). CABINET includes 2 separate randomized studies, one for patients with NCI-CTEPpancreatic NETs and was conducted by the ECOG-ACRIN Cancer Research Group.other for patients with carcinoid tumors. The positive results from this trial were reported atplanned enrollment for the ASCO 2015 Annual Meeting in May 2015pancreatic NET study is 185 patients and subsequently published online in Lancet Oncology in November 2016.for the carcinoid study is 210 patients. Both studies randomize previously treated patients 2:1 to cabozantinib 60 mg daily or placebo. The study met its primary endpoint demonstrating significant increasesfor both studies is PFS per Response Evaluation Criteria in PFS for cabozantinib and the combination of cabozantinib plus erlotinib when individually compared to the erlotinib arm. The safety profile for the combination in the trial was consistent with the established profile of other TKI/TKI combination therapies. InformedSolid Tumors 1.1 as determined by these clinical results, we are working with clinical collaborators to explore cabozantinib’s further development in NSCLC, including potential combination approaches with ICIs, such as within one of the expansion cohorts of COSMIC-021, our phase 1b study with Roche evaluating the combination of cabozantinib and atezolizumab.a blinded IRRC.
Other Cancer Indications
These externally sponsored trials include signal seeking studies of single-agent cabozantinib, novel combinations, and randomized trials. The monotherapy trials are focused on solid tumors including genitourinary neoplasms, gastrointestinal malignancies, lung cancer and a variety of less common tumor types. The combination studies include trials combining cabozantinib with several different ICIs, as well as studies adding cabozantinib to various other anti-cancer therapies, including monoclonal antibodies and(mAbs), chemotherapeutic agents, small molecules which target specific cellular pathways. Randomizedpathways, or radiation. In addition to the various trials within thedescribed above, our CRADA include aincludes an ongoing randomized phase 32 study in neuroendocrine tumors and phase 2 trials in both endometrial cancerNSCLC, also in combination with checkpoint inhibitors and in prostate cancer in combination with docetaxel.an ICI.
A complete listing of all ongoing cabozantinib trials can be found at www.ClinicalTrials.gov.
Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates
We have advanced several other product candidates into clinical trials during recent years, including both small molecules and biotherapeutics that we have discovered or in-licensed and believe may have the potential to benefit patients with a variety of cancers. The following table summarizes our current and planned clinical development activities outside of the cabozantinib franchise:
| CLINICAL DEVELOPMENT PROGRAM FOR PIPELINE | |||||||||||
| Product | Mechanism of Action | Setting | Status Update | ||||||||
| XL092 | Next-generation tyrosine kinase inhibitor (TKI) targeting MET/VEGFR/AXL/MER | Advanced or metastatic solid tumors | Phase 1b trials evaluating single-agent and immune checkpoint inhibitor (ICI) combination regimens ongoing •In combination with atezolizumab and with avelumab (STELLAR-001) •In combination with nivolumab, with nivolumab and ipilimumab and with nivolumab and bempegaldesleukin (STELLAR-002) Potential to initiate late-stage trials in 2022 (including STELLAR-303) | ||||||||
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| XB002 | Next-generation tissue factor (TF)-targeting antibody-drug conjugate (ADC) | Advanced solid tumors | Phase 1 trial evaluating single-agent ongoing Potential to add combination regimens with ICIs and other targeted therapies in 2022 | ||||||||
| XL102 | Potent, selective, orally bioavailable cyclin-dependent kinase 7 (CDK7) inhibitor | Advanced or metastatic solid tumors | Phase 1 trial evaluating single-agent and combination regimens ongoing •In combination with fulvestrant, with abiraterone and prednisone and potentially with other anti-cancer regimens | ||||||||
| XL114 | CARD11-BCL10-MALT1 (CBM) complex inhibitor | Non-Hodgkin’s lymphoma (NHL) | Phase 1 trial evaluating single-agent planned for first half of 2022 | ||||||||
XL092 Development Program
Advanced Solid Tumors - STELLAR-001. Following the FDA’s acceptance of our IND for XL092, in February 2019, we initiated STELLAR-001, a multicenter phase 1b clinical trial evaluating the pharmacokinetics, safety, tolerability and preliminary anti-tumor activity of XL092. STELLAR-001 is divided into dose-escalation and expansion phases. In October 2020, we presented data at the 32nd EORTC-NCI-AACR (ENA) Symposium that suggest XL092 has a desirable therapeutic profile. We believe it pairs the potential for significant anti-tumor activity with a much shorter clinical pharmacokinetic half-life than cabozantinib, and also presents the potential for synergistic effects in combination with ICIs. In consideration of these data, we amended the phase 1 study protocol in October 2020 to include dose-escalation and expansion cohorts for XL092 in combination with atezolizumab, and again in March 2021 to include dose-escalation and expansion cohorts for XL092 in combination avelumab, an ICI developed by Merck KGaA, Darmstadt, Germany (Merck KGaA) and Pfizer Inc. (Pfizer). We are continuing to enroll patients into the dose-escalation cohorts of the combination part of the trial, and we expect that once recommended doses are established for single-agent XL092, XL092 in combination with atezolizumab and XL092 in combination with avelumab, the trial will begin to enroll expansion cohorts for patients with clear cell and non-clear cell RCC, colorectal cancer (CRC), hormone-receptor positive breast cancer mCRPC and urothelial carcinoma (UC). The primary efficacy endpoints for the expansion phase may include ORR per RECIST v. 1.1 and PFS per RECIST v. 1.1.
Advanced Solid Tumors - STELLAR-002. In December 2021, we initiated STELLAR-002, a multicenter phase 1 clinical trial designed to evaluate its pharmacokinetics,evaluating the safety, tolerability and tolerability. The trialefficacy of XL092 in combination with either nivolumab, nivolumab and ipilimumab, or nivolumab and bempegaldesleukin, an investigational CD122-preferential IL-2–pathway agonist developed by Nektar Therapeutics (Nektar). STELLAR-002 is divided into dose-escalation and expansion phases. The dose-escalation phase of the trial is enrolling patients with advanced solid tumors and will determine the recommended dose in patients for each of the XL092 combination regimens. Depending on the dose-escalation results, STELLAR-002 may enroll expansion cohorts for patients with clear cell and non-clear cell RCC, mCRPC and UC. The primary efficacy endpoint of the expansion phase will be ORR, except for the cohort of patients with mCRPC, for which the primary efficacy endpoint will be duration of radiographic PFS. To better understand the individual contribution of the therapies, treatment arms in the expansion cohorts may include XL092 as a single agent in addition to the ICI combination regimens.
In addition to clinical updates for XL092 expected in 2022, we plan to initiate the first global phase 3 pivotal trial for the compound in the first half of the year, and other pivotal trials may follow throughout the year. This first planned trial, STELLAR-303, will evaluate XL092 in combination with atezolizumab versus regorafenib in patients with metastatic microsatellite stable CRC who have progressed after or are intolerant to the current standard of care. Preclinical data and emerging results from STELLAR-001 for XL092, both alone and in combination with ICIs, reinforce our belief in the
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opportunity for XL092, which pairs a target profile similar to cabozantinib with a potentially significantly improved safety profile. The decision to initiate STELLAR-303 is also supported by data from a CRC cohort of COSMIC-021, our phase 1b study evaluating cabozantinib in combination with atezolizumab, and from CAMILLA, a phase 1 IST evaluating cabozantinib in combination with durvalumab or with durvalumab and tremelimumab. Results from both of these trials were presented at the ASCO Gastrointestinal Cancers Symposium in January 2022. We intend to develop XL092 in novel combination regimens in a broad array of future potential indications where cabozantinib has demonstrated RECIST v. 1.1 anti-tumor activity.
XB002 Development Program
XB002 (formerly ICON-2) is our lead TF-targeting ADC program, which we in-licensed from Iconic, Inc. (Iconic). XB002 is an ADC composed of human mAb against TF that is conjugated to a cytotoxic agent. TF is highly expressed on tumor cells and in the tumor microenvironment, and TF overexpression, while not oncogenic itself, facilitates angiogenesis, metastasis and other processes important to tumor development and progression. After binding to TF on tumor cells, XB002 is internalized, and the cytotoxic agent is released, resulting in targeted tumor cell death. XB002 is a rationally designed next-generation ADC that leverages proprietary linker-payload technology. Based on promising preclinical data, we exercised our exclusive option to license XB002 in December 2020, resulting in our assuming responsibility for all subsequent clinical development of XB002. For additional information on our business development activities with Iconic, see “—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities—Iconic.” Following the FDA’s acceptance of our IND for XB002, in June 2021, we initiated a multicenter phase 1, open-label clinical trialdesigned to evaluate itssafety, tolerability, pharmacokinetics and preliminary anti-tumor activity in patients with advanced solid tumors. The trial is divided into dose-escalation and cohort-expansion phases. The dose-escalation phase of the trial is enrolling patients with advanced solid tumors, with the primary objective of determining the maximum tolerated dose or recommended dose levels for intravenous infusion of XB002 as a dose for daily oral administration of XL092 suitable for further evaluation.single agent. Assuming positive data from the initial phase of
the trial, the expansioncohort-expansion phase is designed to further explore the selected dose of XL092XB002 in individual tumor cohorts, wherewhich may include forms of NSCLC, cervical cancer, ovarian cancer, UC, squamous cell head and neck cancers, pancreatic cancer, esophageal cancer, mCRPC, triple negative breast cancer and hormone-receptor positive breast cancer, and will evaluate ORR per RECIST v. 1.1 as a primary endpoint as well as XB002’s safety, tolerability and initialpharmacokinetic profile. We expect to provide clinical updates from the ongoing phase 1 study of XB002 during 2022. We also intend to initiate additional dose-escalation and expansion cohorts to evaluate the potential of XB002 in combination with ICIs and other targeted therapies across a wide range of tumor types, including indications other than those currently addressed by commercially available TF-targeted therapies. Since initiating the XB002 phase 1 trial, we amended our exclusive option and license agreement with Iconic in December 2021 to acquire broad rights to use the anti-TF antibody used in XB002 for any application, including conjugated to other payloads, as well as rights within oncology to a number of other anti-TF antibodies developed by Iconic, including for use in ADCs and multispecific biotherapeutics.
For additional information on our business development activities with Iconic, see “—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities—Iconic.”
XL102 Development Program
XL102 (formerly AUR102) is the lead compound under our research collaboration with Aurigene Discovery Technologies Limited (Aurigene). It is a potent, selective and orally bioavailable covalent inhibitor of CDK7, which is an important regulator of the cellular transcriptional and cell cycle machinery. Based on encouraging preclinical data for XL102, which we and Aurigene presented at the 32nd ENA Symposium in October 2020, we exercised our exclusive option to license XL102 in December 2020, resulting in our assuming responsibility for all subsequent clinical development of XL102. For additional information on our collaboration with Aurigene, see “—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities—Aurigene.”
Following the FDA’s acceptance of our IND for XL102, in January 2021, we initiated a multicenter phase 1, open-label clinical trialdesigned to evaluate itssafety, tolerability, pharmacokinetics and preliminary anti-tumor activity, wouldboth as a single agent and in combination with other anti-cancer therapies, in up to 298 patients with inoperable, locally advanced or metastatic solid tumors. The trial is divided into dose-escalation and cohort-expansion phases. The dose-escalation phase of the trial is enrolling patients with advanced solid tumors, with the primary objective of determining the maximum tolerated dose or recommended dose levels for daily oral administration of XL102 as a single agent, as well as in combination with fulvestrant for patients with hormone-receptor positive breast cancer and with abiraterone and prednisone for patients with mCRPC. Combinations with other agents may also be evaluated. Assuming positive data from the initial phase of the trial, the cohort-expansion phase is designed to further explore the selected dose of XL102 as a
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single agent and in combination regimens in individual tumor cohorts, including ovarian cancer, triple-negative breast cancer, hormone-receptor positive breast cancer and mCRPC, and will evaluate ORR per RECIST v. 1.1, as well as XL102’s safety, tolerability and pharmacokinetic profile. We expect to provide clinical updates from the ongoing phase 1 study of XL102 during 2022.
XL114 Development Program
XL114 (formerly AUR104) is a novel anti-cancer compound that inhibits activation of the CBM complex, a key component of signaling downstream of B- and T-cell receptors, which promotes B- and T-cell lymphoma survival and proliferation. Constitutive activation of B- or T-cell receptor signaling is a common feature of B-cell and T-cell lymphomas, and therefore we believe CBM is an attractive target for the development of new anti-cancer therapies with the potential to treat lymphoid malignancies. Notably, the CBM complex is downstream of BTK, inhibitors of which are approved therapies for certain B-cell lymphomas. Inhibitors of CBM complex activation may therefore provide options for patients who develop resistance to BTK inhibitors. At the American Association of Cancer Research Annual Meeting in April 2021, Aurigene presented preclinical data (Abstract 1266) demonstrating that XL114 exhibited potent anti-proliferative activity in a large panel of cancer cell lines ranging from hematological cancers to solid tumors with excellent selectivity over normal cells. We exercised our exclusive option to in-license XL114 in October 2021, resulting in our assuming responsibility for all subsequent clinical development, manufacturing and commercialization of XL114. For additional information on our collaboration with Aurigene, see “—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities —Aurigene.”
The FDA accepted our IND application for XL114 in October 2021, and we plan to initiate a phase 1 clinical trial evaluating the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of the compound as a monotherapy in patients with non-Hodgkin’s lymphoma (NHL) in the first half of 2022. The trial will be divided into dose-escalation and cohort-expansion phases and will aim to enroll approximately 144 patients with advanced NHL. The dose-escalation phase of the trial will determine the maximum tolerated dose or recommended dose levels for daily oral administration of XL114 as a monotherapy. Assuming positive data from the initial phase of the trial, the cohort-expansion phase will enroll subjects in cohorts with diffuse large cell B-cell lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, and mantle cell lymphoma, and will evaluate ORR based on lymphoma-specific response criteria.
Expansion of the Exelixis Pipeline: Drug Discovery and Business Development ProgramsPipeline
We are actively focused on expandingworking to expand our oncology product pipeline through internal drug discovery efforts, which encompass our diverse small molecule and targetedbiotherapeutics programs exploring multiple modalities and mechanisms of action. This approach provides a high degree of flexibility with respect to target selection and allows us to prioritize those targets that we believe have the greatest chance of yielding impactful therapeutics. As part of our strategy, our drug discovery activities include research collaborations, in-licensing arrangements and other strategic transactions that serve to increase our discovery bandwidth and allow us to access a wide range of technology platforms. We also opened a new laboratory building on our Alameda campus in 2021, effectively tripling our available lab space and significantly enhancing the capacity and capability of our small molecule discovery efforts. As of the date of this Annual Report, we are currently advancing more than 10 discovery programs and expect to progress up to five new development candidates into preclinical development during 2022. In addition, we will continue to engage in business development activities.initiatives with the goal of acquiring and in-licensing promising oncology platforms and assets and then further characterize and develop them utilizing our established preclinical and clinical development infrastructure.
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while still maintaining an agile, competitive approach. We arealso augment our small molecule discovery activities through research collaborations and will continue to be judiciousin-licensing arrangements with other companies engaged in the selection of targets, focusing on those with robust preclinical validation datasets. We remainsmall molecule discovery, including:
•STORM Therapeutics LTD (STORM), which is focused on oncology as a therapeutic area,the discovery and prioritize those targets that we believe, for example, are key componentsdevelopment of signaling pathways frequently deregulated in human cancers or are componentsinhibitors of mechanisms that contribute to tumor-mediated immune suppression. We anticipate that our experience identifying high quality lead compounds against a variety of target classes through use of our propriety compound library, coupled with our expertise in medicinal chemistry, tumor biology and pharmacology, will permit us to prosecute competitive and productive discovery programs in areas of high potential.novel RNA modifying enzymes, including ADAR1;
•StemSynergyTherapeutics, Inc. (StemSynergy) for, which is focused on the discovery and development of novel oncology compounds aimed to inhibit tumor growth by targeting Casein Kinase 1 alpha (CK1α), and the Notch pathway.
For additional information on these research collaborations and in-licensing arrangements related to our small molecule programs, see “—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities.”
Amongst our small molecule programs, furthest along are XL092, which was discovered at Exelixis, and XL102 and XL114, which were discovered at Aurigene. XL092 and XL102 entered the clinic in 2019 and 2021, respectively, and we plan to initiate a componentphase 1 clinical trial for XL114 in the first half of 2022. For additional information on these clinical trial programs, see “—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates.” In addition, we continue to make progress on multiple, additional lead optimization programs for inhibitors of a variety of targets that we believe play significant roles in tumor growth, and we anticipate that some of these other programs could reach development candidate status in 2022.
Biotherapeutics Programs
We are also focusing our drug discovery activities on discovering and advancing various biotherapeutics that have the Wnt signaling pathway implicatedpotential to become anti-cancer therapies, such as bispecific antibodies, ADCs and other innovative treatments. The great potential of these classes has been evidenced by the multiple regulatory approvals for the commercial sale of ADCs in key oncogenic processes. Additionally, in May 2018,the past several years. To facilitate the growth of these programs, we have established multiple research collaborations and in-licensing arrangements and entered into other strategic transactions that provide us with access to antibodies and binders, which are the starting point for use with additional technology platforms that we employ to generate next-generation ADCs or multispecific antibodies. Our current research collaborations and in-licensing arrangements for biotherapeutics programs include:
•WuXi Biologics Ireland Limited, a collaborationwholly owned subsidiary of WuXi Biologics (Cayman) Inc. (individually and license agreement with Invenra, Inc. (Invenra)collectively referred to as WuXi Bio), which is focused on developingleveraging WuXi Bio’s panel of mAbs for the development of ADC, bispecific and certain other novel tumor-targeting biotherapeutics applications;
•Adagene Inc. (Adagene), which is focused on using Adagene’s SAFEbodyTM technology to develop novel masked ADCs or other innovative biotherapeutics with potential for improved therapeutic index;
•Catalent, Inc.’s wholly owned subsidiaries Redwood Bioscience, Inc., R.P. Scherer Technologies, LLC and Catalent Pharma Solutions, Inc. (individually and collectively referred to as Catalent), which is focused on the discovery and development of multiple ADCs using Catalent’s proprietary SMARTag® site-specific bioconjugation technology;
•NBE-Therapeutics AG (NBE), which is focused on the discovery and development of multiple ADCs by leveraging NBE’s unique expertise and proprietary platforms in ADC discovery, including NBE’s SMAC-Technology™ (a site-specific conjugation technology) and novel payloads;
•Iconic, which is focused on the advancement of a next-generation biologics, to discoverTF-targeting ADC program in solid tumors; and develop
•Invenra, Inc. (Invenra), which is focused on the discovery and development of novel binders and multispecific antibodies for the treatment of cancer.
We have already made considerablesignificant progress under our collaborations with both StemSynergy and Invenrathese arrangements and believe we will continue to do so in 2019.2022 and future years. For example, based on promising preclinical data for XB002, we exercised our exclusive option to license XB002 in December 2020. Following the FDA’s acceptance of our IND for XB002 in April 2021, we initiated a phase 1 clinical trial in June 2021. For additional information on our collaboration with StemSynergy,XB002, see “—Collaborations—StemSynergy Collaboration,Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates—XB002 Development Program.” Also, as a direct result of these arrangements, we designated XB010, our first ADC advanced internally, as a development candidate in late 2021.
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XB010, which targets the tumor antigen 5T4, incorporates antibodies sourced from Invenra and was constructed using Catalent’s SMARTag site-specific bioconjugation platform.
In addition, in May 2021, we executed an asset purchase agreement with GamaMabs Pharma SA (GamaMabs), under which we will, upon the closing of the asset purchase and subject to certain conditions, acquire all rights, title and interest in GamaMabs’ antibody program directed at anti-Müllerian hormone receptor 2 (AMHR2), a novel oncology target with relevance in multiple forms of cancer. And most recently, in January 2022, we announced an amendment to our May 2019 exclusive option and license agreement with Iconic to acquire broad rights to use the anti-TF antibody used in XB002 for any application, including conjugated to other payloads. For additional information on these specific research collaborations, in-licensing arrangements and other strategic transactions related to our collaboration with Invenra,biotherapeutics programs, see “—Collaborations—Invenra Collaboration.Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities.”
Collaborations and Business Development Activities
We are seeking additional, external collaborative relationships around assetshave established multiple collaborations with leading biopharmaceutical companies for the commercialization and technologies that complementfurther development of the cabozantinib franchise. Additionally, we have made considerable progress under our in-house drug discoveryexisting research collaborations and development efforts. These collaborative relationships are aimed at expandingin-licensing arrangements to further enhance our early-stage pipeline and expand our ability to discover, develop and commercialize novel therapies with the goal of providing new treatment options for cancer patients and their physicians.
We have established multiple collaborations with leading pharmaceutical companies for the commercializationexpect to enter into additional, external collaborative relationships around assets and furthertechnologies that complement our drug discovery and clinical development of cabozantinib, as well as with smaller, discovery-focused biotechnology companies to expand our product pipeline. Additionally, in lineefforts. Consistent with our business strategy prior to the commercialization of our first product, COMETRIQ, we also entered into other collaborations with leading pharmaceutical companies including Genentech and Daiichi Sankyo and BMS for other compounds and programs in our portfolio. Under each of our collaborations, we are entitled to receive milestones and royalties or, in the case of cobimetinib, royalties from sales outside the U.S. and a share of profits (or losses) from commercialization in the U.S.
Cabozantinib Commercial Collaborations
Ipsen Collaboration
In February 2016, we entered into a collaboration and license agreement with Ipsen for the commercialization and further development of cabozantinib. Pursuant to the terms ofUnder the collaboration agreement, Ipsen received exclusive commercialization rights for current and potential future cabozantinib indications outside of the U.S., Canada and Japan. The collaboration agreement was subsequently amended on three occasions, including in December 2016 to include commercialization rights in Canada. We have also agreed to collaborate with Ipsen on the development of cabozantinib for current and potential future indications. The parties’ efforts are governed through a joint steering committee and appropriate subcommittees established to guide and oversee the collaboration’s operation and strategic direction; provided, however, that we retain final decision-making authority with respect to cabozantinib’s ongoing development.
In consideration for the exclusive license and other rights contained in the collaboration agreement, including commercialization rights in Canada, Ipsen paid us aggregate upfront payments of $210.0 million.million in 2016. As of December 31, 2018,2021, we achieved aggregate milestone payments of $275.0$462.5 million related to regulatory and commercial progress by Ipsen since the inception of the collaboration agreement, including a milestone paymentspayment during 20182021 of (i) $50.0 million upon the EMA filing and the approval of cabozantinib as a treatment for patients with previously untreated RCC, (ii) $25.0$12.5 million upon Ipsen’s achievementsubmission of $100.0 million of net sales cumulatively over four consecutive fiscal quarters, (iii) $50.0 million upona variation application to the EMA filing and the approval of cabozantinibfor CABOMETYX as a treatment for patients with previously treated, HCC, (iv) $5.0RAI-refractory DTC. In addition, we recorded in license revenues a $100.0 million uponmilestone from Ipsen in connection with the approval by Health Canadaachievement of $400.0 million of net sales of cabozantinib forin the treatmentrelated Ipsen license territory over four consecutive quarters, and we expect to receive the milestone payment in the first quarter of adults with advanced RCC who have received prior VEGF-targeted therapy and (v) $20.0 million upon the initiation of COSMIC-312.2022.
We are also eligible to receive future development and regulatory milestone payments from Ipsen, totaling an aggregate of $84.0$46.5 million upon additional approvals of cabozantinib in future indications and/or jurisdictions, as well as contingent payments of up to $519.5$350.0 million and CAD$26.5 million associated with future sales volume milestones. We will further receive royalties on net sales of cabozantinib by Ipsen outside of the U.S. and Japan. We were initially entitled to receive a tiered royalty of 2% to 12% on the initial $150.0 million of net sales; this amount was reached in the second quarter of 2018. As ofDuring the year ended December 31, 20182021 and going forward, we are entitled to receive a tiered royalty of 22% to 26% on annual net sales, (withwith separate tiers for Canada);Canada; these 22% to 26% royalty tiers reset each calendar year. In Canada, we are entitled to receive a tiered royalty of 22% on the first CAD$30.0 million of annual net sales and a tiered royalty thereafter to 26% on annual net sales; these 22% to 26% royalty tiers for Canada will also reset each calendar year. As of December 31, 2018,2021, we have earned royalties of $36.3$272.1 million on net sales of cabozantinib by Ipsen since the inception of the collaboration agreement.
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We received notification that, effective January 1, 2021, Royalty Pharma plc (Royalty Pharma) acquired from GlaxoSmithKline (GSK) all rights, title and interest in royalties on total net sales of any product containing cabozantinib for non-U.S. markets for the full term of the royalty and for the U.S. market through September 2026, after which time U.S. royalties will revert back to GSK. Accordingly, and consistent with our historical agreement with GlaxoSmithKline (GSK),GSK, we are required to pay a 3% royalty to GSKRoyalty Pharma on alltotal net sales of any product incorporating cabozantinib, including net sales by Ipsen.
We are responsible for funding cabozantinib-related development costs for those trials in existence at the time we entered into the collaboration agreement with Ipsen; global development costs for additional trials are shared between the parties, with Ipsen reimbursing us for 35% of such costs, provided Ipsen chooses to opt into such trials. In accordance with the collaboration agreement, Ipsen has opted into and is co-funding:co-funding certain clinical trials, including: CheckMate 9ER; CheckMate 040 (though-9ER, COSMIC-021, COSMIC-311, COSMIC-312, CONTACT-01 and CONTACT-02. With respect to Ipsen’s decision in the second quarter of 2021 to opt into and co-fund COSMIC-311 development costs, Ipsen will not be co-funding the triplet armis now responsible for 35% of the study evaluating cabozantinib with nivolumabglobal development costs of COSMIC-311 and ipilimumab);is obligated to reimburse us for these costs, as well as an additional payment calculated as a percentage of COSMIC-311 development costs, triggered by the dose escalation phase and first eight expansion cohortstiming of COSMIC-021; and COSMIC-312.the exercise of its option.
We remain responsible for manufacturing and supply of cabozantinib for all development and commercialization activities under the collaboration agreement. In connection with the collaboration agreement,Relatedly, we entered into a supply agreement with Ipsen to supply finished and labeled drug product to Ipsen for distribution in the territories outside of the U.S. and Japan for the term of the collaboration agreement as well as a quality agreement that provides respective quality responsibilities for the aforementioned supply. Furthermore, at the time we entered into the collaboration agreement, the parties also entered into a pharmacovigilance agreement, which defines each partner’s responsibilities for safety reporting. The pharmacovigilance agreement also requires us to maintain the global safety database for cabozantinib. To meet our obligations to regulatory authorities for the reporting of safety data from territories outside of the U.S. and Japan from sources other than our sponsored global clinical development trials, we rely on data collected and reported to us by Ipsen.
Unless earlier terminated, earlier, the collaboration agreement has a term that continues, on a product-by-product and country-by-country basis, until the latter of (i)(1) the expiration of patent claims related to cabozantinib, (ii)(2) the expiration of regulatory exclusivity covering cabozantinib or (iii)(3) ten years after the first commercial sale of cabozantinib, other than COMETRIQ. The supply agreement will continue in effect until expiration or termination of the collaboration agreement. The collaboration agreement may be terminated for cause by either party based on uncured material breach of either the collaboration agreement or the supply agreement by the other party, bankruptcy of the other party or for safety reasons. We may terminate the collaboration agreement if Ipsen challenges or opposes any patent covered by the collaboration
agreement. Ipsen may terminate the collaboration agreement if the FDA or EMA orders or requires substantially all cabozantinib clinical trials to be terminated. Ipsen also has the right to terminate the collaboration agreement on a region-by-region basis after the first commercial sale of cabozantinib in advanced RCC in the given region. Upon termination by either party, all licenses granted by us to Ipsen will automatically terminate, and, except in the event of a termination by Ipsen for our material breach, the licenses granted by Ipsen to us shall survive such termination and shall automatically become worldwide, or, if Ipsen were to terminate only for a particular region, then for the terminated region. Following termination by us for Ipsen’s material breach, or termination by Ipsen without cause or because we undergo a change of control by a party engaged in a competing program, Ipsen is prohibited from competing with us for a period of time.
Takeda Collaboration
In January 2017, we entered into a collaboration and license agreement with Takeda. PursuantTakeda, which was subsequently amended on three occasions to, thisamong other things, modify the amount of reimbursements we receive for costs associated with our required pharmacovigilance activities and milestones we are eligible to receive, as well as modify certain cost sharing obligations related to the Japan-specific development costs associated with CONTACT-01 and CONTACT-02. Under the collaboration agreement, Takeda has exclusive commercialization rights for current and potential future cabozantinib indications in Japan, and the parties have agreed to collaborate on the clinical development of cabozantinib in Japan. The operation and strategic direction of the parties’ collaboration is governed through a joint executive committee and appropriate subcommittees.
In consideration for the exclusive license and other rights contained in the collaboration agreement, we received aan upfront payment of $50.0 million upfront nonrefundable payment from Takeda. Effective March 2018,Takeda in 2017. As of December 31, 2021, we amendedhave also achieved regulatory and development milestones in the aggregate of $127.0 million related to regulatory and commercial progress by Takeda since the inception of the collaboration agreement, including milestone payments during 2021 of (1) $20.0 million upon Takeda’s first commercial sale in Japan of CABOMETYX in combination with OPDIVO for the treatment of patients with unresectable or metastatic RCC and (2) $15.0 million in connection with the initiations of CONTACT-01 and CONTACT-02. We are eligible
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to modify the milestones wereceive additional regulatory and development milestone payments, without limit, for additional potential future indications.
We are further eligible to receive under this agreement, and ascommercial milestones, including milestone payments earned for the first commercial sale of December 31, 2018, we are eligible to receive development, regulatory and first-sale milestone paymentsa product, of up to $90.0 million related to both previously treated and previously untreated RCC and previously treated HCC, as well as additional development, regulatory and first-sale milestone payments for potential future indications. The collaboration agreement$119.0 million. We also provides that we are eligible to receive pre-specified payments of up to $83.0 million associated with sales volume milestones and royalties on the net sales of cabozantinib in Japan. We are entitled to receive a tiered royalty of 15% to 24% on the initial $300.0 million of net sales, and following this initial $300.0 million of net sales, we are then entitled to receive a tiered royalty of 20% to 30% on annual net sales thereafter; these 20% to 30% royalty tiers will reset each calendar year. As of December 31, 2021, we have earned royalties of $10.2 million on net sales of cabozantinib by Takeda since the inception of the collaboration agreement.
Consistent with our historical agreement with GSK, we are required to pay a 3% royalty to GSKRoyalty Pharma on alltotal net sales of any product incorporating cabozantinib, including net sales by Takeda.
Except for CONTACT-01 and CONTACT-02, Takeda is responsible for 20% of the costs associated with the global cabozantinib development plan’s current and future trials, provided Takeda opts into such trials, and 100% of costs associated with the cabozantinib development activities that are exclusively for the benefit of Japan. In accordance with the collaboration agreement, Takeda has opted into and is co-funding CheckMate 9ER.-9ER, certain cohorts of COSMIC-021, CONTACT-01 and CONTACT-02.
Unless earlier terminated, the collaboration agreement has a term that continues, on a product-by-product basis, until the earlier of (i)(1) two years after first generic entry with respect to such product in Japan or (ii)(2) the later of (A) the expiration of patent claims related to cabozantinib and (B) the expiration of regulatory exclusivity covering cabozantinib in Japan. The collaboration agreement may be terminated for cause by either party based on uncured material breach by the other party, bankruptcy of the other party or for safety reasons. For clarity, Takeda’s failure to achieve specified levels of commercial performance, based upon sales volume and/or promotional effort, during the first six years of the collaboration will constitute a material breach of the collaboration agreement. We may terminate the agreement if Takeda challenges or opposes any patent covered by the collaboration agreement. At any time prior to August 1, 2023, the parties may mutually agree to terminate the collaboration agreement if Japan’s Pharmaceuticals and Medical Devices Agency is unlikely to grant any approval of the marketing authorization application (MAA) in any cancer indication in Japan. After the commercial launch of cabozantinib in Japan, Takeda may terminate the collaboration agreement upon twelve months’ prior written notice following the third anniversary of the first commercial sale of cabozantinib in Japan. Upon termination by either party, all licenses granted by us to Takeda will automatically terminate, and the licenses granted by Takeda to us shall survive such termination and shall automatically become worldwide.
Cabozantinib Development Collaborations
BMS
In February 2017, we entered into a clinical trial collaboration agreement with BMS for the purpose of exploring the therapeutic potential of cabozantinib in combination with BMS’s ICIs, nivolumab and/or ipilimumab, to treat a variety of types of cancer. As part of the collaboration, we are evaluating these combinationsthe triplet combination of cabozantinib, nivolumab and ipilimumab as a treatment optionsoption for RCC and HCC in the CheckMate 9ER and CheckMate 040 trials, respectively. We also intend to evaluate these combinations in other phase 3 pivotal trials in various other tumor types, including UC.COSMIC-313 trial. For descriptionsa description of the Checkmate 9ER and Checkmate 040 trials,COSMIC-313 trial, see “—Exelixis Development Programs—Cabozantinib Development Program—Trials Conducted Under our Clinical Collaboration Agreements—Combination Studies with BMS.”
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applicable clinical trial, and unless otherwise agreed betweenresponsibility for the parties,payment of costs for each such trial will be shared equally betweendetermined on a trial-by-trial basis. Following the parties, unless twoFDA’s approval of CABOMETYX in combination with OPDIVO as a first-line treatment of patients with advanced RCC, we and BMS compounds will be utilized in such trial, in which case BMS will bear two-thirdscommenced the commercial launch of the costs for such study treatment armscombination and we will bear one-third of the costs. Unless earlier terminated, the collaboration agreement will remain in effect until the completion of all clinical trials under the collaboration, all related trial data has been deliveredhave agreed to both partiespursue commercialization and the completion of any then agreed upon analysis. The collaboration agreement may be terminated for cause by either party based on uncured material breach by the other party, bankruptcy of the other party or for safety reasons. Upon termination by either party, the licenses granted to each party to conduct a combined therapy trial will terminate.marketing efforts independently.
Roche
In February 2017, we entered into a master clinical supply agreement with Roche for the purpose of evaluating cabozantinib and Roche’s ICI, atezolizumab, in locally advanced or metastatic solid tumors. Pursuant to the terms ofUnder this agreement with Roche, in June 2017, we initiated COSMIC-021 and in December 2018, we initiated COSMIC-312. We are the trial sponsor of both trials, and Roche is providing atezolizumab free of charge. For descriptions of the COSMIC-021 and COSMIC-312 trials, see “—Exelixis Development Programs—Cabozantinib Development Program—Trials Conducted Under our Clinical Collaboration Agreements—Combination Studies with Roche.”
Under the joint clinical research agreement, each party granted to the other a non-exclusive, worldwide (excluding, in our case, territory already the subject of a license by us to Takeda), non-transferable, royalty-free license, with a right to sublicense (subject to limitations), to use the other party’s intellectual property and compounds solely as necessary for the party to perform its obligations under the joint clinical research agreement. The parties’ efforts will be governed through a joint steering committee established to guide and oversee the collaboration and the conduct of the combined therapy trials. Each party will be responsible for providing clinical supply for all combined therapy trials, and the cost of the supply will be borne by such party. The clinical trial expenses for each combined therapy trial agreed to be conducted jointly under the joint clinical research agreement will be shared equally between the parties, and the clinical trial expenses for each additional combined therapy trial not agreed to be conducted jointly under the joint clinical research agreement will be borne by the proposing party, except that the cost of clinical supply for all combined therapy trials will be borne by the party that owns the applicable product.
Unless earlier terminated, the joint clinical research agreement provides that it will remain in effect until the completion of all combined therapy trials under the collaboration, the delivery of all related trial data to both parties, and the completion of any then agreed-upon additional analyses. The joint clinical research agreement may be terminated for cause by either party based on any uncured material breach by the other party, bankruptcy of the other party or for safety reasons. Upon termination by either party, the licenses granted to each party will terminate upon completion of any ongoing activities under the joint clinical research agreement.
XL092 Clinical Collaborations
In January 2018,an effort to diversify our exploration of the therapeutic potential of XL092, we have also entered into multiple supply agreements to evaluate XL092 in various combination trials, including with Roche’s atezolizumab, Merck KGaA and Pfizer’s avelumab, BMS’ nivolumab and ipilimumab and Nektar’s bempegaldesleukin. These supply agreements will facilitate the efficient exploration of the safety and efficacy of XL092 in combinations with a variety of established cancer therapies as we continue to build a broad development program for XL092. For descriptions of our ongoing clinical trials evaluating XL092 in combination with other therapies, see “—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates—XL092 Development Program.”
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Research Collaborations, In-licensing Arrangements and Other Business Development Activities
STORM
In October 2021, we entered into an exclusive collaboration and license agreement with StemSynergySTORM to discover and advance novel drug candidates intended for the treatment of cancer. Our collaboration focuses initially on the RNA modifying enzyme ADAR1, building on early work by STORM applying its proprietary RNA epigenetic platform, as well as exploring an additional undisclosed target. Under the agreement, we made an upfront payment in exchange for exclusive licenses to these two discovery programs. STORM is responsible for discovery and generation of lead candidates for both target programs, and we will assume responsibility for IND-enabling studies and all subsequent clinical development, manufacturing and commercialization activities.STORM is eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales. We have also committed to contribute research funding to STORM for discovery and preclinical development work for each program.
GamaMabs
In May 2021, we entered into an asset purchase agreement with GamaMabs to acquire all rights, title and interest in GamaMabs’ AMHR2 antibody program. Under the agreement, we made an upfront payment in exchange for an initial technology transfer of certain materials and documents, additional payments for subsequent technology transfers and will make a final payment upon the closing of the transaction. As a result of the transaction, we will own or control 100% of GamaMabs’ AMHR2 antibody program, including all assets pertaining to GamaMabs’ mAb drug product murlentamab (GM-102). GamaMabs is eligible for potential development and regulatory milestone payments.
WuXi Bio
In March 2021, we entered into an exclusive license agreement with WuXi Bio to support the continued expansion of our oncology biotherapeutics pipeline by leveraging WuXi Bio’s panel of mAbs for the development of ADC, bispecific and certain other novel tumor-targeting biotherapeutics applications. Under the agreement, we made an upfront payment in exchange for an exclusive license to a panel of mAbs directed to a preclinically validated target discovered using WuXi Bio’s integrated technology platforms. We will assume responsibility for all subsequent clinical development, manufacturing and commercialization activities under the agreement.WuXi Bio is eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales.
Adagene
In February 2021, we entered into a collaboration and license agreement with Adagene to utilize Adagene’s SAFEbody technology platform to generate masked versions of mAbs from our growing preclinical pipeline for the development of ADCs or other innovative biotherapeutics against Exelixis-nominated targets. Under the agreement, we made an upfront payment in exchange for an exclusive, worldwide license to develop and commercialize any potential ADC products generated by Adagene with respect to an initial target, as well as a second target we may nominate during the collaboration term. For each target that we nominate, we would then assume responsibility for all subsequent clinical development, manufacturing and commercialization for that program.Adagene is eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales .
Catalent
In September 2020, we entered into a collaboration and license agreement with Catalent to develop multiple ADCs using Catalent’s proprietary SMARTag site-specific bioconjugation technology. Under the agreement, we made an upfront payment in exchange for an exclusive option to license up to four targets using Catalent’s ADC platform over a three-year period. In addition, we have the right to extend the target selection term to five years and nominate up to two additional targets for an additional payment. For each option we decide to exercise, we will be required to pay an exercise fee, and we would then assume responsibility for all subsequent clinical development, manufacturing and commercialization for that program. Catalent would then become eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales. We have also committed to contribute research funding to Catalent for discovery and preclinical development work.
NBE
In September 2020, we entered into a collaboration and license agreement with NBE to discover and develop multiple ADCs for oncology applications by leveraging NBE’s unique expertise and proprietary platforms in ADC discovery,
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including NBE’s SMAC-Technology and novel payloads. Under the Agreement, we made an upfront payment in exchange for exclusive options to nominate four targets using NBE’s ADC platform over a two-year period. In addition, within the first 18 months of the agreement term, we also have the right to extend the target selection term to three years for an additional payment. For each option we decide to exercise, we will be required to pay an exercise fee, and we would then assume responsibility for all subsequent clinical development, manufacturing and commercialization connected with any resulting program. NBE would then become eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales. We have also committed to contribute research funding to NBE for discovery and preclinical development work.
Aurigene
In July 2019, we entered into an exclusive collaboration, option and license agreement with Aurigene to in-license as many as six oncology target programs to discover and develop small molecules as therapies for cancer, and in April 2021, we expanded the collaboration to include three additional early discovery programs for a total of nine programs. Under the agreement, we made upfront payments in exchange for exclusive options to license eight of the nine programs to date, and we will pay an additional upfront payment upon the nomination of the ninth program. Based on encouraging preclinical data for XL102, the lead Aurigene program targeting CDK7, we exercised our exclusive option to license XL102 in December 2020, resulting in our assuming responsibility for all subsequent clinical development, manufacturing and commercialization of XL102 and payment of an exercise fee to Aurigene. We also submitted an IND for XL102 in November 2020, and following the FDA’s acceptance of the IND in December 2020, we initiated a phase 1 clinical trial of XL102 in January 2021 designed to evaluate its pharmacokinetics, safety, tolerability and preliminary efficacy, both as a single agent and in combination with other anticancer therapies. For additional information on XL102, see “—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates—XL102 Development Program.” In addition, we exercised our exclusive option to in-license XL114, Aurigene’s novel CBM inhibitor, in October 2021, resulting in our assuming responsibility for all subsequent clinical development, manufacturing and commercialization of XL114 and payment of an option exercise fee to Aurigene. Following the FDA’s acceptance of our IND application for the small molecule in October 2021, we plan to initiate a phase 1 clinical trial evaluating XL114 as a monotherapy in patients with NHL in the first half of 2022. For additional information on XL114, see “—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates—XL114 Development Program.” With respect to each of XL102 and XL114, Aurigene is eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales.
Beyond XL102 and XL114, we are continuing to work with Aurigene to advance the other small molecule programs through preclinical development. For each additional option we decide to exercise, we will be required to pay an exercise fee, and we would then assume responsibility for all subsequent clinical development, manufacturing and commercialization for that program. Aurigene would then become eligible for potential development, regulatory and commercial milestone payments, as well as royalties on potential sales. We are also responsible for research funding for the discovery and preclinical development of novel oncology compounds targeting CK1α, a component of the Wnt signaling pathway implicated in key oncogenic processes. Activation of β-catenin, a key downstream component of the pathway, is increased in multiple tumors, including a majority of colorectal cancers, where mutations in the APC gene that result in β-catenin stabilization are prevalent. Compounds targeting CK1α have also been shown to induce degradation of β-catenin and pygopus, another member of the pathway, in preclinical CRC models, and to inhibit the growth of tumors. Importantly, their GI-sparing qualities may help overcome limitations of other approaches targeting the Wnt pathway.work on these programs. Under the terms ofagreement, Aurigene retains limited development and commercial rights for India and Russia.
Iconic
In May 2019, we entered into an exclusive option and license agreement with Iconic to advance an innovative next-generation ADC program for cancer, leveraging Iconic’s expertise in targeting TF in solid tumors. Under the original May 2019 agreement, we will partner with StemSynergygained an exclusive option to conduct preclinical and clinical studies with compounds targeting CK1α. We paid StemSynergylicense XB002, Iconic’s lead TF ADC program, in exchange for an upfront payment of $3.0 millionto Iconic and a commitment for preclinical development funding. Based on encouraging preclinical data, we exercised our exclusive option to license XB002 in initial research and development funding, and we plan to provide StemSynergy with additional research and development funding of up to $1.2 million during 2019 on an as needed basis. StemSynergy will also be eligibleDecember 2020, resulting in our assuming responsibility for up to $56.5 million in milestones for the first product to emerge from the collaboration, including preclinical andall subsequent clinical development, manufacturing and regulatory milestone payments, commercial milestones,commercialization for XB002 and payment of an option exercise fee to Iconic. Following the FDA’s acceptance of our IND for XB002 in April 2021, we initiated a phase 1 clinical trial of XB002 in June 2021 designed to evaluate its pharmacokinetics, safety, tolerability and preliminary efficacy as a monotherapy in patients with advanced solid tumors. For additional information on XLB002, see “—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates—XB002 Development Program.”
In January 2022, we announced an amendment to our agreement with Iconic, which we entered into in December 2021, to acquire broad rights to use the anti-TF antibody used in XB002 for any application, including conjugated to other payloads, as well as single-digit royalties on worldwide sales. Werights within oncology to a number of other anti-TF antibodies developed by Iconic, including for use in ADCs and multispecific biotherapeutics. Under the amended agreement, we made a final payment to Iconic and will not
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owe Iconic any further payments, but we will continue to be solely responsible for the commercialization of products that arise from the collaboration.milestone payments and royalties owed to other companies pursuant to prior agreements between Iconic and those companies.
Invenra Collaboration
In May 2018, we entered into a collaboration and license agreement with Invenra which is focused on developing next-generation biologics, to discover and develop multispecific antibodies for the treatment of cancer. Invenra is responsible for antibody lead discovery and generation while we will lead IND-enabling studies, manufacturing, clinical development in single-agent and combination therapy regimens, and future regulatory and commercialization activities. The collaboration agreement also provides that we will receive an exclusive, worldwide license to one preclinical, multispecific antibody asset, and that we will pursue up to sixmultiple additional discovery projects across three different programs during the term of the collaboration, which in total are directed to three discovery programs.
collaboration. In consideration for the exclusive worldwide license and other rights contained in the collaboration agreement, we paid Invenra an upfront payment of $2.0 million and a project initiation fee of $2.0 million. In JanuaryOctober 2019, we initiatedexpanded our secondcollaboration to include the development of novel binders against six additional targets, which we can use to generate multispecific antibodies based on Invenra’s B-BodyTM technology platform, or with other platforms and formats at our option. We amended the agreement again in March 2020 and January 2021 to enable the use of target binders in non-Invenra platform-based modalities, such as ADC platforms, and to enable the development of biparatropic antibodies, respectively. Then in August 2021, we further expanded our collaboration to include an additional 20 targets for biotherapeutics discovery project,and development, for which we paid an additional project initiation fee of $2.0 million.agreed to pay Invenra exclusivity payments and research program funding over a three-year period.
Under the collaboration, Invenra is eligible to receive payments of up to $131.5 million based on the achievement of specificfor project initiation fees and potential development, regulatory and regulatory milestones for a product containing the lead preclinical asset in the first indication. Upon successful commercialization of a product, Invenra is eligible to receive globalcommercial milestone payments, up to $325.0 million if certain sales thresholds are achieved as well as single-digit tiered royalties on net sales of theany approved product.products. We also have the right to initiate four additional discovery projectsexercise options with respect to certain of Invenra’s other research programs in exchange for development subject to an upfrontoption exercise payment, of $2.0 millionand Invenra is eligible for each project, as well as additional global milestone payments and royalties for any products that arise from these optioned research programs.
StemSynergy
In January 2018, we entered into an exclusive collaboration and license agreement with StemSynergy for the discovery efforts.
Other Collaborations
Prior to the commercialization of our first product, COMETRIQ, our primary business strategy was focused on the development and out-license of compounds to pharmaceutical and biotechnology companies under collaboration agreements that allowed us to retain economic participation in compounds and support additional development of our proprietary products. Our collaboration agreements with Genentech and Daiichi Sankyo and BMS described below are representative of this historical strategy. We have since evolved and are now a fully-integrated biopharmaceutical company focused on driving the expansion and depth of our product offerings through the continued development of the cabozantinib internalfranchise and drug discovery efforts, including research collaborations, in-licensing arrangements and execution ofother strategic transactions that align with our oncology drug development, regulatory and commercialization expertise, all to improve care and outcomes for people with cancer around the world. While the historical collaboration agreements described below have the potential to provide future revenue, and while we have already received some collaboration revenues from these arrangements, we do not expect to receive significant revenues from these historical collaboration agreements unless and until our partnered compounds generate substantial sales in the territories and indications where they are approved, or if not yet approved, enter late-stage clinical development.approved. If these events occur, then the milestone payments, royalties or other rights and benefits under our historical collaboration agreements could become substantial.
Genentech - Cobimetinib
In December 2006, we out-licensed the further development and commercialization of cobimetinib to Genentech pursuant to a worldwide collaboration agreement. Cobimetinib is a reversible inhibitor of MEK, a kinase that is a
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component of the RAS/RAF/MEK/ERK pathway. This pathway mediates signaling downstream of growth factor receptors, and is prominently activated in a wide variety of human tumors. Under the terms of the collaboration agreement, we developed cobimetinib through the determination of the maximum tolerated dose in a phase 1 clinical trial, and Genentech had the option to co-develop cobimetinib, an option that Genentech exercised, and in March 2009, we granted to Genentechreceived an exclusive worldwide revenue-bearing license to cobimetinib at which point Genentech becameand is responsible for completingall future clinical development of the phase 1 clinical trial and subsequent clinical development. We received aggregate upfront and milestone payments of $50.0 million under our collaboration agreement with Genentech and are not eligible for any additional milestone payments.
compound. On November 10, 2015, the FDA approved cobimetinib, under the brand name COTELLIC, in combination with Genentech’s ZelborafZELBORAF (vemurafenib) as a treatment for patients with BRAF V600E or V600K mutation-positive advanced melanoma. COTELLIC in combination with ZelborafZELBORAF has also been approved in Switzerland, the EU, Canada, Australia, Brazil and multiple additional countries for use in the same indication. Prior toOn July 30, 2020, the FDA’s approval of COTELLIC, in November 2013, we exercised an option under the collaboration agreement to co-promote COTELLIC in the U.S., which allows for us to provide up to 25% of the total sales force forFDA approved cobimetinib indications in the U.S. Between November 2015 and December 2017, we fielded 25% of the sales force promoting COTELLIC, in combination with Zelboraf as aGenentech’s ZELBORAF and TECENTRIQ® (atezolizumab) for the treatment for patients withof BRAF V600 mutation-positive advanced melanoma in the U.S. However, following a review of the commercial landscape, commencing in January 2018, we and Genentech scaled back the personal promotion of COTELLIC in this indication in the U.S. This decision is not indicative of any change in our intention to promote COTELLIC for other therapeutic indications for which it may be approved in the future.
Under the terms of our collaboration agreement, as amended in July 2017, we share in the profits and losses received or incurred in connection with COTELLIC’s commercialization in the U.S. This profit and loss share has multiple tiers: we receive 50% of profits and losses from the first $200.0 million of U.S. actual sales, decreasing to 30% of profits and losses from U.S. actual sales in excess of $400.0 million. These tiers will reset each calendar year. The revenue for each sale of COTELLIC applied to the profit and loss statement for the collaboration agreement (Genentech Collaboration P&L) is calculated using the average of the quarterly net selling prices of COTELLIC and any additional branded Genentech product(s) prescribed with COTELLIC in such sale. U.S. commercialization costs for COTELLIC are then applied to the Genentech Collaboration P&L, subject to reduction based on the number of Genentech products in any given combination including COTELLIC. In addition to our profit share in the U.S., under the terms of the collaboration agreement, we are entitled to low double-digit royalties on net sales of COTELLIC outside the U.S. During 2018,2021, we earned royalties of $5.6$4.1 million on net sales of COTELLIC outside the U.S. and a $8.1 million profit on the profit and loss sharing of U.S. actual sales which are recorded in Collaborationcollaboration services revenues.
In addition to its established commercialization of COTELLIC, Genentech continues to make significant progress with respect to the clinical development, regulatory status and commercial potential of cobimetinib. Cobimetinib is being evaluated in a broad development program consisting of more than 50multiple clinical trials by Genentech or through Genentech’s investigator sponsored trial program, including two phase 3 pivotal trials currently underway exploring the combination of cobimetinib with atezolizumab or atezolizumab alone in BRAF wild type melanoma (IMspire170) and the combination of cobimetinib with atezolizumab and vemurafenib in BRAF V600 mutant melanoma (IMspire150). Additionally, although IMblaze370, a third phase 3 pivotal trial conducted by Genentech evaluating the combination of cobimetinib with atezolizumab in CRC did not meet its primary endpoint as announced in May 2018, Genentech continues to pursue the cobimetinib development program and is conducting a series of early-stage clinical trials investigating the combination of cobimetinib and atezolizumab in multiple tumor settings.IST program. Should these trials prove positiveyield supporting data and Genentech obtain regulatory approvals based on such positive results,supporting data, we believe that cobimetinib couldmay provide us with a potentially meaningfulan additional source of revenue in the future.
In March 2006, we entered into a collaboration agreement with Daiichi Sankyo for the discovery, development and commercialization of novel therapies targeted against the MR, a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. Under the terms of thecollaboration agreement, we granted to Daiichi Sankyo an exclusive, worldwide license to certain intellectual property primarily relating to compounds that modulate MR, including esaxerenone, an oral, non-steroidal, selective MR antagonist. Daiichi Sankyo is responsible for all further preclinical and clinical development, regulatory, manufacturing and commercialization activities for the compounds and we do not have rights to reacquire such compounds, except as described below. Duringcompounds.
In January 2019, the research term, which concluded in November 2007, we jointly identified drug candidates with Daiichi Sankyo for further development. Esaxerenone is the only remaining drug candidate identifiedJapanese MHLW first approved esaxerenone under the collaboration that continues to be developed by Daiichi Sankyo, and we are entitled to receive payments upon attainment of pre-specified development, regulatory and commercialization milestones for esaxerenone
Daiichi Sankyo also continues to advancehas further advanced the development program for esaxerenone, with an ongoingand in November 2019, Daiichi Sankyo announced positive results from a phase 3 pivotal trial evaluating esaxerenone as a treatment option for patients in Japan with diabetic nephropathy. Should this trial prove positive and Daiichi Sankyo obtain regulatory approval based on such positivethese results, and taking into account the approval of MINNEBRO by the MHLW in January 2019 for the treatment of hypertension and Daiichi Sankyo’s subsequent commercial sales of MINNEBRO, we believe that esaxerenone willmay provide an additional source of revenue in the future.
Manufacturing and Product Supply
We do not own or operate manufacturing facilities,or distribution facilities or resources for chemistry, manufacturing and control (CMC) development activities, preclinical, clinical or commercial production and distribution offor our current products. Instead, we have multiple contractual agreements in place withrely on various third-party contract manufacturing organizations who,to conduct these operations on our behalf, manufacture clinicalbehalf. As our operations continue to grow in these areas, we continue to expand our supply chain through secondary third-party contract manufacturers, distributors and suppliers. Specifically, we entered into agreements with secondary contract manufacturing organizations to produce additional commercial supplies of CABOMETYX tablets and COMETRIQ. Ascabozantinib drug substance, which bolsters our operationscommercial supply chain and serves to mitigate the risk of supply chain interruptions or other failures. For our portfolio of small molecules and biotherapeutics, we continue to expand due to our development and commercial progress, we expect to enter into new agreements with additional third-party contract manufacturers and suppliers as needed. This will continue for the foreseeable future for all of our product candidates and all of our current and future commercial products. We have selectednetwork through well-established and reputable global third-party contract manufacturers for our drug substanceCMC development and drug product manufacturing that have good
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regulatory standing, largesuitable manufacturing capacities and multiple manufacturing sites within their business footprint.capabilities. These third parties must comply with applicable regulatory requirements, including the FDA’s Current Good Manufacturing Practices,Practice (GMP), the EC’s Guidelines on Good Distribution Practice (GDP), as well as other stringent regulatory requirements enforced by the FDA or foreign regulatory agencies, as applicable, and are subject to routine inspections by such regulatory agencies.
We monitor and evaluate the performance of our third-party contract manufacturers on an ongoing basis to ensurefor compliance with these requirements and to affirm their continuing capabilities to meet both our commercial and clinical
needs. We also have contracted with a third-party logistics provider, with multiple distribution locations, to provide shipping and warehousing services for our commercial supply of both CABOMETYX and COMETRIQ in the U.S. We employ highly skilled personnel with both technical and manufacturing experience to diligently manage the activities at our third-party contract manufacturers and other supply chain partners, and our quality department audits them on a periodic basis.
We source raw materials that are used to manufacture our drug substance from multiple third-party suppliers in Asia, Europe and Europe.North America. We stock sufficient quantities of these materials and provide them to our third-party drug substance contract manufacturers to ensureso they can manufacture adequate drug substance quantities per our requirements, for both clinical and commercial purposes. We then store drug substance at third-party facilities and provide appropriate amounts to our third-party drug product contract manufacturers, who then manufacture, package and label our specified quantities of finished goods for COMETRIQ and CABOMETYX, respectively. In addition, we rely on our third-party contract manufacturers to source materials such as excipients, components and reagents, which are required to manufacture our drug substance and finished drug product.
Marketing Sales and DistributionSales
We have a fully integrated commercial team consisting of sales, marketing, market access, and commercial operations functions. Our sales team promotes CABOMETYX and COMETRIQ in the U.S. In addition, although we currently do not co-promote COTELLIC alongside Genentech, we have the right to do so and will do so if we, in consultation with Genentech, deem it useful and appropriate to realize COTELLIC’s commercial objectives. We use customary pharmaceutical company practices to market our products in the U.S. and concentrate our efforts on oncologists, oncology nurses, pharmacists and pharmacists. other healthcare professionals. In addition to using customary in-person pharmaceutical company practices, we also utilize digital marketing technologies to expand our engagement opportunities with customers.
Our commercial products, CABOMETYX and COMETRIQ, are sold initially through wholesale distribution and specialty pharmacy channels and then, if applicable, resold to hospitals and other organizations that provide CABOMETYX and COMETRIQ to end-user patients. To facilitate our commercial activities in the U.S., we also employ various third-party vendors,third parties, such as advertising agencies, market research firms and vendors providing other sales-support related services as needed.needed, including digital marketing and other non-personal promotion. We believe that our commercial team and distribution practices are sufficient to ensurefacilitate our marketing efforts reachin reaching our target audience and deliverour delivery of our products to patients in a timely and compliant fashion.
In addition, we rely on Ipsen and Takeda for ongoing and further commercialization and distribution of CABOMETYX in territories outside of the U.S., as well as for access and distribution activities for the approved products under named patient use programs or similar programs with the effect of introducing earlier patient access to CABOMETYX,
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and we also rely on Ipsen for these same activities with respect to the commercialization and distribution of COMETRIQ outside of the U.S. For COTELLIC, we rely on Genentech, as our collaboration partner, for all current and future commercialization and marketing activities, with the exception of the limited co-promotion activities highlighted above.
To help ensure that all eligible patients in the U.S. have appropriate access to CABOMETYX and COMETRIQ, we have established a comprehensive reimbursement and patient support program called Exelixis Access Services (EASE). Through EASE, we provide co-pay assistance to qualified, commercially insured patients to help minimize out-of-pocket costs and provide free drug to uninsured or under-insured patients who meet certain clinical and financial criteria. In addition, EASE provides comprehensive reimbursement support services, such as prior authorization support, benefits investigation and, if needed, appeals support. Beyond financial assistance, patients who participate in EASE also receive treatment coordination through a dedicated case manager, as well as clinical outreach and support from a network of oncology nurses or other healthcare professionals who help many of these patients better understand how to take their medication and mitigate side effects.
Laboratory Safety Program
Due to the focus of our business in discovering and developing drug products, many of our employees work in our on-site laboratory facilities. All new laboratory staff are trained on chemical hygiene, the use of personal protective equipment, and certain other relevant laboratory safety topics, such as working with blood-borne pathogens, and current staff are retrained regularly. We also extend these trainings to facilities staff and others who support our work in the labs. In an effort to maintain a safe environment for all staff, we regularly perform thorough safety inspections of our laboratories, and continuously update our procedures based on the observations made during these inspections. Additionally, we conduct periodic industrial hygiene monitoring to ensure lab staff working with certain known hazardous chemicals do not exceed regulated exposure limits, and we regularly test and certify fume hoods, biosafety cabinets and other individual pieces of equipment on which employees rely to maintain a safe work environment.
Workplace Safety Measures in Response to COVID-19
We will continue to monitor the latest guidance issued by health authorities and have instituted several policies and procedures to protect against the spread of COVID-19 among our workforce. Since the third quarter of 2021, we have implemented a vaccination mandate and maintain several enhanced safety and social distancing protocols at our headquarters. In addition, we also offer on-site, rapid PCR COVID-19 testing, and utilize a mobile device app and web interface, which enable our team members to perform daily symptom tracking and schedule on-site tests at the Exelixis headquarters, and which also provide contact tracing and educational resources for any team member who may have tested positive.
Other policies and procedures currently include frequent disinfection of common areas by our operations staff and investments in re-engineering workspace safety, such as providing ample supplies of hand sanitizer, sanitizing wipes and facemasks for use by our staff, and adjusting our ventilation systems in an effort to minimize risks of airborne transmission. Although the COVID-19 pandemic has presented several new challenges for us, to date, we have only experienced a modest impact on our productivity without significant interruptions in our general business operations. For a more detailed discussion of the impact of the COVID-19 pandemic and our risk mitigation efforts, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—COVID-19 Update” in Part II, Item 7 of this Annual Report on Form 10-K.
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Government Regulation
Clinical Development
The FDA and comparable regulatory agencies in state and local jurisdictions and in foreign countries impose substantial requirements upon the clinical development, manufacture and marketing of pharmaceutical products. These agencies and other federal, state and local entities regulate, among other things, research and development activities and the testing, marketing approval, manufacture, quality control, safety, effectiveness, labeling, storage, distribution, post-marketing safety reporting, export, import, record keeping, advertising and promotion of our products.
The process required by the FDA before product candidates may be marketed in the U.S. generally involves the following:
•nonclinical laboratory and animal tests, some of which must be conducted in accordance with Good Laboratory Practices;Practices (GLP);
•submission of an IND, which contains results of nonclinical studies (e.g., laboratory evaluations of the chemistry, formulation, stability and toxicity of the product candidate), together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, and must become effective before human clinical trials may begin;
•approval by an independent institutional review board or ethics committee at each clinical trial site before each trial may be initiated;
•adequate and well-controlled human clinical trials conducted in accordance with the protocol, IND and Good Clinical Practice (GCP) to establish the safety and efficacy of the investigational drug candidate for its proposed intended use;
•for drug products, submission of ana New Drug Application (NDA) to the FDA for commercial marketing, or generally of a supplemental New Drug Application (sNDA),an sNDA, for approval of a new indication if the product is already approved for another indication;
•for biologicalbiotherapeutic products, submission of a Biologics License Application (BLA) to the FDA for commercial marketing, or generally a supplemental Biologics License Application (sBLA) for approval of a new indication if the product is already approved for another indication;
•pre-approval inspection of manufacturing facilities and selected clinical investigators, clinical trial sites and/or Exelixis as the clinical trial sponsor for their compliance with Good Manufacturing Practices (GMP)GMP and Good Clinical Practices (GCP);GCP, respectively;
•payment of user fees for FDA review of an NDA or BLA unless a fee waiver applies;
•agreement with the FDA on the final labeling for the product;
•if the FDA convenes an advisory committee, satisfactory completion of the advisory committee review; and
•FDA approval of the NDA or sNDA, or BLA or sBLA.
For purposes of NDA approval, human clinical trials are typically conducted in three sequential phases that may overlap.overlap or be combined:
•Phase 1 - Studies,studies, which involve the initial introduction of a new drug product candidate into humans, are initially conducted in a limited number of subjects to test the product candidate for safety, tolerability, absorption, metabolism, distribution and excretion in healthy humans or patients. In rare cases, a Phase 1 study that is designed to assess effectiveness may serve as the basis for FDA marketing approval of a drug or for a label expansion. For instance, at FDA’s discretion, a product may receive approval based on a Phase 1b study if effectiveness results from the study are extremely compelling, approval of the drug would address a significant unmet patient need, and the drug is being approved through the accelerated approval pathway. As discussed below, Accelerated Approval generally requires a post-approval study to confirm clinical benefit.
•Phase 2 - Studiesstudies are conducted with groups of patients afflicted with a specified disease in order to provide enough data to evaluate the preliminary efficacy, optimal dosage, and common short-term side effect and risks associated with the drug. Multiple phase 2 clinical trials may be conducted by the sponsor to obtain information prior to beginning larger and more expensive phase 3 clinical trials. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects. In some cases, a sponsor may decide to run what is referred to as a “phase 2b”
•Phase 3 - When earlier phase evaluations provide preliminary evidence suggesting that a dosage range of the product is effective and has an acceptable safety profile, phase 3 trialsstudies are performedconducted to gather the additional information about effectiveness and safety that is needed toacross a higher number of patients and evaluate the overall benefit-risk relationship of the drug product candidate following earlier phase evaluations, which will have provided preliminary evidence suggesting an effective dosage range
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and acceptable safety profile for the product candidate. Phase 3 trials are also intended to provide an adequate basis for physician labeling. Phase 3 trials are undertaken in large patient populations to further evaluate dosage, to provide statistically significant evidencelabeling of clinical efficacy and to further test for safety in an expanded patient population at multiple clinical trial sites.the product if it is approved.
The FDA may require, or companies may pursue, additional clinical trials after a product is approved. These so-called phase 4post-marketing or “phase 4” studies may be madedeemed a condition to be satisfied after a drug receives approval. Failure to satisfy such post-marketing commitments can result in FDA enforcement action, up to and including withdrawal of NDA approval. The results of phase 4 studies can confirm the effectiveness
FDA Review and Approval
For approval of a product candidate and can provide important safety informationnew drug or changes to augment the FDA’s adverselabeling of an approved drug, reaction reporting system. Theincluding new indications, the results of product development, preclinical studies and clinical trials are submitted to the FDA as part of an NDA, or as part of an sNDA. The submission of an NDA requires payment of a substantial user fee to the FDA. The FDA may convene an advisory committee to provide clinical insight on NDA review questions. Althoughquestions, although the FDA is not required to follow the recommendations of an advisory committee, the agency usually does so.committee. The FDA may initially issue a Refuse to File letter for an incomplete NDA or sNDA, or it may deny approval of an NDA or sNDA by way of a Complete Response letter if the applicable regulatory criteria are not satisfied, or it mayalternatively require additional clinical and/or nonclinical data and/or an additional phase 3 pivotal clinical trial. Even if such data are submitted, the FDA may ultimately decide that the NDA or sNDA does not satisfy the criteria for approval. An NDA may be approved with significant restrictions on its labeling, marketing and distribution under a Risk Evaluation and Mitigation Strategy. Once issued, the FDA may withdraw product approval if ongoing regulatory standards are not met or if safety problems occur after the product reaches the market. In addition, the FDA may require testing and surveillance programs to monitor the effect of approved products that have been commercialized, and the FDA has the power to prevent or limit further marketing of a product based on the results of these post-marketing programs.
Satisfaction of FDA development and approval requirements or similar requirements of state, local and foreign regulatory agencies typically takes several years, and the actual time required may vary substantially based upon the type, complexity and novelty of the product or disease. Government regulation may delay or prevent marketing of product candidates for new diseases for a considerable period of time and impose costly procedures upon our activities. The FDA or any other regulatory agency may not grant approvals for new indications for our product candidates on a timely basis, if at all. Success in early stage clinical trials does not ensure success in later stage clinical trials. Targets and pathways identified in vitro may be determined to be less relevant in clinical studies and results in animal model studies may not be predictive of human clinical results. Data obtained from clinical activities are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval. Even if a product candidate receives regulatory approval, the approval may be significantly limited to specific disease states, patient populations and dosages. Further, even after regulatory approval is obtained, later discovery of previously unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market, including withdrawal of the NDA approval.
Any products manufactured or distributed by us pursuant to FDA approvals are subject to continuing regulation by the FDA, including obtaining prior FDA approval of certain changes to the approved NDA, record-keeping requirements, and reporting of adverse experiences with, and interruptions in the manufacture of, the drug. Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies,agencies. Thus, we and our third-party contract manufacturing organizations are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with GMP, which impose certain manufacturing requirements including(including procedural and documentation requirements,requirements) upon us and our third-party manufacturers.
In the U.S., the Orphan Drug Act of 1983, as amended, is intended to incentivizeprovides incentives for the development of drugs and biologicalbiotherapeutic products for rare diseases or conditions that affect fewer than 200,000 people in the U.S. (or that affects more than 200,000 persons in the U.S. and for which there is no reasonable expectation that the cost of developing and making available the drug in the U.S. for such disease or condition will be recovered from sales of the drug in the U.S.). If aCertain of the incentives turn on the drug isfirst being developed for a rare disease or condition, todesignated as an orphan drug. To be eligible for designation as an orphan drug (Orphan Drug Designation), the drug must have the potential to treat such rare disease or condition as described above. In addition, the FDA must not have previously approved a drug considered the “same drug,” as defined in the FDA’s orphan drug regulations, for the same orphan-designated indication. If the FDA has previously approved another same drug for the same indication to obtain orphan drug designation,or the sponsor of the subsequent drug would be required tomust provide a plausible hypothesis of clinical superiority over the previously approved drug to obtain an orphan designation.same drug. Upon FDA receipt of Orphan Drug Designation, the sponsor is eligible for tax credits of up to 50%25% for qualified clinical trial expenses the ability to apply for grant funding, and waiver of the Prescription Drug User Fee Act (PDUFA) application fee. Following the passage of the Tax Cuts and Jobs Act of 2017, for clinical trial expenses incurred in tax years 2018 and going forward, the tax credit is reduced to 25%. In addition, upon marketing approval, an orphan-designated drug could be eligible for seven years of market exclusivity if no drug considered the same drug was previously approved for the same orphan condition (or if the subsequent drug is demonstrated to be clinically superior to any such previously approved orphan-designated indication.same drug). Such orphan drug exclusivity, if awarded, would only block the approval of any drug considered the same drug for the same orphan indication. Moreover, a subsequent same drug could break a previouslyan approved drug’s orphan exclusivity through a demonstration of clinical superiority over the previously approved drug.
Expedited FDA Approval Pathways
The FDA has various programs including Fast Track, priority review and accelerated approval, whichthat are intended to expedite or simplify the process for developing and reviewing promising drugs, or to provide for the approval of a drug on the basis of a surrogate endpoint. Generally, drugs that are eligible for these programs are those for serious or life-threatening conditions, those with the potential to address unmet medical needs and those that offer meaningful benefits over existing treatments. For example, Examples of such programs included Fast Track designation, breakthrough therapy designation, priority review and accelerated approval, and the eligibility criteria of and benefits for each program vary:
•Fast Track is a process designed to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening diseases or conditions that demonstrate the potential to fill unmet medical needs. needs, by providing, among other things, eligibility for accelerated approval if relevant criteria are met, and rolling review,
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which allows submission of individually completed sections of an NDA or for FDA review before the entire submission is completed.
•Breakthrough therapy designation is a process designed to expedite the development and review of drugs that are 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. Drugs designated as breakthrough therapies are also eligible for accelerated approval. The FDA will seek to ensure the sponsor of a breakthrough therapy product candidate receives intensive guidance on an efficient drug development program, intensive involvement of senior managers and experienced staff on a proactive, collaborative and cross-disciplinary review, and rolling review.
•Priority review is designed to shorten the review period for drugs that treat serious conditions and that, if approved, would offer significant advances in safety or effectiveness or would provide a treatment where no adequate therapy exists. Under priority review, the FDA aims to take action on the application within six months as compared to a standard review time of 10 months. Certain other types of drug applications areSponsors may also eligible for priority review. Although Fast Track andobtain a priority review do not affect the standardsvoucher upon approval of an NDA for approval, the FDA will attemptcertain qualifying diseases and conditions that can be applied to facilitate early and frequent meetings with a sponsor of a Fast Track designated drug and expedite review of the application for a drug designated for priority review. subsequent NDA submission
•Accelerated approval provides for an earlier approval for a new drug that is intended to treat a serious or life-threatening disease or condition and that fillsprovides a meaningful advantage over available therapies and demonstrates an unmet medical need basedeffect on a surrogate endpoint, or certainan intermediate clinical endpoints,endpoint, which is considered reasonably likely to predict clinical benefit. As a condition of approval, the FDA may requirerequires that a sponsor of a product candidate receiving accelerated approval perform post-marketing clinical trials or provide data on established clinical endpoints from the same trial to confirm the clinically meaningful outcomeclinical benefit as predicted by the surrogate marker trial. In additionThe failure to conduct such trials, or confirm the Fast Track,clinically meaningful outcome in such trials, may result in withdrawal of the approval of the drug or the indication approved under accelerated approval and priority review programs, approval.
Specifically, with respect to oncology products, the FDA also designates Breakthrough Therapy statusmay review applications under the Real-Time Oncology Review (RTOR) pilot program established by the FDA’s Oncology Center of Excellence. The RTOR pilot program, which allows an applicant to drugspre-submit components of the application to allow the FDA to review clinical data before the complete filing is submitted, aims to explore a more efficient review process to ensure that safe and effective treatments are intended, alone or in combination with one or more other drugs,available to treat a serious or life-threatening disease or condition,patients as early as possible, while maintaining and preliminary clinical evidence indicates thatimproving review quality. Drugs considered for review under the drug mayRTOR pilot program must be likely to demonstrate substantial improvementimprovements over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Drugs designated as breakthrough therapies are also eligible for accelerated approval. The FDA will seek to ensure the sponsor of aavailable therapy, which may include drugs previously granted breakthrough therapy product candidate receives: intensive guidance on an efficient drug development program; intensive involvement of senior managersdesignation for the same or other indications, and experienced staff on a proactive, collaborativemust have straight-forward study designs and cross-disciplinary review;endpoints that can be easily interpreted.
Abbreviated FDA Approval Pathways and rolling review.Generic Products
The Drug Price Competition and Patent Term Restoration Act of 1984 (The Hatch-Waxman Act)
•Abbreviated New Drug Application (ANDA). An ANDA may be approved by the FDA if the applicant demonstrates that the proposed generic product is the same as the approved drug, which is referred to as the Reference Listed Drug (RLD). Generally, an ANDA must contain data and information showing that the proposed generic product and RLD (1) have the same active ingredient, in the same strength and dosage form, to be delivered via the same route of administration, (2) are intended for the same uses, and (3) are bioequivalent. This is instead of independently demonstrating the proposed product’s safety and effectiveness which are inferred from the fact that the product is the same as the RLD, which the FDA
•505(b)(2) NDAs. A 505(b)(2) applicationNDA is onean application for which one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. Under Section 505(b)(2) NDA of the FDCA,Federal Food, Drug, and Cosmetic Act (FDCA), an applicant may rely, in part, on the FDA’s previous approval of a similar product, or published literature, in support of its application. If the 505(b)(2) applicant establishes that reliance on the FDA’s prior findings of safety and efficacy for an approved product is
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scientifically appropriate, it may eliminate the need to conduct certain preclinical or clinical studies. The FDA may require additional studies or measurements, including comparability studies.
Unlike a full NDA for which the sponsor has conducted or obtained a right of reference to all the data essential to approval, the filing of both an ANDA application andor a 505(b)(2) applicationNDA may be delayed due to patent or exclusivity protections covering an approved product. The Hatch-Waxman Act provides (a) up to five years of exclusivity for the first approval of a new chemical entity (NCE) exclusivity and (b) three years of exclusivity for approval of an NDA or supplemental applicationsNDA for a product that is not an NCE but rather where the application contains new clinical studies conducted or sponsored by the sponsor and considered essential to the approval of the NDA or sNDA (three-year “changes” exclusivity). NCE exclusivity runs from the time of approval of the NDA and bars FDA from accepting for review of any ANDA or 505(b)(2) applicationNDA for a drug containing the same active moiety for five years (or for four years if the application contains a paragraphParagraph IV certification that a reference product patent is invalid or not infringed by the ANDA/505(b)(2) NDA product). The three-year “changes” exclusivity generally bars the FDA from approving any ANDA or 505(b)(2) NDA application that relies on the information supporting the approval of the drug or the change to the drug for which the information was submitted and the exclusivity granted.
Both Congress and the FDA are considering, and have enacted, various legislative and regulatory proposals focused on drug competition, including legislation focused on drug patenting and provision of drug to generic applicants for testing. For example, the Ensuring Innovation Act, enacted in April 2021, amended the FDA’s statutory authority for granting NCE exclusivity to reflect the agency’s existing regulations and longstanding interpretation that award NCE exclusivity based on a drug’s active moiety, as opposed to its active ingredient, which is intended to limit the applicability of NCE exclusivity, thereby potentially facilitating generic competition. The FDA has also released, and continues to implement, a Drug Competition Action Plan, which proposes actions to broaden access to generic drugs and lower consumers’ healthcare costs by, among other things, improving the efficiency of the generic drug approval process and supporting the development of complex generic drugs. In addition, the Further Consolidated Appropriations Act, 2020, which incorporated the framework from the Creating and Restoring Equal Access To Equivalent Samples (CREATES) legislation, purports to promote competition in the market for drugs and biotherapeutic products by facilitating the timely entry of lower-cost generic and biosimilar versions of those drugs and biotherapeutic products, including by allowing ANDA, 505(b)(2) NDA or biosimilar developers to obtain access to branded drug and biotherapeutic product samples.
Orange Book Listing. An NDA sponsor must identify to the FDA patents that claim the drug substance or drug product or approved method of using the drug. When the drug is approved, those patents are among the information about the product that is listed in the FDA publication, Approved Drug Products with Therapeutic Equivalence Evaluations, which is referred to as the Orange Book. Any applicant who files an ANDA or a 505(b)(2) NDA must certify, for each patent listed in the Orange Book for the RLD that (1) no patent information on the drug product that is the subject of the application has been submitted to the FDA, (2) such patent has expired, (3) the listed patent will expire on a particular date and approval is sought after patent expiration, or (4) such patent is invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. An ANDA or 505(b)(2) NDA applicant may also submit a statement that it intends to carve-out from the labeling of its product an RLD’s use that is protected by exclusivity or a method of use patent. The fourth certification described above is known as a Paragraph IV certification. A notice of the Paragraph IV certification must be provided to each owner of the patent that is the subject of the certification and to the reference NDA holder. The reference NDA holder and patent owners may initiate a patent infringement lawsuit in response to the Paragraph IV notice. Filing such a lawsuit within 45 days of the receipt of the Paragraph IV certification notice prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earlier of 30 months, expiration of the patent, settlement of the lawsuit, or a decision in the infringement case that is favorable to the ANDA or 505(b)(2) NDA applicant. The ANDA or 505(b)(2) applicationNDA also will not receive final approval until any applicable non-patent exclusivity listed in the Orange Book for the RLD has expired. We intend to defend vigorously any patents for our approved products.
In addition to regulations in the U.S., we are subject to regulations of other countries governing clinical trials and the manufacturing, commercial sales and distribution of our products outside of the U.S. Whether or not we obtain FDA approval for a product, we must obtain approval by the comparable regulatory authorities of countries outside of the U.S. before we can commence clinical trials in such countries and approval of the regulators of such countries or economic areas, such as the EU, before we may market products in those countries or areas. The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from place to place, and the time may be longer or shorter than that required for FDA approval.
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The way clinical trials are conducted in the EU will undergohas undergone a major change whenwith the application of Regulation (EU) 536/2014, governing clinical trials in the EU, repealing the existing Directive 2001/20/EC comes into application in 2019.EC. This new regulation harmonizes the assessment and supervision processes for clinical trials throughout the EU, via an EU portal and database. Thedatabase, which the EMA will set up and maintain the portal and database, in collaboration with the Member States and the EC. Following the EC’s confirmation of full functionality of the Clinical Trials Information System (CTIS) through an independent audit, which was published in the Official Journal of the European Union in August 2021, Regulation (EU) 536/2014 became applicable concurrent with the CTIS “go-live” date on January 31, 2022.
Under EU regulatory systems, a company may submit MAAsa marketing authorization application (MAA) either under centralized or decentralized procedure. Under the centralized procedure, MAAs are submitted to the EMA for scientific review by the Committee for Medicinal
Products for Human Use (CHMP) so that an opinion is issued on product approvability. The opinion is considered by the EC which is responsible for granting the centralized marketing authorization in the form of a binding EC decision. If the application is approved, the EC grants a single marketing authorization that is valid for all EU member statesMember States as well as Iceland, Liechtenstein and Norway, collectively the European Economic Area (EEA).Area. The decentralized and mutual recognition procedures, as well as national authorization procedure are available for products for which the centralized procedure is not compulsory. The mutual recognition procedure provides for the EU member statesMember States selected by the applicant to mutually recognize a national marketing authorization that has already been granted by the competent authority of another member state,Member State, referred to as the Reference Member State (RMS). The decentralized procedure is used when the product in question has yet to be granted a marketing authorization in any member state.Member State. Under this procedure the applicant can select the member stateMember State that will act as the RMS. In both the mutual recognition and decentralized procedures, the RMS reviews the application and submits its assessment of the application to the member statesMember States where marketing authorizations are being sought, referred to as Concerned Member States. Within 90 days of receiving the application and assessment report, each Concerned Member State must decide whether to recognize the RMS assessment.assessment or reject it on the basis of potential serious risk to public health. If a member state does not agree with the assessment, and the disputed points cannot be resolved, the matter is eventually referred to the Coordination Group on Mutual Recognition and Decentralised proceduresProcedures in the first instance to reach an agreement and failing to reach such an agreement, a referral to the EMA and the CHMP for arbitration that will result in an opinion to form the basis of a decision to be issued by the EC binding on all member states.Member States. If the application is successful during the decentralized or mutual recognition procedure, national marketing authorizations will be granted by the competent authorities in each of the member statesMember States chosen by the applicant.
Conditional marketing authorizations may be granted in the centralized procedure for a limited number of medicinal products for human use referenced in EU law applicable to conditional marketing authorizations where the clinical dataset is not comprehensive, if (1) the risk-benefit balance of the product is positive, (2) it is likely that the applicant will be in a position to provide the required comprehensive clinical trial data, (3) unmet medical needs will be fulfilled and (4) the benefit to public health of the immediate availability on the market of the medicinal product outweighs the risk inherent in the fact that additional data are still required. Specific obligations, such as the completion of ongoing or new studies and obligations relating to the collection of pharmacovigilance data, may be amongst the conditions stipulated in the marketing authorization.
As in the U.S., we may apply for designation of a product as an Orphanorphan drug for the treatment of a specific indication in the EU before the application for marketing authorization is made. In the EU, orphan designation is available for products in development which are either: (a) intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons in the EU,EU; or (b) intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community andaffecting a larger number of persons but when, without incentives, it is unlikely that sales of the drug in the EU would be sufficient to justify the necessary investment in developing the medicinal product. Additionally, the sponsor of an application for designation of a product as an orphan drug designationin the EU must establish that there exists no satisfactory authorized method of diagnosis, prevention, or treatment of the condition or even if such treatment exists, the product will be of significant benefit to those affected by that condition.
Orphan drugs in the EU enjoy economic and marketing benefits, including up to ten years of market exclusivity for the approved indication unless another applicant for a similar medicinal product can show that its product is safer, more effective or otherwise clinically superior to the orphan-designated product. The period of market exclusivity may be reduced to six years if at the end of the fifth year it is established that the criteria for orphan designation are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.
Healthcare and Privacy Regulation
Federal and state healthcare laws, including fraud and abuse and health information privacy and security laws, also apply togovern our business. If we fail to comply with those laws, we could face substantial penalties and our business, results of operations, financial condition and prospects could be adversely affected. The laws that may affect our ability to operate
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include, but are not limited to: the federal Anti-Kickback Statute (AKS), which prohibits.prohibits, among other things, soliciting, receiving, offering or paying remuneration, directly or indirectly, to induce or in returnreward for, the purchase or recommendation of an item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs;Medicaid; the FDCA and its implementing regulations, which prohibit, among other things, the introduction or delivery for introduction into interstate commerce of any drug that is adulterated or misbranded; and federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalty laws, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payers that are false or fraudulent. Additionally, we are subject to state law equivalents of each of the above federal laws, which may be broader in scope and apply regardless of whether the payer is a federalgovernmental healthcare program, and many of which differ from each other in significant ways and may not have the same effect, further complicate compliance efforts.
Numerous federal and state laws, including state security breach notification laws, state health information privacy laws and federal and state consumer protection laws, govern the collection, use and disclosure of personal information. For example, in June 2018, California Governor Jerry Brown signed the California Consumer Privacy Act of 2018, as amended (CCPA), which takes effectwent into operation on January 1, 2020 and will broadly definedefines personal information, giveaffords California residents expanded privacy rights and protections and provideprovides for civil penalties for violations and a private right of action forrelated to certain data security breaches. There are similarThese protections will be expanded by the California Privacy Rights Act (CPRA), which was approved by California voters in November 2020 and will be operational in most key respects on January 1, 2023. Similar legislative proposals have passed or are being advanced in other states, as well as in Congress.and Congress is considering additional federal privacy legislation. In addition, most healthcare providersprofessionals and facilities who are expected tomay prescribe our products and from whom we may obtain patient health information, are subject to privacy and security requirements under the Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology and Clinical Health Act (HIPAA). Although we are not directly subjectconsidered to be a covered entity or business associate under HIPAA with respect to our clinical and commercial activities, we could be subject to criminal penalties if we obtain and/use or disclose individually identifiable health information from a HIPAA-covered entity, including healthcare providers, in a manner that is not authorized or permitted by HIPAA. The legislative and regulatory landscape for privacy and data protection continues to evolve, and there has been an increasing amount of focus on privacy and data protection issues with the potential to affect our business, including recently enacted laws in a majority ofall 50 states requiring security breach notification. Thesenotification in some circumstances. The CCPA, CPRA, HIPAA and these other laws could create liability for us or increase our cost of doing business. Other countries also have, or are developing, laws governing the collection, use and transmission of personal information. International laws, such as the EU General Data Protection Regulation 2016/679 (GDPR), could also apply to our operations. Failure to provide adequate privacy protections and Swiss Federal Act on Data Protection, regulate the processing of personal data within the EUmaintain compliance with applicable privacy laws could jeopardize business transactions across borders and between countriesresult in the EU and countries outside of the EU, including the U.S. On April 27, 2016, the EU legislature adopted the GDPR, which replaced the prior Directive 95/46/EC when it took effect on May 25, 2018, and it is directly applicable in all Member States. The GDPR applies to EU-based organizations engaged in the processing of personal data belonging to EU data subjects. The GDPR has an extra-territorial effect in the sense that it applies to a “controller” or “processor” who is not established in the EU and is engaged in processing of personal data of EU subjects. Furthermore, in October 2015, the Court of Justice of the EU declared the previous framework, the International Safe Harbor Privacy Principles (the Safe Harbor) invalid for data transfer between the U.S. and the EU. The Safe Harbor has now been replaced by the EU-U.S. Privacy Shield, a framework for transatlantic exchanges of personal data for commercial purposes between the EU and the U.S. in accordance with the principles of the GDPR. Accordingly, there may be an immediate impact on companies located in the U.S. as they devote resources to comply with these new obligations. The GDPR establishes a tiered approach to penalties for breach which enables the data protection authorities of the various Member States to impose fines for certain infringements, including the breach of requirements relating to international transfers or the basic principles for processing of personal data (such as conditions for obtaining consent from that individual whose data is being transferred). The severity of these fines may be up to the higher of 4% of annual worldwide revenue or €20 million.significant penalties.
In addition, the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act (the PPACA)(PPACA) created a federal requirement under the federal Open Payments program, that requires certain manufacturers to track and report to the Centers for Medicare and& Medicaid Services annually certain payments and other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistance and nurse practitioners) and teaching hospitals, made inas well as ownership interests held by such physicians and their immediate family during the previous calendar year. In addition, there are also an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. These laws may affect our sales, marketing, and other promotional activities by imposing administrative and compliance burdens on us. In addition, given the lack of clarity with respect to these laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state and federal authorities.
Because our products are covered in the U.S. by the Medicaid programs, we have various obligations, including government price reporting and rebate requirements, which generally require us to pay substantial rebates or offer our products be offereddrugs at substantial rebates/discounts to Medicaid and certain purchasers (including “covered entities” purchasing under the 340B Drug Discount Program (the 340B Program)). We are also required to discount suchour products to authorized users of the Federal Supply Schedule of the General Services Administration, under which additional laws and requirements apply. These programs require submission of pricing data and calculation of discounts and rebates pursuant to complex statutory formulas and regulatory guidance, as well as the entry into government procurement contracts governed by the Federal Acquisition Regulations, and the guidance governing such calculations is not always clear. Compliance with such requirements can require significant investment in personnel, systems and resources, but failureresources. Failure to properly calculate prices, or to offer required discounts or rebates could subject us to substantial penalties.Subject to the application in the EU of the Transparency Directive 89/105/EEC, which aims to ensure the transparency of measures adopted to control pricing
Coverage and reimbursement, pricing and reimbursement in the EU/EEA is governed by national rules and policy and may vary from Member State to Member State.
Reimbursement
Sales of our approved products and any future products of ours will depend, in part, on the extent to which their costs will be covered by third-party payers, such as government health programs, commercial insurance and managed healthcare organizations. PatientsEach third-party payer may be less likely to use ourhave its own policy regarding what products if coverage is not providedit will cover, the conditions under which it will cover such products, and reimbursement is inadequate to cover a significant portion of the cost of our products. In addition, although to date qualified patients who
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does not imply that an adequateguarantee what reimbursement rate, if any, will be approved. Additionally, a third-party payer’s decisionPatients may be less likely to use our products if coverage is not provided and reimbursement may not cover a particular drug product does not ensure that other payers will also provide coverage forsignificant portion of the drug product, or will provide coverage at an adequate reimbursement rate.cost of our products.
In the U.S. and other potentially significant markets for our products, government authorities and third-party payers are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovativeproducts and therapies, which may result in lower average selling prices. In some cases, for example, third-party payers try to encourage the use of less expensive generic products through their prescription benefits coverage and reimbursement and co-pay policies. Further, the increased emphasis on managed healthcare in the U.S. and on country-specific and national pricing and reimbursement controls in the EU will put additional pressure on product pricing, reimbursement and usage, which may adversely affect our future product 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. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing coverage and/or reimbursement controls and measures, could have a material adverse impact on our net product revenues and results of operations.
Healthcare Reform
The U.S. and some foreign jurisdictionscountries are considering proposals or have enacted legislative and regulatory changes to the healthcare system that could affect our ability to sell our products profitably. Among policy makers and payers in the U.S. and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.
There has been particular and increasing legislative and enforcement interest in the U.S. with respect to drug pricing practices, particularly with respect to drugs that have been subject to relatively large price increases over relatively short time periods. At the federal level,practices. In particular, there have been several recent U.S. Congressional inquiries, hearings and proposed billsand enacted federal legislation and rules, as well as executive orders, designed to, among other things, bringthings: reduce or limit the prices of drugs and make them more transparencyaffordable for patients (including, for example, by tying the prices that Medicare reimburses for physician-administered drugs to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs. Also, the Trump administration’s budget proposal for fiscal year 2019 contains drug price control measures that could be enacted during the 2019 budget process orprices of drugs in other future legislation, including measures to permitcountries); reform the structure and financing of Medicare Part D planspharmaceutical benefits; implement additional data collection and transparency reporting regarding drug pricing, rebates, fees and other remuneration provided by drug manufacturers; enable the government to negotiate prices under Medicare; revise rules associated with the calculation of average manufacturer price of certain drugsand best price under Medicaid; eliminate the AKS discount safe harbor protection for manufacturer rebate arrangements with Medicare Part B,D plan sponsors; create new AKS safe harbors applicable to allow some statescertain point-of-sale discounts to negotiate drug pricespatients and fixed fee administrative fee payment arrangements with pharmacy benefit managers; and revise the rebate methodology under the Medicaid and to eliminate cost sharing for generic drugs for low-income patients. Further,Drug Rebate Program. For instance, President Biden issued an executive order in October 2018, the Centers for Medicare & Medicaid Services (CMS) proposed a rule that would require drug manufacturers to disclose drug prices in television advertisements. While any proposed measure will require authorization through additionalJuly 2021 supporting legislation to become effective,enact some of these drug pricing reforms, and in response, the U.S. Department of Health and Human Services (HHS) released a Comprehensive Plan for Addressing High Drug Prices in September 2021 with specific legislative and administrative policies that Congress could enact to help improve affordability of and the Trump administration have each indicated that they will continueaccess to seek new legislative and/or administrative measures to control drug costs.prescription drugs. At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biologicalbiotherapeutic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access andpricing or reimbursement at the state government level, limitations on discounts to patients, marketing cost disclosure and transparency measures, and, in some cases, policies to encourage importation from other countries (subject to federal approval) and bulk purchasing. Withpurchasing, including the National Medicaid Pooling Initiative. These laws may affect our sales, marketing, and other promotional activities by imposing administrative and compliance burdens on us. In addition, given the lack of clarity with respect to drug pricing transparency, for example, in October 2017, California Governor Jerry Brown signed legislation known as SB-17, which requires, among other provisions, pharmaceutical manufacturers to provide notice of price increases above a defined threshold to certain purchasersthese laws and related reportstheir implementation, our reporting actions could be subject to the government. SB-17 is currently subject to challenge, but inpenalty provisions of the meantime, manufacturers must comply with its requirements.pertinent state and federal authorities.
As a result of these developments and trends, third-party payers are increasingly attempting to contain healthcare costs by limiting coverage and the level of reimbursement of new drugs. These entities could refuse, limit or condition
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coverage for our products, such as by using tiered reimbursement or pressing for new forms of contracting, including, for example, the PPACA. Since January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the PPACA or otherwise circumvent some of the requirements for health insurance mandatedmovement by the PPACA. Concurrently, Congress has considered legislation that would repeal or repeal and replace all or part of the PPACA. While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain taxes under the PPACA recently have been enacted. The Tax Cuts and Jobs Act of 2017 includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the PPACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” Additionally, on January 23, 2018, President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain PPACA-mandated fees, including the so-called “Cadillac” tax on certain high cost employer-sponsored insurance plans, the annual fee imposed on certain health insurance providers based on market share, and the medical device excise tax on non-exempt medical devices. Congress may continue to consider legislation to repeal and replace some or all elements of the PPACA, and in December 2018, a Texas U.S. District
In addition, in some non-U.S. jurisdictions,foreign countries, the proposed pricing for a drug must be approved before its cost may be funded within the respective national healthcare system. The requirements governing drug pricing vary widely from country to country. For example, EU member statesMember States may restrict the range of medicinal products for which their national healthcare systems provide reimbursement and may control the prices of medicinal products for human use. A member stateMember State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profits the medicinal product generates for the company placing it on the market. Pricing and reimbursement negotiations with governmental authorities or payers in EU Member States can take six to 12 months or longer after the initial marketing authorization is granted for a product, or after the marketing authorization for a new indication is granted. To obtain reimbursement and/or pricing approval in some countries, drug manufacturers and collaboration partners may also be required to conduct a study or otherwise provide data that seeks to establish the cost effectiveness of a new drug compared with other available established therapies. Other cost-control initiatives are similarly focused on affordability and accessibility, such as the Regulation on Health Technology Assessment (HTA) adopted in December 2021 and other upcoming legislative and policy changes aimed at increasing cooperation between EU Member States, and once enacted may further impact the price and reimbursement status of many medicinal products. There can be no assurance that any country that has price controls, or reimbursement limitations or other requirements for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products on cost-effectiveness grounds. Historically, products launched in countries in the EU Member States and other non-U.S. jurisdictions do not follow the price structures of the U.S., and they generally tend to be priced significantly lower.
Competition
There are many companies focused on the development of small molecules, antibodies and antibodiesother treatments for cancer. Our competitors and potential competitors include major pharmaceutical and biotechnology companies, as well as academic research institutions, clinical reference laboratories and government agencies that are pursuing research activities similar to ours. Many of the organizations competing with us have greater capital resources, larger research and development staff and facilities, more experience in obtainingdeeper regulatory approvalsexpertise and more extensive product manufacturing and commercial capabilities than we do, which may allowafford them to have a competitive advantage.
Competition for Cabozantinib
We believe that our ability to successfully compete will depend on, among other things:
•efficacy, safety and reliability of cabozantinib;cabozantinib, both alone and in combination with other therapies;
•timing and scope of regulatory approval;
•the speed at which we develop cabozantinib for the treatment of additional tumor types beyond its approved indications;
•our ability to complete clinical development and obtain regulatory approvals for cabozantinib;cabozantinib, both alone and in combination with other therapies;
•our ability to manufacture and sell commercial quantities of cabozantinib product to the market;
•our ability to successfully commercialize cabozantinib, both as a single agent and as part of any combination therapy regimen, and secure coverage and adequate reimbursement in approved indications;
•product acceptance by physicians and other health care providers;
•the level of our collaboration partners’ investments in the resources necessary to successfully commercialize cabozantinib, or any combination therapy regimen that includes cabozantinib, in territories where it is approved outside of the U.S.; they are approved;
•skills of our employees and our ability to recruit and retain skilled employees;
•protection of our intellectual property;property, including our ability to enforce our intellectual property rights against potential generic competition; and
•the availability of substantial capital resources to fund development and commercialization activities.
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We believe that the quality and breadth of activity observed with cabozantinib, the skill of our employees and our ability to recruit and retain skilled employees, our patent portfolio and our capabilities for research and drug development are competitive strengths. However, many large pharmaceutical and biotechnology companies have significantly larger intellectual property estates than we do, more substantial capital resources than we have, and greater capabilities and experience than we do in preclinical and clinical development, sales, marketing, manufacturing and regulatory affairs.
Below is a summary of the principal competition for cabozantinib in the indications for which it is approved or for which it has been or is currently being evaluated in potentially label-enabling trials, both as a single agent and in combination with other therapeutic agents, has become highly prevalenttherapies. The information below does not include all competitor products, but rather those approved products that have or we believe may capture significant market share within their respective indications, or with respect to therapies still in indications for which our productsdevelopment, those that are approved, CABOMETYXlikely to overlap with patient populations that are or may become less marketable if our clinical trials fail to show efficacybe treated with cabozantinib or a combination therapy regimen that includes cabozantinib.
Competition in comparison to competing ICI products or ICI product combinations. Furthermore, the complexities of such a strategy has and may continue to require collaboration with some of our competitors.Approved Cabozantinib Indications
CABOMETYX - RCC: We believe the principal competition for CABOMETYX in advanced RCC includes: BMS’ nivolumab;the combination of Merck & Co.’s pembrolizumab and Pfizer’s axitinib; the combination of BMS’s ipilimumab and nivolumab; Pfizer’s axitinib, sunitinib and temsirolimus, each as single-agent therapies; Novartis’ everolimus and pazopanib, each as single-agent therapies; Bayer’s and Onyx Pharmaceuticals’ (a wholly-owned subsidiary of Amgen) (Onyx’s) sorafenib; Roche’s bevacizumab; the combination of Merck & Co.’s pembrolizumab and Eisai’s lenvatinib and Novartis’ everolimus; and Prometheus’ aldesleukin.lenvatinib. Additionally, there are a variety of therapies being developed for advanced RCC, including: the combination of Roche’s bevacizumab and atezolizumab; the combinationPeloton Therapeutics’ (a wholly owned subsidiary of Merck’s pembrolizumabMerck & Co.) belzutifan (also known as MK-6482) and Eisai’s lenvatinib; the combination of Merck’sMerck & Co.’s pembrolizumab, Eisai’s lenvatinib and Pfizer’s axitinib;Peloton Therapeutics’ belzutifan; the combination of Pfizer’s avelumabMerck & Co.’s pembrolizumab and axitinib;quavonlimab and Eisai’s lenvatinib; and the combination of Calithera’s CB-938BMS’ nivolumab and Novartis’ everolimus; AVEO Pharmaceutical’s tivozanib; and generic versions of sorafenib, everolimus and sunitinib.Nektar’s bempegaldesleukin.
The competitive landscape for RCC is evolving rapidly, especially given the entrance and increased adoption of ICI combination therapies and potential entrance of ICI-TKI combination therapies into the RCC treatment landscape, particularly in the first-line setting. This will leadhas led to newchanging trends in prescribing and sequencing of certain drugs and combinations across different lines of therapy. It is therefore difficult to predict how these changes will affect sales of CABOMETYX during 20192022 and going forward.
CABOMETYX - HCC: We believe the principal competition for CABOMETYX in previously treated HCC includes: Bayer’s regorafenib; Bayer’s and Onyx’s sorafenib; BMS’ nivolumab; Eisai’s levantinib; and Merck’s pembrolizumab.lenvatinib. Additionally, there are a variety of therapies being developed for previously treated HCC, including the combination of Roche’s atezolizumab and either Eisai’s Lenvatinib or Bayer’s and Onyx’s sorafenib.
The competitive landscape for HCC has significantly changed with the increased adoption of ICI combination therapies in the first-line setting, which may lead to an increase in prescribing and sequencing of TKIs in subsequent lines of therapy. It is difficult to predict how these changes will affect sales of CABOMETYX during 2022 and going forward.
CABOMETYX - DTC: We believe the principal competition for CABOMETYX in its previously treated DTC indication includes two treatments that are also approved for previously untreated DTC: Bayer’s and Onyx’s sorafenib; and Eisai’s lenvatinib. In addition, we believe there is also competition for CABOMETYX from therapies approved to treat patients with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are RAI-refractory (if RAI is appropriate), including: Blueprint Medicine’s and Roche’s pralsetinib; and Loxo Oncology’s (a wholly owned subsidiary of Eli Lilly’s ramucirumab; and generic versionsLilly) selpercatinib.
Other than the approvals of sorafenib.RET inhibitors to treat certain DTC patients, there has been little change in the competitive landscape for RAI-refractory DTC treatments during recent years. Due the limited number of ongoing late-stage clinical trials in this DTC indication, we do not except additional competitors to emerge during 2022.
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COMETRIQ - MTC: We believe that the principal competing anti-cancer therapy to COMETRIQ in progressive, metastatic MTC is Genzyme’s vandetanib, which has been approved by the FDA and the EC for the treatment of symptomatic or progressive MTC in patients with unresectable, locally advanced, or metastatic disease. We believedisease, as well as other therapies that COMETRIQ also faces competition as a treatment for progressive, metastatic MTC from off-label use of certain treatments, including: Bayer’s and Onyx’s sorafenib; Pfizer’s sunitinib; Takeda’s ponatinib; Novartis’ pazopanib; and Eisai’s lenvatinib. Additionally, there are a variety of compounds being developed for MTC with early-stage clinical trials in progress, including: Blueprint Medicine Corporation’s BLU-667 (for certain subsets of MTC patients); and Loxo Oncology, Inc.’s LOXO-292 (which washave been recently granted Breakthrough Therapy Designation by the FDA for the treatment ofapproved to treat patients with advanced or metastatic RET-mutant MTC who require systemic therapy, have progressed following priorincluding: Blueprint Medicine’s and Roche’s pralsetinib; and Loxo Oncology’s selpercatinib.
Other than the recent approvals of RET inhibitors to treat certain MTC patients, there has been little change in the treatment landscape for progressive, metastatic MTC during recent years, and have no acceptable alternative treatment options).due to the limited number of ongoing late-stage clinical trials in this indication, we do not expect many additional competitors to emerge in 2022.
Competition in Potential Cabozantinib Indications Beyond RCC, MTC and previously treated
Cabozantinib in combination with ICI - HCC: We have initiated COSMIC-311, a phase 3 pivotal trial evaluating cabozantinib in patients with DTC who have progressed after up to two prior VEGFR-targeted therapies, and COSMIC-312, athe phase 3 pivotal trial evaluating the combination of cabozantinib and atezolizumab in patients with previously untreated HCC. However, HCC, is continuing as planned to final analysis of OS, and we face a rapidly evolving treatment landscapeintend to submit an sNDA to the FDA for the treatment of both of these indications, as other therapies have recently received regulatory approval or are in advanced stages of clinical development, which may impaircombination regimen if supported by the relative value of CABOMETYX or a combination of CABOMETYX with an ICI in DTC and previously untreated HCC, respectively. Should cabozantinib be approved for this indication of DTC, we believe its principal competition may include: Bayer’s and Onyx’s sorafenib; and Eisai’s lenvatinib.final OS analysis. Should the combination of cabozantinib and atezolizumab be approved for the treatment of patients with previously untreated advanced HCC, we believe its principal competition may include: Eisai’s levantinib; Bayer’s and Onyx’s sorafenib; BMS’s nivolumab; the combination of Merck’sMerck & Co.’s pembrolizumab and Eisai’s lenvatinib; BeiGen and Celgene’s tislelizumab; the combination of Roche’s bevacizumab and atezolizumab;
Cabozantinib in combination with ICI – NSCLC: We are evaluating the combination of cabozantinib and atezolizumab in CONTACT-01, a phase 3 pivotal trial evaluating the combination of cabozantinib and atezolizumab in patients with metastatic NSCLC who have been previously treated with an ICI and platinum-containing chemotherapy. Should the combination of cabozantinib and atezolizumab be approved for the treatment of patients with NSCLC, we believe its principal competition may include: Sanofi’s docetaxel; the combination of Sanofi’s docetaxel and Eli Lilly’s ramucirumab; the combination of BMS’ nivolumab and Mirati’s sitravatinib; the combination of Merck & Co.’s pembrolizumab and Eisai’s lenvatinib; Daiichi Sankyo’s DS-1062; and generic versions of sorafenib. Examples of potential competition for cabozantinibdocetaxel.
Cabozantinib in other cancer indications include: other VEGF pathway inhibitors, including Genentech’s bevacizumab and Pfizer’s axitinib; other RET inhibitors including Eisai’s lenvatinib and Takeda’s ponatinib; other MET inhibitors, including Astra Zeneca’s savolitinib, Pfizer’s crizotinib and Mirati’s glesatinib; and ICIs such as BMS’s ipilimumab and nivolumab, Merck’s pembrolizumab and Roche’s atezolizumab.
combination with ICI – mCRPC:We believe that cobimetinib’s principal competition amongst targeted agents includes:are evaluating the combination of Novartis’ trametinibcabozantinib and dabrafenib; andatezolizumab in CONTACT-02, a phase 3 pivotal trial evaluating the combination of Array’s encorafenibcabozantinib and binimetinib. Within the class of ICIs, we believe that cobimetinib’s principal competition includes:atezolizumab in patients with mCRPC who have been previously treated with one NHT. Should the combination of BMS’s ipilimumabcabozantinib and nivolumab; and Merck’s pembrolizumab. The second category, ICIs, are of particular competitive importance vis-a-vis cobimetinib in advanced melanoma as they are already FDAatezolizumab be approved in melanoma patient populations that overlap with those that may be eligible for cobimetinib, they have been rapidly incorporated into the NCCN treatment guidelines, and they are viewed with a high degree of enthusiasm by physicians and key opinion leaders. Ongoing and future trials incorporating ICIs, including combination trials, may further impact usage of cobimetinib in melanoma and potentially in additional tumor types in which cobimetinib may ultimately gain approval.
Competition for Cobimetinib and Esaxerenone
There is approved by the MHLW. Finerenone is still in developmentcompetition for this indication,both cobimetinib and results from ongoing clinical studies are not expected during 2019.
Patents and Proprietary Rights
We actively seek patent protection in the U.S., EuropeEU and selected other foreign countriesjurisdictions to cover our drug candidates and related technologies. Patents extend for varying periods according to the date of patent filing or grant and the legal term of patents in the various countries where patent protection is obtained. The actual protection afforded by a patent, which can vary from country to country, depends on the type of patent, the scope of its coverage and the availability of legal remedies in the country. We have numerous patents and pending patent applications that relate to methods of screening drug targets, compounds that modulate drug targets, as well as methods of making and using such compounds.
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While many patent applications have been filed relating to the drug candidates that we have developed, the majority of these are not yet issued or allowed. WeTo our knowledge, we own all global patents associated with cabozantinib and cobimetinib, and we either own or have in-licensed all global patents for our other drug candidates, referencedas further described below.
Cabozantinib
Cabozantinib is covered by 10more than 15 issued patents in the U.S., building from U.S. Pat. No. 7,579,473, for the composition-of-mattercomposition of matter of cabozantinib (the ‘473 Patent) and pharmaceutical compositions thereof. This composition of matter patent would expire in September 2024, but we have been granted a patent term extension to extend the term to August 2026. The following table describes the US patents that cover our marketed cabozantinib products, and which are listed in the Orange Book. Except as otherwise noted, the stated expiration dates include any patent term extensions already granted. In addition to the composition of matter patent referenced above, the table includes patents directed to, among other things, particular salts, polymorphs, formulations, or use of the compound in the treatment of specified diseases or conditions. We continue to pursue additional patents and patent term extensions in the U.S. and other territories covering various aspects of our cabozantinib products that may, if issued, extend exclusivity beyond the expiration of the patents listed in the table.
| Product | Patent No. | General Subject Matter | Patent Expiration | ||||||||
| CABOMETYX | 7,579,473 | Composition of matter | 2026 | ||||||||
| 8,497,284 | Methods of treatment | 2024 | |||||||||
| 8,877,776 | Salt and polymorphic forms of cabozantinib | 2030 | |||||||||
| 9,724,342 | Formulations of cabozantinib | 2033 | |||||||||
| 10,034,873 | Methods of treatment | 2031 | |||||||||
| 10,039,757 | Methods of treatment | 2031 | |||||||||
| 11,091,439 | Salt and polymorphic forms of cabozantinib | 2030 | |||||||||
| 11,091,440 | Formulations of cabozantinib | 2030 | |||||||||
| 11,098,015 | Methods of treatment | 2030 | |||||||||
| 11,141,413 | Methods of treatment | 2037 | |||||||||
| COMETRIQ | 7,579,473 | Composition of matter | 2026 | ||||||||
| 8,877,776 | Salt and polymorphic forms of cabozantinib | 2030 | |||||||||
| 9,717,720 | Formulations of cabozantinib | 2032 | |||||||||
| 11,091,439 | Salt and polymorphic forms of cabozantinib | 2030 | |||||||||
| 11,091,440 | Formulations of cabozantinib | 2030 | |||||||||
| 11,098,015 | Methods of treatment | 2030 | |||||||||
Given the importance of our intellectual property portfolio to our business operations, we intend to vigorously enforce our rights and defend against challenges that have arisen or may arise with respect to patents and patent applications required for the commercialization of medicines containing cabozantinib. For example, in September 2019, we received a Paragraph IV notice letter regarding an ANDA submitted to the FDA by MSN Pharmaceuticals, Inc. (MSN), requesting approval to market a generic version of CABOMETYX tablets, which MSN then amended with additional Paragraph IV certifications in May 2020 to include the ‘473 Patent and U.S. Patent No. 8,497,284. In response, we filed patent infringement lawsuits against MSN in the United States District Court for the District of Delaware (the Delaware District Court) in October 2019 and May 2020, which were later consolidated and include infringement claims related to the ‘473 Patent and U.S. Patent No. 8,497,284. In addition, in May 2021, we received Paragraph IV certification notice letters regarding an ANDA submitted to the FDA by Teva Pharmaceuticals Development, Inc. and Teva Pharmaceuticals USA, Inc. (individually and collectively referred to as Teva), requesting approval to market a generic version of CABOMETYX tablets. In response, we filed a patent infringement lawsuit against Teva, along with Teva Pharmaceutical Industries Limited (Teva Parent), in the Delaware District Court in June 2021. We cannot predict the outcome of these lawsuits or provide assurance that these lawsuits will prevent the introduction of a generic version of CABOMETYX for any particular length of time, or at all. For a more detailed discussion of these litigation matters, see “Legal Proceedings” in Part I, Item 3 of this Annual Report on Form 10-K.
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| Product | Patent No. | General Subject Matter | Patent Expiration |
| CABOMETYX | 7,579,473 | Composition of matter | 2026 |
| 8,497,284 | Methods of treatment | 2024 | |
| 8,877,776 | Salt and polymorphic forms of cabozantinib | 2030 | |
| 9,724,342 | Formulations of cabozantinib | 2033 | |
| 10,039,757 | Methods of treatment | 2031 | |
| 10,034,873 | Methods of treatment | 2031(1) | |
| COMETRIQ | 7,579,473 | Composition of matter | 2026 |
| 8,877,776 | Salt and polymorphic forms of cabozantinib | 2030 | |
| 9,717,720 | Formulations of cabozantinib | 2032 | |
In Europe,the EU, cabozantinib is protected by issued patents covering the composition-of-mattercomposition of matter and methods of use. The issued patent would expire in September 2024, but we have applied for and either have obtained, or expect to obtain Supplementary Protection Certificates in Europethe EU to extend the term to 2029. In addition to the composition of matter patent, the table below includes certain later-expiring patents directed to the commercial product, including, particular salts, polymorphs, formulations, or use of the compound in the treatment of specified diseases or conditions.
| Product | Patent No. | General Subject Matter | Patent Expiration | ||||||||
| CABOMETYX | 2213661 | Composition of matter and methods of treatment | 2029 | ||||||||
| 2387563 | Salt and polymorphic forms of cabozantinib and methods of treatment | 2030 | |||||||||
| COMETRIQ | 2213661 | Composition of matter and methods of treatment | 2029 | ||||||||
| 2387563 | Salt and polymorphic forms of cabozantinib and methods of treatment | 2030 | |||||||||
| Product | Patent No. | General Subject Matter | Patent Expiration |
| CABOMETYX | 2213661 | Composition of matter and methods of treatment | 2029 |
| 2387563 | Salt and polymorphic forms of cabozantinib and methods of treatment | 2030 | |
| COMETRIQ | 2213661 | Composition of matter and methods of treatment | 2029 |
| 2387563 | Salt and polymorphic forms of cabozantinib and methods of treatment | 2030 | |
In September 2021, in a final decision before the Technical Board of Appeal, the Opposition Division of the European Patent Office upheld the validity of EP patent 2387563, directed to crystalline forms of cabozantinib malate, pharmaceutical compositions and certain uses thereof. This ruling favors continuing exclusivity of our cabozantinib patent portfolio in the EU through the expiration date of EP patent 2387563 in 2030.
Similarly, in Japan, cabozantinib is protected by an issued patentpatents covering the composition-of-matter,composition of matter, and salts thereof, as well as pharmaceutical compositions and related methods of use. We intend to applyuse, and Takeda has applied for patent term extension in Japan to extend the term to 2029. Foreign counterparts of the issued U.S. and European composition of matter patents have been issued in Australia and Canada and are anticipated to expire in 2024. We have other filed patent applications and issued patents in the U.S. and other selected countries covering certain synthetic methods, salts, polymorphs, formulations, prodrugs, metabolites and combinations of cabozantinib that, if issued, are anticipated to expire as late as 2035.2037. Outside the U.S. and Japan, cabozantinib is licensed to Ipsen;Ipsen, and in Japan, cabozantinib is licensed to Takeda, each in accordance with the respective collaboration agreements. A discussion of risks and uncertainties that may affect our patent position and other proprietary rights is set forth in “Risk Factors,” contained in Part I, Item 1A of this Annual Report on Form 10-K.
Other Drug Candidates
We also have issued patents and pending patent applications, and will continue to file new patent applications, in the U.S., Europethe EU and other selected countries covering the composition-of-matter of our other drug candidates in clinical and/or preclinical
We have obtained licenses from various parties that give us rights to technologies that we deem to be necessary or desirable for our research and development. These licenses (both exclusive and non-exclusive) may require us to pay royalties as well as upfront and milestone payments.
We require our scientific personnel to maintain laboratory notebooks and other research records in accordance with our policies, which are designed to strengthen and support our intellectual property protection. In addition to our patented intellectual property, we also rely on trade secrets and other proprietary information, especially when we do not believe that patentprotection is appropriate or can be obtained. We also require all of our employees and consultants, outside scientific collaborators, sponsored researchers and other advisors who receive proprietary information from us to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all proprietary information developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. Furthermore, our agreements with employees and, in most circumstances, our agreements with consultants, outside scientific collaborators, sponsored researchers and other advisors expressly provide that all inventions, concepts, developments, copyrights, trademarks or other intellectual property developed by an employee during the employment period, or developed by a service provider during the service period or utilizing our proprietary drugs or information, shall be our exclusive property. There can be no assurance, however, that these agreements will provide meaningful protection or adequate remedies for our trade secrets in the event of unauthorized use or disclosure of such information.
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Human Capital Management
Our Employees and Commitment to Diversity, Equity and Inclusion
As of December 31, 2018,2021, we had 484954 full-time equivalent employees, allrepresenting a 23% increase in our employee workforce as compared to December 31, 2020. Of these employees, 509 are members of whichour various research and development teams and 445 are located in the U.S.members of our various commercial and general and administrative teams. Of these employees, 149 hold Ph.D. degrees, 19 hold M.D. (or foreign equivalent) degrees, 30 hold PharmD degrees and 88 hold other professional degrees such as a J.D. or M.B.A. None of our employees are represented by a labor union, and we consider our employee relations to be good.
During the past five years, our employee turnover has remained consistently below average for the U.S. life sciences industry generally. Given our expanding operations and need to further grow our headcount to support our business, we continually assess employee turnover, recruitment initiatives, compensation and benefits programs, safety in performing critical laboratory work, diversity and other matters relevant to human capital management, and we review results with our Board of Directors on a periodic basis.
We are an equal opportunity employer and maintain policies that prohibit unlawful discrimination based on race, color, religion, gender, sexual orientation, gender identity/expression, national origin/ancestry, age, disability, marital and veteran status. We are proud to employ a diverse workforce that, as of December 31, 2021, was 55% non-white and 53% women. In addition, as of December 31, 2021, 50% of our positions that manage other employees directly were held by non-whites and 47% were held by women, and after giving effect to the hiring of our new Chief Medical Officer in January 2022, women made up 33% of our senior leadership team. We strive to build and nurture a culture where all employees feel empowered to be their authentic selves. We respect and appreciate each employee’s unique perspective and experiences, and value their contributions to our mission. It is important that we celebrate, encourage and support similarities and differences to drive innovation for the benefit of our employees, patients and community.
Culture, Compensation and Benefits
At Exelixis, we value being exceptional in what we do and how we lead, excelling for patients by going the extra mile to care for them and exceeding together as a business and contributor to the scientific community. We strive to live these values every day across the company, integrating them into everything from our interview, hiring and onboarding processes, to our performance evaluation, rewards and promotion programs.
We provide generous compensation packages designed to attract and retain high-quality employees, and all of our employees are eligible for cash bonuses and grants of equity awards. We regularly evaluate our compensation programs with an independent compensation consultant and utilize industry benchmarking in an effort to ensure they are competitive compared to similar biotechnology and biopharmaceutical companies with which we compete for talent, as well as fair and equitable across our workforce with respect to gender, race and other personal characteristics. In addition, we are proud to provide a variety of programs and services to help employees meet and balance their needs at work, at home and in life, including an attractive mix of healthcare, insurance and other benefit plans. We deliver a benefits program that is designed to keep our employees and their families healthy, which includes not only medical, dental and vision benefits, but also dependent care, mental health and other wellness benefits. For a discussion of workplace safety measures we have taken, including as a result of the COVID-19 pandemic, see “—Environmental, Health and Safety.”
Beyond compensation and benefits, we also value career development for all employees, and we offer a tuition reimbursement program, as well as professional development courses ranging from technical training, competency-based workshops and leadership development programs facilitated by external partners who are experts in their respective fields. Direct managers also take an active role in identifying individualized development plans to assist their employees in realizing their full potential and creating opportunities for promotions and added responsibilities that enhance the engagement and retention of our workforce.
Corporate Information
We were incorporated in Delaware in November 1994 as Exelixis Pharmaceuticals, Inc. and changed our name to Exelixis, Inc. in February 2000. Our principal executive offices are located at 1851 Harbor Bay Parkway, Alameda, California 94502. Our telephone number is (650) 837-7000. We maintain a site on the worldwide web at www.exelixis.com; however, information found on our website is not incorporated by reference into this report.
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We make available free of charge on or through our website our Securities and Exchange Commission (SEC) filings, including our annual report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. The SEC maintains a site on the worldwide web that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov.
Item 1A. Risk Factors
In addition to the factorsrisks discussed elsewhere in this report, the following are important factors that make an investment in our securities speculative or risky, and that could cause actual results or events to differ materially from those contained in any forward-looking statements made by us or on our behalf. The risks and uncertainties described below are not the only ones we face. Additional risks and uncertainties not currently known to us or that we deem immaterial also may impair our business operations. If any of the following risks or such other risks actually occur, our business and the value of your investment in our company could be harmed.
Risks Related to the Commercialization of Our Business and IndustryProducts
Our ability to grow our company is critically dependent upon the commercial success of CABOMETYX in its approved indications and the furthercontinued clinical development, regulatory approval, clinical acceptance and commercial success of the cabozantinib franchise in additional indications.
Our ability to grow revenues from sales of CABOMETYX will dependdepends upon the degree of market acceptance among physicians, patients, health carehealthcare payers, and the medical community.
Our ability to increase or maintain revenues from sales of CABOMETYX for its approved indications is, and if approved for additional indications will be, highly dependent upon the extent of market acceptance of CABOMETYX among physicians, patients, foreign and U.S. government health carehealthcare payers such as Medicare and Medicaid, commercial health carehealthcare plans and the medical community. Market acceptance for CABOMETYX could be impacted by numerous factors, including the effectiveness and safety profile, or the perceived effectiveness and safety profile, of CABOMETYX compared to competing products, the strength of CABOMETYX sales and marketing efforts and changes in pricing and reimbursement for CABOMETYX. If CABOMETYX does not continue to be prescribed broadly for the treatment of advanced RCC and achieve market acceptance for the treatment of previously treated HCC, we may not be able to growpatients in its approved indications, our product revenues. The degree of market acceptance of CABOMETYX will depend upon a number of factors, including:
Our competitors may develop products and technologies that impair the relative value of our marketed products and any future product candidates.
The pharmaceutical, biopharmaceutical and biotechnology industries areindustry is competitive highly diversified and are characterized by rapidconstant technological change and diverse offerings of products, particularly in the area of novel oncology therapies. Many of the organizations competing with usour competitors have greater capital resources, larger research and development staff and facilities, more experience in obtainingdeeper regulatory approvalsexpertise and more extensive product manufacturing and commercial capabilities than we do, which may allowafford them to have a competitive advantage. Further, our
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competitors may be more effective at using their technologies to developin-licensing and developing new commercial products. As a result, our competitors may be able to more easily develop products that wouldcould render our products, and those of our collaborators,collaboration partners, obsolete and noncompetitive. There may also be drug candidates that we are not aware of at an earlier stage of development that may compete with our marketed products and product candidates. We face, and will continue to face, intense competition from biotechnology, biopharmaceutical and pharmaceutical companies, as well as academic research institutions, clinical reference laboratories and government agencies that are pursuing scientific and clinical research activities similar to ours. Delays in
Furthermore, the development of cabozantinib for the treatment of additional tumor types, for example, could allow our competitors to bring products to market before us.
If we are unable to maintain or scale adequateincrease our sales, marketing, market access and product distribution capabilities for our products, or enter into or maintain agreements with third parties to do so, we may be unable to maximize product revenues, which could have a material adverse impact on our business, financial condition and results of operations.
Maintaining our sales, marketing, market access and product distribution capabilities requires significant resources, and there are numerous risks involved with managing such amaintaining and continuously improving our commercial organization, including our potential inability to successfully recruit, train, retain and incentivize adequate numbers of qualified and effective sales and marketing personnel. We are competing for talent with numerous commercial-stagecommercial- and precommercial-stage, oncology-focused biotechbiopharmaceutical companies seeking to build out and maintain their commercial organizations, as well as other large pharmaceuticallarger biopharmaceutical organizations that have extensive, well-funded and more experienced sales and marketing operations, and we may be unable to maintain or adequately scale our commercial organization as a result of such competition. If we cannot maintain effective sales, marketing, market access and product distribution capabilities, we may be unable to maximize the commercial potential of CABOMETYX and COMETRIQ in their approved indications. Also, to the extent that the commercial opportunities for CABOMETYX grow over time, we may not properly judgescale the requisite size and experience of our current commercialization teams or the level of distribution necessary to market and sell CABOMETYX successfully in multiplean expanded number of indications. If we are unable to maintain or scale our organizationcommercial function appropriately, or should we have to revert back to primarily telephonic and virtual interactions in lieu of in-person meetings with healthcare professionals for an extended period of time as a result of the COVID-19 pandemic, we may not be able to maximize product revenues, which could have a material adverse impact on our business, financial condition and results of operations.
Our ability to commercialize our products successfully is highly dependent on the extent to which health insurance coverage and adequate reimbursement is, and will be, available from third-party payers, including foreign and U.S. governmental payers, such as Medicare and Medicaid, and private health insurers. Third-party payers continue to scrutinize and manage access to pharmaceutical products and services and may limit reimbursement for newly approved products and indications. Patients mayare generally not be capable of paying for CABOMETYX or COMETRIQ themselves and may rely on third-party payers to pay for, or subsidize, the costs of their medications, among other medical costs. Accordingly, market acceptance of CABOMETYX and COMETRIQ is dependent on the extent to which coverage and reimbursement is available from third-party payers. These entities could refuse, limit or condition coverage for our products, such as by using tiered reimbursement or pressing for new forms of contracting. If third-party payers do not provide coverage or adequate reimbursement for CABOMETYX or COMETRIQ, our revenues and results of operations will suffer. In addition, even if third-party payers provide some coverage or reimbursement for CABOMETYX or COMETRIQ, the availability of such coverage or reimbursement for prescription drugs under private health insurance and managed care plans, which often varies based on the type of contract or plan purchased, may not be sufficient for patients to afford CABOMETYX or COMETRIQ. Third-party payers continue to scrutinize and manage the prices charged for pharmaceutical products and services, and many also limit reimbursement for newly-approved products and indications.
Current healthcare laws and regulations in the U.S. and future legislative or regulatory reforms to the U.S. healthcare system may affect our ability to commercialize our marketed products profitably.
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market for the pharmaceutical industrysale, insurance coverage and distribution of pharmaceuticals has been a particular focus of these efforts and has beenwould likely be significantly affected by any major legislative or regulatory initiatives.
In addition, there are pending federal and recent Congressional hearings have brought increased public attention to the costs of prescription drugs. These actions and the uncertainty about the future of the PPACA and healthcare laws may put downward pressure on pharmaceutical pricing and increase our regulatory burdens and operating costs.
Pricing for pharmaceutical products in the U.S. has come under increasing attention and scrutiny by federal and state governments, legislative bodies and enforcement agencies. These activitiesThis may result in actions that have the effect of reducing our revenue or harming our business or reputation.
At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biologicalbiotherapeutic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access andpricing or reimbursement at the state government level, limitations on discounts to patients, marketing cost disclosure and transparency measures, and, in some cases, policies to encourage importation from other countries (subject to federal approval) and bulk purchasing, including
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the National Medicaid Pooling Initiative. With respectIn particular, the obligation to drug pricing transparency, for example, in October 2017, California Governor Jerry Brown signed SB-17, which requires, among other provisions, pharmaceutical manufacturers to provide notice of price increases above a defined threshold to certain purchasers and related reports to the government. SB-17 is currently subject to challenge, but in the meantime, manufacturers must comply with its requirements. We do not know what form legislative proposals concerning drug prices may take in other states or how they would affect us. It is possible that these laws would encourage federal and state healthcare programs to reduce the amount of reimbursements they provide for prescription drugs, and any reduction in reimbursement from these government healthcare programs may result in a similar reduction in payments from private payers. We also believe that pricing transparency requirements, such as the requirement for us, in certain circumstances, to provide lengthy notices of price increases to purchasers under laws such as California’s SB-17 may influence customer ordering patterns for CABOMETYX and COMETRIQ, and that this,which in turn may increase the volatility of our revenues as a reflection of changes in inventory volumes. Therefore, the implementationFurthermore, adoption of these costdrug pricing transparency regulations, and our associated compliance obligations, may increase our general and administrative costs and/or diminish our revenues. Implementation of these federal and/or state cost-containment measures or other healthcare reforms may result in fluctuations in our results of operations and limit our ability to generate product revenue or commercialize our current products, and in the case of drug pricing transparency regulations, may result in fluctuations in our results of operations.
Lengthy regulatory pricing and reimbursement procedures and cost control initiatives imposed by governments outside the U.S. could delay the marketing of and/or those for which we may receive regulatory approvalresult in downward pressure on the future.price of our approved products, resulting in a decrease in revenue.
Additionally, cost-control initiatives, increasingly based on affordability and accessibility, as well as post-marketing assessments of the added value of CABOMETYX and COMETRIQ as compared to existing treatments, could decreaseinfluence the priceprices paid for and net revenues we realize from CABOMETYX and our collaboration partner, Ipsen, might establishCOMETRIQ, or the indications for CABOMETYX,which we are able to obtain reimbursement, which would result in lower license revenues to us.
The entrance of generic competitors and legislative and regulatory landscape for privacyaction designed to reduce barriers to the development, approval and data protectionadoption of generic drugs in the U.S. continues to evolve, and there has been an increasing amount of focuscould limit the revenue we derive from our products, most notably CABOMETYX, which could have a material adverse impact on privacy and data protection issues with the potential to affect our business, including state security breach notification laws, state health information privacy lawsfinancial condition and federal and state consumer protection laws, that govern the collection, use and disclosureresults of personal information. For example, in June 2018, California Governor Jerry Brown signed the CCPA, which takes effect on January 1, 2020 and will broadly define personal information, give California residents expanded privacy rights and protections and provide for civil penalties for violations and a private right of action for data breaches. There are similar legislative proposals being advanced in other states, as well as in Congress. In addition, most healthcare providers who are expected to prescribe our products, and from whom we obtain patient health information, are subject to privacy and security requirements under HIPAA. Although we are not directly subject to HIPAA, we could be subject to criminal penalties if we knowingly obtain individually identifiable health information from a HIPAA-covered entity in a manner that is not authorized or permitted by HIPAA. Other countries also have, or are developing, laws governing the collection, use and transmission of personal information. For example, the EU Data Privacy Directive (95/46/EC) and implementing legislation in the various national Member States of the EU was replaced on May 25, 2018 by the more restrictive GDPR, which now regulates the processing of personal data within the EU and between countries in the EU and countries outside of the EU, including the U.S. Switzerland is updating the Swiss Data Protection Act, and updates to data protection laws in other countries may occur in due course. In connection with these new laws, in particular the CCPA and GDPR, we have modified certain of our policies and procedures with respect to the collection and processing of personal data to the extent necessary given our operations and commensurate with similar companies in our industry. We will continue to review all future privacy and other regulations implemented pursuant to the CCPA, GDPR and other applicable laws to assess whether additional procedural safeguards are warranted, which may cause us to incur additional expenses or otherwise limit our ability to collect and process personal data. Failure to provide adequate privacy protections and maintain compliance with these laws and regulations could jeopardize certain domestic and cross-border business transactions and create additional liabilities for us, including the imposition of sanctions or other penalties, as well as increase our cost of doing business.
Under the FDCA, the FDA can approve an ANDA for a generic version of a branded drug without the applicant undertaking the human clinical testing necessary to obtain approval to market a new drug. The FDA can also approve a
The U.S. federal government has also taken numerous legislative and regulatory actions to bringexpedite the development and approval of generic drugs and biosimilars. Both Congress and the FDA are considering, and have enacted,
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various legislative and regulatory proposals focused on drug competition, including legislation focused on drug patenting and provision of drug to market. Companiesgeneric applicants for testing. For example, the Ensuring Innovation Act, enacted in April 2021, amended the FDA’s statutory authority for granting NCE exclusivity to reflect the agency’s existing regulations and longstanding interpretation that produceaward NCE exclusivity based on a drug’s active moiety, as opposed to its active ingredient, which is intended to limit the applicability of NCE exclusivity, thereby potentially facilitating generic equivalents are generally ablecompetition. The FDA has also released a Drug Competition Action Plan, which proposes actions to offer their products atbroaden access to generic drugs and lower prices. Thus, regardlessconsumers’ healthcare costs by, among other things, improving the efficiency of the generic drug approval process and supporting the development of complex generic drugs. In addition, the Further Consolidated Appropriations Act, 2020, which incorporated the framework from the CREATES legislation, purports to promote competition in the market for drugs and biotherapeutic products by facilitating the timely entry of lower-cost generic and biosimilar versions of those drugs and biotherapeutic products, including by allowing ANDA, 505(b)(2) NDA or biosimilar developers to obtain access to branded drug and biotherapeutic product samples. While the full impact of these provisions is unclear at this time, its provisions do have the potential to facilitate the development and future approval of generic versions of our products, introducing generic competition that could have a material adverse impact on our business, financial condition and results of operations.
Risks Related to Healthcare Regulatory and Other Legal Compliance Matters
We are subject to healthcare laws, regulations and enforcement; our failure to comply with those laws could have a material adverse impact on our business, financial condition and results of operations.
We are subject to federal and state healthcare laws and regulations, which laws and regulations are enforced by the federal government and the states in which we conduct our business. Should our compliance controls prove ineffective at preventing or mitigating the risk and impact of improper business conduct or inaccurate reporting, we could be subject to enforcement of the following, including, without limitation:
•the federal AKS;
•the FDCA and its implementing regulations;
•federal civil and criminal false claims laws, including the civil False Claims Act, and the Civil Monetary Penalties Law;
•federal criminal laws that prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
•HIPAA and its implementing regulations, as amended;
•state law equivalents of each of the above federal laws;
•the Open Payments program of the PPACA;
•state and local laws and regulations that require drug manufacturers to file reports relating to marketing activities, payments and other remuneration and items of value provided to healthcare professionals and entities; and
•state and federal pharmaceutical price and price reporting laws and regulations.
In addition, we may be subject to the Foreign Corrupt Practices Act, a U.S. law which regulates certain financial relationships with foreign government officials (which could include, for example, medical professionals employed by national healthcare programs) and its foreign equivalents, as well as federal and state consumer protection and unfair competition laws.
These federal and state healthcare laws and regulations govern drug marketing practices, including off-label promotion. If our operations are found, or even alleged, to be in violation of the laws described above or other governmental regulations that apply to us, we, or our officers or employees, may be subject to significant penalties, including administrative civil and criminal penalties, damages, fines, regulatory approval pathway,penalties, the introductioncurtailment or restructuring of a generic version ofour operations, exclusion from participation in Medicare, Medicaid and other federal and state healthcare programs, imprisonment, reputational harm, additional reporting requirements and oversight, any of which would adversely affect our marketedability to sell our products and operate our business and also adversely affect our financial results. Furthermore, responding to any such allegation and/or defending against any such enforcement actions can be time-consuming and would require significant financial and personnel resources. Therefore, if any state or the federal government initiates an enforcement action against us, our business may be impaired, and even if we are ultimately successful in our defense, litigating these actions could result in verysubstantial costs and divert the attention of management.
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Enhanced governmental and private scrutiny over, or investigations or litigation involving, pharmaceutical manufacturer patient assistance programs and donations to patient assistance foundations created by charitable organizations could negatively impact our business practices, harm our reputation, divert the attention of management and increase our expenses.
To help patients afford our products, we have a patient assistance program and also occasionally make donations to independent charitable foundations that help financially needy patients. These types of programs designed to assist patients with affording pharmaceuticals have become the subject of Congressional interest and enhanced government scrutiny. The HHS Office of Inspector General established guidelines permitting pharmaceutical manufacturers to make donations to charitable organizations that provide co-pay assistance to Medicare patients, provided that manufacturers meet certain specified compliance requirements. In the event we make such donations but are found not to have complied with these guidelines and other laws or regulations respecting the operation of these programs, we could be subject to significant decreasesdamages, fines, penalties or other criminal, civil or administrative sanctions or enforcement actions. We also rely on a third-party hub provider and exercise oversight to monitor patient assistance program activities. Hub providers are generally hired by manufacturers to assist patients with insurance coverage, financial assistance and treatment support after the patients receive a prescription from their healthcare professional. For manufacturers of specialty pharmaceuticals (including our marketed products), the ability to have a single point of contact for their therapies helps ensure efficient medication distribution to patients. Accordingly, our hub activities are also subject to scrutiny and may create risk for us if not conducted appropriately. A variety of entities, including independent charitable foundations and pharmaceutical manufacturers, but not including our company, have received subpoenas from the U.S. Department of Justice and other enforcement authorities seeking information related to their patient assistance programs and support. Should we or our hub providers receive a subpoena or other process, regardless of whether we are ultimately found to have complied with the regulations governing patient assistance programs, this type of government investigation could negatively impact our business practices, harm our reputation, divert the attention of management and increase our expenses.
We are subject to laws and regulations relating to privacy, data protection and the collection and processing of personal data. Failure to maintain compliance with these regulations could create additional liabilities for us.
The legislative and regulatory landscape for privacy and data protection continues to evolve in the overall salesU.S. and other jurisdictions around the world. For example, the CCPA went into operation in 2020 and affords California residents expanded privacy rights and protections, including civil penalties for violations and statutory damages under a private right of action for data security breaches. These protections will be expanded by the CPRA, which will be operational in most key respects on January 1, 2023. Similar legislative proposals have passed or pricesare being advanced in other states, and Congress is also considering additional federal privacy legislation. In addition, most healthcare professionals and facilities are subject to privacy and security requirements under HIPAA with respect to our clinical and commercial activities. Although we are not considered to be a covered entity or business associate under HIPAA, we could be subject to penalties if we use or disclose individually identifiable health information in a manner not authorized or permitted by HIPAA. Other countries also have, or are developing, laws governing the collection, use and transmission of personal information. For example, in the EU, the GDPR regulates the processing of personal data of individuals within the EU, even if, under certain circumstances, that processing occurs outside the EU, and also places restrictions on transfers of such data to countries outside of the EU, including the U.S. Should we fail to provide adequate privacy or data security protections or maintain compliance with these marketed productslaws and materially harmregulations, including the CCPA, CPRA and GDPR, we could be subject to sanctions or other penalties, litigation, an increase in our cost of doing business and financial condition.questions concerning the validity of our data processing activities, including clinical trials.
Risks Related to Growth of Our Product Portfolio and Research and Development
Clinical testing of cabozantinib for new indications, or of new potential product candidates, is a lengthy, costly, complex and uncertain process andthat may fail ultimately to demonstrate safety and efficacy.efficacy data for those products sufficiently differentiated to compete in our highly competitive market environment.
Clinical trials are inherently risky and may reveal that cabozantinib, despite its approval for certain indications, or a new potential product candidate, is ineffective or has an unacceptable safety profile with respect to an intended use. Such results may significantly decrease the likelihood of regulatory approval inof a particularproduct candidate or of an approved product for a new indication. Moreover, the results of preliminary studies do not necessarily predict clinical or commercial success, and later stagelate-stage or other potentially label-enabling clinical trials may fail to confirm the results observed in earlier stageearly-stage trials or preliminary studies. Although we have established timelines for manufacturing and clinical development of cabozantinib
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and our other product candidates based on existing knowledge of our compounds in development and industry metrics, we may not be able to meet those timelines.
We may experience numerous unforeseen events, during or as a result of clinical testing,investigations, that could delay or prevent commercialization of cabozantinib in new indications or of our othernew product candidates, including:and in some cases, as described in the risk factor titled, “If the COVID-19 pandemic is further prolonged or becomes more severe, our business operations and corresponding financial results could suffer, which could have a material adverse impact on our financial condition and prospects for growth,” the COVID-19 pandemic has already increased and may further increase the potential for such events to occur. These events may include:
•lack of acceptable efficacy or a tolerable safety profile;
•negative or inconclusive clinical trial results maythat require us to conduct further testing or to abandon projects that we had expected to be promising;projects;
•discovery or commercialization by our competitors of other compounds or therapies that show significantly improved safety or efficacy compared to cabozantinib or our other product candidates;
•our inability to identify and maintain a sufficient number of trial sites, many of which may already be engaged in other clinical trial programs;sites;
•lower-than-anticipated patient registration or enrollment in our clinical testing, resultingtesting;
•additional complexities posed by clinical trials evaluating cabozantinib or our other product candidates in combination with other therapies, including extended timelines to provide for collaboration on clinical development planning, the delay or cancellation of clinical testing;
failure by our collaboratorscollaboration partners to provide us on a timely basis with an adequate and timely supply of product that complies with the applicable quality and regulatory requirements for a combination trial;trial
•reduced staffing or shortages in laboratory supplies and other resources necessary to complete the trials;
•failure of our third-party contract research organizations or investigators to satisfy their contractual obligations, including deviating from any trial protocols; and
•withholding of authorization from regulators or institutional review boards may withhold authorization to commence or conduct clinical trials of cabozantinib or another product candidate,delays, variations, suspensions or delay, suspend or terminateterminations of clinical research for various reasons, including noncompliance with regulatory requirements or theira determination by these regulators and institutional review boards that participating patients are being exposed to unacceptable health risks.
If we were to have significantthere are further delays in or termination of the clinical testing of cabozantinib or our other product candidates as a result ofdue to any of the events described above or otherwise, our expenses could increase and our ability to generate revenues could be impaired, either of which could adversely impact our financial results. Furthermore, we rely on our clinical and commercial collaboration partners to fund a significant portion of theour clinical development of cabozantinib and our product candidates.programs. Should one or all of our collaboration partners decline to support future planned clinical trials, we will be entirely responsible for the financial obligations associated withfinancing the further development of the cabozantinib franchise or our other product candidates and, as a result, we may be unable to execute our current business plans, which could have a material adverse impact on our business, financial condition and results of operations.
We may not be able to rapidly or effectively continuepursue the further development of the cabozantinib franchise or our other product candidates or meet current or future requirements of the FDA or regulatory authorities in other jurisdictions including those identified based onin accordance with our discussions with the FDAstated timelines or such other regulatory authorities.at all. Our planned clinical trials may not begin on time, or at all, may not be completed on schedule, or at all, may not be sufficient for registration of our product candidates or otherwise may not result in an approvable product.
The duration and the cost of clinical trials vary significantly as a result of factors relating to the clinical trial, including, among others:
the characteristics of the product candidate under investigation;
the number of patients who ultimately participate in the clinical trial;
the duration of patient follow-up that is appropriate in view of the results or required by regulatory authorities;
follow-up; the number of clinical sites included in the trials; and
the length of time required to enroll suitable patient subjects.eligible patients.
Any delay could limit our ability to generate revenues, cause us to incur additional expense and cause the market price of our common stock to decline significantly. Our partners under our collaboration agreements may experience similar risks with respect to the compounds we have out-licensed to them. If any of the events described above were to occur with such programs or compounds, the likelihood of receipt of milestones and royalties under such collaboration agreements could decrease.
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The regulatory approval processes of the FDA and comparable foreign regulatory authorities are lengthy, uncertain and uncertain,subject to change, and may not result in regulatory approvals for additional cabozantinib indications or for our other product candidates, which could have a material adverse impact on our business, financial condition and results of operations.
The activities associated with the research, development and commercialization of the cabozantinib franchise and our other product candidates are subject to extensive regulation by the FDA and other regulatory agencies in the U.S. and, as well as by comparable regulatory authorities in other countries.territories. The processprocesses of obtaining regulatory approvals in the U.S. and other foreign jurisdictions is expensive and often takes many years, if approval is obtained at all, and they can vary substantially based upon the type, complexity and novelty of the product candidates involved. For example, before an NDA or sNDA can be submitted to the FDA, or a MAAmarketing authorization application to the EMA or any application or submission to comparable regulatory authorities in other jurisdictions, the product candidate must undergo extensive clinical trials, which can take many years and require substantial expenditures.
Any clinical trial may fail to produce results satisfactory to the FDA or regulatory authorities in other jurisdictions. For example, the FDA could determine that the design of a clinical trial is inadequate to produce reliable results. The regulatory process also requires preclinical testing, and data obtained from preclinical and clinical activities are susceptible to varying interpretations. The FDA has substantial discretion in the approval process and may refuse to approve any NDA or sNDA or decide that our data is insufficient for approval and require additional preclinical, clinical or other studies. For example, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent regulatory approval of cabozantinib for any individual, additional indications.
In addition, we may encounter delays or rejections may be encountered based upon changes in regulatory policy, for product approval during the period of product development and regulatory agency review, which maycould cause delays in the approval or rejection of an application for cabozantinib or for our other product candidates. For example, the FDA launched Project Optimus in 2021 as an initiative to reform the dose optimization and dose selection paradigm in oncology drug development, which was driven by the FDA’s concerns that the current paradigm for dose selection may result in doses and schedules of molecularly targeted therapies that are inadequately characterized before initiating pivotal trials. Through collaboration with the biopharmaceutical industry, academia and other stakeholders, the FDA’s goal for this initiative is to advance an oncology dose-finding and dose optimization paradigm that emphasizes dose selections that maximize efficacy as well as safety and tolerability. In support of this initiative, FDA may request sponsors of oncology product candidates to conduct dose optimization studies pre- or post-approval. Recently, in part due to questions raised by the process underlying the approval of the Alzheimer’s disease drug Aduhelm®,government authorities and other stakeholders have been scrutinizing the accelerated approval pathway, with some stakeholders advocating for reforms. Even prior to the Aduhelm approval, FDA has held Oncologic Drugs Advisory Committee meetings to discuss accelerated approvals for which confirmatory trials have not verified clinical benefit. Such scrutiny, among other factors, has resulted in voluntary withdrawals of certain products and indications approved on an accelerated basis. Moreover, spurred by the Aduhelm controversy, the HHS Office of Inspector General has initiated an assessment of how the FDA implements the accelerated approval pathway. At this time, it is not clear what impact, if any, these developments may have on the statutory accelerated approval pathway or our business, financial condition and results of operations.
Even if the FDA or a comparable authority in another jurisdiction approves cabozantinib for one or more new indications, beyond advanced RCC, previously treated HCC and MTC, or one of our other product candidates, thesuch approval may be limited, imposing significant restrictions on the indicated uses, conditions for use, labeling, distribution, advertising, promotion, marketing and/or production of the product and could impose ongoing requirements for post-approvalpost-marketing studies, including additional research and developmentclinical trials, all of which may result in significant expense and clinical trials. For example,limit our and our collaboration partners’ ability to commercialize cabozantinib in one or more new indications. Failure to complete post-marketing requirements of the FDA in connection with the FDA’sa specific approval of COMETRIQ for the treatment of progressive, metastatic MTC, we are subject to a post-marketing requirement to conduct a clinical study comparing a lower dose of cabozantinib to the approved dose of 140 mg daily cabozantinib in progressive, metastatic MTC. Failure to complete any post-marketing requirements in accordance with the timelines and conditions set forth by the FDA could significantly increase costs or delay, limit or eliminateultimately restrict the commercialization of cabozantinib. Further, thesecabozantinib in that indication. Regulatory agencies maycould also impose various administrative, civil or criminal sanctions for failure to comply with regulatory requirements, including withdrawal of product approval.
operations.
We may be unable to expand our discovery and development pipeline, which could limit our growth and revenue potential.
Our business is focused on the discovery, development and commercialization of new medicines for difficult-to-treat cancers. In this regard, we are pursuing internalhave invested in substantial technical, financial and human resources toward drug discovery effortsactivities with the goal of identifying new product candidates to advance into clinical trials. Internal discovery efforts to identify new product candidates require substantial technical, financial and human resources. These internal discovery efforts mayNotwithstanding this investment, many programs that initially show promise in identifying potential product candidates, yetwill ultimately fail to yield product candidates for clinical development for a number ofmultiple reasons. For example, potential product candidates may, on further study, be shown to have inadequate efficacy, harmful side effects, suboptimal pharmaceutical profiles or other characteristics suggesting that they are unlikely to be commercially viable products.
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Apart from our internaldrug discovery efforts, our strategy to expand our development pipeline is also dependent on our ability to successfully identify and acquire or in-license relevant product candidates.candidates and technologies. However, the in-licensing and acquisition of product candidates and technologies is a highly competitive area, and many other companies are pursuing the same or similar product candidates and technologies to those that we may consider attractive. In particular, larger companies with more well-established and diverse revenue streams may have a competitive advantage over us due to their size, financialcapital resources and more extensive clinical development and commercialization capabilities.capabilities may have a competitive advantage over us. Furthermore, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We may also be unable to in-license or acquire additional relevant product candidates and technologies on acceptable terms that would allow us to realize an appropriate return on our investment. If we are unable to develop suitable product candidates through internal discovery effort or if we are unable to successfully obtain rights to suitable product candidates, our business, financial condition and prospects for growth could suffer. Even if we succeed in our efforts to obtain rights to suitable product candidates and technologies, the competitive business environment may result in higher acquisition or licensing costs, and our investment in these potential products and technologies will remain subject to the inherent risks associated with the development and commercialization of new medicines. In certain circumstances, we may also be reliant on the licensor for the continued development of the in-licensed technology and their efforts to safeguard their underlying intellectual property.
With respect to acquisitions, we may not be able to integrate the target company successfully into our existing business, maintain the key business relationships of the target company, or retain key personnel of anthe acquired business. Furthermore, we could assume unknown or contingent liabilities or otherwise incur unanticipated expenses. Any acquisitions or investments made by us also could result in our spending significant amounts, issuing dilutive securities, assuming or incurring significant debt obligations and contingent liabilities, incurring large one-time expenses and acquiring intangible assets that could result in significant future amortization expense and significant write-offs, any of which could harm our operating results.
Risks Related to OurFinancial Matters and Capital Requirements Accounting
Our profitability could be negatively impacted if expenses associated with our extensive clinical development, business development and Financial Results
Although we reported net income of $690.1$231.1 million and $111.8 million for the yearyears ended December 31, 20182021 and 2020, respectively, we may not be able to maintain or increase profitability on a quarterly or annual basis, and we are unable to predict the extent of long-range future profits or losses. The amount of our net profits or losses will depend, in part, on: the level of sales of CABOMETYX and COMETRIQ in the U.S.; our achievement of clinical,development, regulatory and commercial milestones, if any, under our collaboration agreements with Ipsen and Takeda;agreements; the amount of royalties from sales of CABOMETYX and COMETRIQ outside of the U.S. under our collaboration agreements with Ipsen and Takeda;agreements; other collaboration revenues; and the level of our expenses,
including those associated with our extensive drug discovery, clinical development and commercializationbusiness development activities, both for the cabozantinib franchise and any pipelineour earlier-stage product candidates, as well as our general business expansion efforts.plans. Our expected future expenses in particular may also be increased by inflationary pressures, whether resulting from the effects of the COVID-19 pandemic or otherwise, which could increase the costs of outside services, labor, raw materials and finished drug product. We expect to continue to spend significant additionalsubstantial amounts to fund the continued development of the cabozantinib franchise for additional indications and the commercialization of our approved products. In addition, we willintend to continue to expand our oncology product pipeline through our drug discovery efforts, including research collaborations, in-licensing arrangements and the execution ofother strategic transactions that align with our oncology drug development, regulatory and commercial expertise, which efforts could involve substantial costs. To offset these costs in the future, we will need to generate substantial revenues. If these costs exceed our current expectations, or we fail to achieve anticipated revenue targets, the market value of our common stock may decline.
If additional capital is not available to us when we need it, we may be forcedunable to limit the expansion ofexpand our product development programs or commercialization efforts.
Our commitment of cash resources to CABOMETYX and the reinvestment in our product pipeline through the continued development of the cabozantinib franchise and our earlier-stage product candidates, and increasing drug discovery activities, as well as through the execution of strategicbusiness development transactions, could require us to obtain additional capital. We may seek such additional capital through some or all of the following methods: corporate collaborations; licensing arrangements; and public or private debt or equity financings. Our ability to obtain additional capital may depend on prevailing economic conditions and financial, business and other factors beyond our control. Disruptions in the U.S. and global financial markets, including any disruptions resulting from government shutdowns, the UK’s pending withdrawal from the EU, rising interest rate environments, increased or changed tariffs and trade restrictions or otherwise, may adversely impact the availability and cost of credit, as well as our ability to raise money in the capital markets. Economic and capital markets conditions have been, and continue to be, volatile. Continued instability in these market conditions may limit our ability to access the capital necessary to fund and grow our business. Accordingly, weWe do not know whether additional capital will be available when needed, or that, if available, we will obtain additional capital on
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terms favorable to us or our stockholders. If we are unable to raise additional funds when we need them, we may be requiredunable to limit the expansion ofexpand our product development programs or commercialization efforts,offerings and maintain business growth, which could have a material adverse impact on our business, financial condition and results of operations.
Risks Related to Our Relationships with Third Parties
We rely on Ipsen and Takeda for the commercial success of CABOMETYX in its approved indications outside of the U.S., and we are dependentunable to control the amount or timing of resources expended by these collaboration partners in the commercialization of CABOMETYX in its approved indications outside of the U.S.
We rely upon the regulatory, commercial, medical affairs, market access and other expertise and resources of our collaboration partners, Ipsen and Takeda, for commercialization of CABOMETYX in their respective territories outside of the U.S. We cannot control the amount and timing of resources that our collaboration partners dedicate to the commercialization of CABOMETYX, or to its marketing and distribution, and our ability to generate revenues from the commercialization of CABOMETYX by our collaboration partners depends on their ability to obtain and maintain regulatory approvals for, achieve market acceptance of, and to otherwise effectively market, CABOMETYX in its approved indications in their respective territories. Further, the operations of our collaboration partners, and ultimately their sales of CABOMETYX in their respective territories outside of the U.S., could be adversely affected by the degree and effectiveness of their respective corporate responses to the COVID-19 pandemic, as well as by the imposition of governmental price or other controls, political and economic instability, trade restrictions or barriers and changes in tariffs, escalating global trade and political tensions, or other factors. If our collaboration partners are unable or unwilling to invest the resources necessary to commercialize CABOMETYX successfully in the EU, Japan and other international territories where it has been approved, this could reduce the amount of revenue we are due to receive under these collaboration agreements, thus resulting in harm to our business and operations.
Our clinical, regulatory and commercial collaborations with major companies make us reliant on those companies for their continued performance and investments, which subjectsubjects us to a number of risks.
We have established clinical and commercial collaborations with leading pharmaceutical and biotechnologybiopharmaceutical companies including, Ipsen, Takeda, Genentech, Daiichi Sankyo and BMS for the development and ultimate commercialization of certain compounds generated from our research and development efforts. Our dependence on our relationships with collaborators for the development and commercialization of compoundsour products, and our dependence on these collaboration partners subjects us to a number of risks, including:including, but not limited to:
•our collaboration partners’ decision to terminate our collaboration, or their failure to comply with the terms of our collaboration agreements and related ancillary agreements, either intentionally or as a result of negligence or other insufficient performance;
•our inability to control the amount and timing of resources that our collaborators or potential future collaborators willcollaboration partners devote to the development or commercialization of drug candidates or to their marketing and distribution;our products;
•the possibility that collaboratorsour collaboration partners may stop or delay clinical trials, fail to supply us on a timely basis with the product required for a combination trial, or deliver product that fails to meet appropriate quality and regulatory standards and results in a market recall or withdrawal, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a drug candidate, repeat or conduct new clinical trials or require a new formulation of a drug candidate for clinical testing;standards;
•disputes that may arise between us and our collaboratorscollaboration partners that result in the delay or termination of the research, development or commercialization of our drug candidates, or that diminish or delay receipt of the economic benefits we are entitled to receive under the collaboration, or that result in costly litigation or arbitration that diverts management’s attention and resources;arbitration;
•the possibility that our collaboratorscollaboration partners may experience financial difficulties;difficulties that prevent them from fulfilling their obligations under our agreements;
•our collaborators’ lack of success in their effortscollaboration partners’ inability to obtain regulatory approvals in a timely manner, or at all;
•our collaborators’collaboration partners’ failure to comply with legal and regulatory requirements relevant to the authorization, marketing, distribution and supply of our marketed products in the territories outside the U.S. where they are approved; and
•our collaboration partners’ failure to properly maintain or defend our intellectual property rights or their use of our intellectual property rights or proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property rights or expose us to potential litigation;
If any of these risks materialize, we may not receive collaboration revenues or otherwise realize anticipated benefits from such collaborations, and our product development efforts and prospects for growth could be delayed or disrupted, all of which could have a material adverse impact on our business, financial condition and results of operations.
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Our growth potential is dependent in part upon companies with which we have entered into research collaborations, in-licensing arrangements and similar business development relationships.
To expand our early-stage product pipeline, we have augmented our drug discovery activities with multiple research collaborations and in-licensing arrangements with other companies. Our dependence on our relationships with these research and in-licensing partners subjects us to numerous risks, including, but not limited to:
•our research and in-licensing partners’ decision to terminate our relationship, or their failure to comply with the terms of our agreements, either intentionally or as a result of negligent performance;
•disputes that may arise between us and our research and in-licensing partners that result in the delay or termination of research activities with respect to any in-licensed assets or supporting technology platforms;
•the possibility that our research and in-licensing partners may experience financial difficulties that prevent them from fulfilling their obligations under our agreements;
•our research and in-licensing partners’ failure to properly maintain or defend their intellectual property rights or their use of third-party intellectual property rights or proprietary information in such a way as to invite litigation that could jeopardize or invalidate our license to develop these assets or utilize technology platforms;
•laws, regulations or practices imposed by countries outside the U.S. that could impact or inhibit scientific research or the development of healthcare products by foreign competitors or otherwise disadvantage healthcare products made by foreign competitors, as well as general political or economic instability in those countries, any of which could complicate, interfere with or impede our relationships with our ex-U.S. research, development and in-licensing partners; and
•our research and in-licensing partners’ failure to comply with applicable healthcare laws, as well as established guidelines, laws and regulations related to GMP and GLP.
If any of these risks materialize, we may not be able to expand our product pipeline or otherwise realize a return on the resources we will have invested to develop these early-stage assets, which could have a material adverse impact on our financial condition and prospects for growth.
If third parties upon which we rely to perform clinical trials for cabozantinib in new indications or for new potential product candidates do not perform as contractually required or expected, we may not be able to obtain regulatory approval for or commercialize cabozantinib or other product candidates beyond currently approved indications.
We do not have the ability to conduct clinical trials for cabozantinib or for new potential product candidates independently, including our post-marketing commitments in connection with the approval of COMETRIQ in progressive,
We lack internalour own manufacturing and distribution capabilities necessary for us to produce materials required for certain preclinical activities and to produce and distribute our products for clinical development or for commercial sale, and relyour reliance on third parties to do so, whichfor these services subjects us to various risks.
We do not own or operate manufacturing facilities,or distribution facilities or resources for CMC development activities, preclinical, clinical or commercial production and distribution offor our products.current products and new product candidates. Instead, we have multiple contractual agreements in place withrely on various third-party contract manufacturing organizations that,to conduct these operations on our behalf, manufacture clinical and commercial supplies of CABOMETYX and COMETRIQ.behalf. As our operations continue to grow in these areas, we continue to expand due to our development and commercial progress, we expect to enter into new agreements with additionalsupply chain through secondary third-party contract manufacturers, distributors and suppliers as needed. This will continue for the foreseeable future for all of our product candidates and all of our current and future commercial products.
suppliers. To establish and manage our supply chain requires a significant financial commitment, the creation of numerous third-party contractual relationships and continued oversight of these third parties to ensurefulfill compliance with applicable regulatory requirements. Although we maintain significant resources to directly and effectively oversee the activities and relationships with the companies in our supply chain, we do not have direct control over their operations.
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Our third-party contract manufacturers may not be able to produce material on a timely basis or manufacture material with the required quality standards, or in the quantity required to meet our preclinical, clinical development and commercial needs and applicable regulatory requirements.requirements, including as a result of the COVID-19 pandemic. Although we have not yet experienced significant production delays or seen significant impairment to our supply chain as a result of the COVID-19 pandemic, our third-party contract manufacturers, distributors and suppliers could experience operational delays due to facility closures and other hardships as a result of the COVID-19 pandemic or otherwise, which could impact our supply chain by potentially causing delays to or disruptions in the supply of our commercial or clinical products or product candidates. If our third-party contract manufacturers, distributors and suppliers do not continue to supply us with our products or product candidates in a timely fashion and in compliance with applicable quality and regulatory requirements, or if they otherwise fail or refuse to comply with their obligations to us under our supplymanufacturing, distribution and manufacturingsupply arrangements, we may not have adequate remedies for any breach. Furthermore, their failure to supply us could impair or preclude our ability to meet ourmeeting commercial or clinical product supply requirements or our supply needs for clinical trials, including those being conducted in collaboration withus or our partners, which could delay our product development and future commercialization efforts and have a material adverse impact on our business, financial condition and results of operations. ThroughIn addition, through our third-party contract manufacturers and data service providers, we have implemented product serialization designedcontinue to provide serialized commercial products as required to comply with the DSCSA, pursuant to which all prescription pharmaceutical products manufactured and distributed in the U.S. were required to be serialized as of November 27, 2018.DSCSA. If our third-party contract manufacturers or data service providers fail to support our efforts to continue to comply with DSCSA and any future federal or state electronic pedigree requirements, we may face legal penalties or be restricted from selling our products.
We work with scientific and clinical advisors and collaborators at academic and other institutions, as well as third-party contractors in various locations throughout the world, that assist us in our research and development efforts, including in drug discovery and preclinical development strategy. These advisors and collaboratorsthird parties are not our employees and may have other commitments or pursue other opportunitiescontractual obligations that limit their availability to us. Although these third-party scientific advisors and collaboratorscontractors generally agree not to do competing work, if a conflict of interest between their work for us and their work for another entity arises, we may lose their services. There has also been increased scrutiny surrounding the disclosures of payments made to medical researchers from companies in the pharmaceutical industry, and it is possible that the academic and other institutions that employ these medical researchers may prevent us from engaging them as scientific advisors and collaboratorscontractors or otherwise limit our access to these experts, or that the scientific advisors themselves may now be more reluctant to work with industry partners. In anyEven if these scientific advisors and contractors with whom we have engaged intend to meet their contractual obligations, their ability to perform services may be impacted by increased demand for such services from other companies or by other external factors, such as reduced capacity to perform services, as we experienced in the early stages of these circumstances,the COVID-19 pandemic. If we mayexperience additional delays in the receipt of services, lose
work performed by these scientific advisors and collaboratorscontractors or beare unable to engage them in the first place, and our discovery and development efforts with respect to the matters on which they were working or would work in the future may be significantly delayed or otherwise adversely affected. In addition, although our advisors and collaborators sign agreements not to disclose our confidential information, it is possible that valuable proprietary knowledge may become publicly known through them.
Risks Related to Our Information Technology Data Privacy and Intellectual Property
Data breaches, cyber-attacks and other failures in our information technology operations and infrastructure could compromise our intellectual property or other sensitive information, damage our operations and cause significant harm to our business and reputation.
In the ordinary course of our business, we and our third-party service providers, such as contract research organizations, collect, maintain and transmit sensitive data on our networks and systems, including our intellectual property and proprietary or confidential business information (such as research data and personal information) and confidential information with respect to our customers, clinical trial patients and our businesscollaboration partners. We have also outsourced significant elements of our information technology infrastructure to third parties and, as a result, such third parties may or could have access to our confidential information. The secure maintenance of this information is critical to our business and reputation, and while we have enhanced and are continuing to enhance our cyber-securitycybersecurity efforts commensurate with the growth and complexity of our business, our systems and those of third-party service providers may be vulnerable to a cyber-attack. In addition, we are heavily dependent on the functioning of our information technology infrastructure to carry out our business processes, such as external and internal communications or access to clinical data and other key business information. Accordingly, both inadvertent disruptions to this infrastructure and cyber-attacks could cause us to incur significant remediation or litigation costs, result in product development delays, disrupt keycritical business operations, and divert attention of management andexpend key information technology resources.resources and divert the attention of management.
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Although the aggregate impact of cyber-attacks on our operations and financial condition has not been material to date, we and our third-party service providers have frequently been the target of threats of this nature and expect them to continue. These threats can come from a variety of sources, ranging in sophistication from an individual hacker to a state-sponsored attack and motive (including corporate espionage). Cyber threats may be generic, or they may be custom-crafted against our information systems. Cyber-attacks continue to become more prevalent and much harder to detect and defend against. Our network and storage applications and those of our contract manufacturing organizations, contract research organizations or vendors may be subject to unauthorized access by hackers or breached due to operator error, malfeasance or other system disruptions. It is often difficult to anticipate or immediately detect such incidents and the damage caused by such incidents. TheseAny future data breaches and anybreach and/or unauthorized access or disclosure of our information or intellectual property could compromise our intellectual property and expose our sensitive business information (oror sensitive business information of our collaboration partners, which may lead to significant liability for us).us. A data security breach could also lead to public exposure of personal information of our clinical trial patients, employees or others and others. Any such event that leadsresult in harm to unauthorized access, use or disclosure of personal information, including personal information regarding our patients or employees, could harm our reputation and business, compel us to comply with federal and/or state breach notification laws and foreign law equivalents (includingincluding the GDPR),GDPR, subject us to investigations and mandatory corrective action, andor otherwise subject us to liability under laws and regulations that protect the privacy and security of personal information, which could disrupt our business, result in increased costs or loss of revenue, and/or result in significant financial exposure. Furthermore, the costs of maintaining or upgrading our cyber-securitycybersecurity systems (including the recruitment and retention of experienced information technology professionals, who are in high demand) at the level necessary to keep up with our expanding operations and prevent against potential attacks are increasing, and despite our best efforts, our network security and data recovery measures and those of our vendorsthird-party service providers may still not be adequate to protect against such security breaches and disruptions, which could cause material harm to our business, financial condition and results of operations.
If we are unable to adequately protect our intellectual property, third parties may be able to use our technology, which could adversely affect our ability to compete in the market.
Our success will depend in part upon our ability to obtain patents and maintain adequate protection of the intellectual property related to our technologies and products. The patent positions of biopharmaceutical companies, including our patent position, are generally uncertain and involve complex legal and factual questions. We will be able to protect our intellectual property rights from unauthorized use by third parties only to the extent that our technologies are covered by valid and enforceable patents or are effectively maintained as trade secrets. We will continue to apply for patents covering our technologies and products as, where and when we deem lawful and appropriate. However, these
applications may be challenged or may fail to result in issued patents. Our issued patents have been and may in the future be challenged by third parties as invalid or unenforceable under U.S. or foreign laws, or they may be infringed by third parties, and we are from time to time involved in the defense and enforcement of our patents or other intellectual property rights in a court of law, U.S. Patent and Trademark Office inter partes review or reexamination proceeding, foreign opposition proceeding or related legal and administrative proceeding in the U.S. and elsewhere. The costs of defending our patents or enforcing our proprietary rights in post-issuance administrative proceedings and litigation can be substantial and the outcome can be uncertain. An adverse outcome may allow third parties to use our intellectual property without a license and/or allow third parties to introduce generic and other competing products, any of which would negatively impact our business. Third parties may also attempt to invalidate or design around our patents, or assert that they are invalid or otherwise unenforceable, and seek to introduce generic versions of cabozantinib. In addition, shouldFor example, we received Paragraph IV certification notice letters from MSN and Teva concerning the respective ANDAs that each had filed with the FDA seeking approval to market their respective generic versions of CABOMETYX tablets. Should MSN, Teva or any other third parties receive FDA approval of an ANDA foror a generic version of cabozantinib or an 505(b)(2) NDA with respect to cabozantinib, and if our patents covering cabozantinib were held to be invalid (or ifit is possible that such competing generic versions of cabozantinib were found to not infringe our patents), then theycompany or companies could introduce generic versions of cabozantinib or other such 505(b)(2)our marketed products before our patents expire if they do not infringe our patents or if it is determined that our patents are invalid or unenforceable, and the resulting generic competition would negatively affectcould have a material adverse impact on our business, financial condition and results of operations.
In addition, because patent applications can take many years to issue, third parties may have pending applications, unknown to us, which may later result in issued patents that cover the production, manufacture, commercialization or use of our product candidates. Our existing patents and any future patents we obtain may not be sufficiently broad to prevent others from practicing our technologies or from developing competing products. They may also be negatively impacted by the decisions of foreign courts, which could limit the protection contemplated by the original regulatory approval and our ability to thwart the development of competing products that might otherwise have been determined to infringe our intellectual property rights. Furthermore, others may independently develop similar or alternative technologies or design around our patents. In addition, our patents may be challenged or invalidated or may fail to provide us with any competitive advantages, if, for example, others were the first to invent or to file patent applications for closely related inventions.
The laws of some foreign countries do not protect intellectual property rights to the same extent as the laws of the U.S., and many companies have encountered significant problems in protecting and defending such rights in foreign jurisdictions. Many countries, including certain countries in Europe,the EU, have compulsory licensing laws based on related EU rules, under which a patent owner may be compelled to grant licenses to third parties (for example, the patent owner has failed to “work” the invention in that country or the third-partythird party has patented improvements). In addition, many countries
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limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of the patent. Initiatives seeking compulsory licensing of life-saving drugs are also becoming increasingly prevalent in developing countries either through direct legislation or international initiatives. Governments in those developing countries could require that we grant compulsory licenses to allow competitors to manufacture and sell their own versions of our products or product candidates, thereby reducing our product sales. Moreover, the legal systems of certain countries, particularly certain developing countries, do not favor the aggressive enforcement of patent and other intellectual property protection, which makes it difficult to stop infringement. We also rely on trade secret protection for some of our confidential and proprietary information. We have takeninformation, and we are taking security measures to protect our proprietary information and trade secrets, butparticularly in light of recent instances of data loss and misappropriation of intellectual property in the biopharmaceutical industry. However, these measures may not provide adequate protection. Whileprotection, and while we seek to protect our proprietary information by entering into confidentiality agreements with employees, collaboratorspartners and consultants, as well as maintain cybersecurity protocols within our information technology infrastructure, we cannot assure youprovide assurance that our proprietary information will not be disclosed, or that we can meaningfully protect our trade secrets. In addition, our competitors may independently develop substantially equivalent proprietary information or may otherwise gain access to our trade secrets.
Litigation or third-party claims of intellectual property infringement could require us to spend substantial time and money and adversely affect our ability to develop and commercialize products.
Our commercial success depends in part upon our ability to avoid infringing patents and proprietary rights of third parties and not to breach any licenses that we have entered into with regard to our technologies and the technologies of third parties. Other parties have filed, and in the future are likely to file, patent applications covering products and technologies that we have developed or intend to develop. If patents covering technologies required by our operations are issued to others, we may have to obtain licenses from third parties, which may not be available on commercially reasonable terms, or at all, and may require us to pay substantial royalties, grant a cross-license to some of our patents to another patent holder or redesign the formulation of a product candidate so that we do not infringe third-party patents, which may be impossible to accomplish or could require substantial time and expense.
In addition, we may be subject to claims that our employees or independent contractors have inadvertently or otherwise used or disclosed trade secrets or other proprietary information of their former employers, or that they used or sought to use patent inventions belonging to their former employers. Furthermore, third parties may obtain patents that relate to our technologies and claim that use of such technologies infringes on their patents or otherwise employs their proprietary technology without authorization. Regardless of their merit, such claims could require us to incur substantial costs includingand divert the diversionattention of management and key technical
personnel in defending ourselves against any such claims or enforcing our own patents. In the event that aof any third party’s successful claim of patent infringement is brought against us,or misappropriation of trade secrets, we may lose valuable intellectual property rights or personnel, which could impede or prevent the achievement of our product development goals, or we may be required to pay damages and obtain one or more licenses from these third parties, subjecting us to substantial royalty payment obligations. We may not be able to obtain these licenses on commercially reasonable terms, or at all. Defense of any lawsuit or failure to obtain any of these licenses could adversely affect our ability to develop and commercialize products.
If the COVID-19 pandemic is further prolonged or becomes more severe, our business operations and corresponding financial results could suffer, which could have a material adverse impact on our financial condition and prospects for growth.
To date, the COVID-19 pandemic has had a modest impact on our business operations, in particular with respect to our clinical trial, drug discovery and commercial activities. For example, to varying degrees and at different rates across our clinical trials, we experienced declines in screening and enrollment activity during the early days of the COVID-19 pandemic, as well as delays in new site activations and restrictions on the access to treatment sites that we, our employees or independent contractors have wrongfully used or disclosed alleged trade secrets of their former employers.
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Moreover, quarantines and travel restrictions have impeded and may continue to impede patient movement or interrupt healthcare services, which we anticipate over time, could also delay, interfere with and potentially negatively impact clinical trial execution, and ultimately results, particularly with respect to clinical trials evaluating our or our collaboration partners’ product candidates that must be administered via intravenous infusion. In addition, increased costs connected with our efforts to mitigate the adverse impacts resulting from the COVID-19 pandemic on our clinical trials could cause the expenses we incur in conducting those clinical trials to increase considerably. Depending upon the duration and severity of the COVID-19 pandemic, we could also experience delays in planning and conducting new clinical trials of the investigative product candidates entering and advancing through our development pipeline, which could severely harmincrease the operating expenses associated with these trials and adversely affect their timelines for completion and ultimately our business.ability to obtain regulatory approvals.
While we believe that our commercial business has, to date, only experienced a modest impact related to the COVID-19 pandemic, it remains possible that over a longer period, changes to our standard sales and marketing practices, including any shifts from in-person back to primarily telephonic and virtual interactions with healthcare professionals, could negatively impact the flow of important information regarding our medicines, which along with obstacles to patient access to healthcare professionals, could diminish sales of our marketed products.
Although as of the date of this Annual Report on Form 10-K, we continue to maintain sufficient safety stock inventories for our drug substance and drug products and have not experienced significant production delays or seen significant impairment to our supply chain as a result of the COVID-19 pandemic, our third-party contract manufacturers and suppliers could experience operational delays due to facility closures and other hardships as a result of the COVID-19 pandemic, which could impact our supply chain by potentially causing delays to or disruptions in the supply of our commercial or clinical products or product candidates. These delays or disruptions could be further exacerbated if the COVID-19 pandemic begins to impact essential distribution systems, which could substantially increase delivery times and costs, or otherwise adversely affect our ability to provide our products to customers and clinical trial sites and generate product revenues.
In addition, as a result of broad economic shifts during and as a consequence of efforts to address unemployment and other negative economic effects of the COVID-19 pandemic, we may experience reductions in the net price of our products. For example, there may be a substantial shift from private health insurance coverage to government insurance coverage, or additional downward pressure on the prices government purchasers will pay for our products due to significant increases in government debt incurred in connection with relief efforts, as well as significant increases in demand for our patient assistance and/or free drug program or other impacts that may not be foreseeable, all or any of which would adversely affect our product revenues.
While we expect the COVID-19 pandemic to continue to have varying degrees of adverse impact on our business operations and, potentially in the future, our financial results, the extent of such adverse impact will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time. Such developments include, but are not limited to: continued spread of the Delta and Omicron variants in the U.S. and other countries and the potential emergence of other SARS-CoV-2 variants that may prove especially contagious or virulent, the ultimate duration of the pandemic and resulting disruptions to normal business and personal activities in the U.S. and in other countries, and the effectiveness of actions taken globally to contain and treat the disease, including the rate at which vaccinations are made available and are administered, the percentage of the population that becomes fully vaccinated and the effectiveness of the vaccines against Delta, Omicron or other SARS-CoV-2 variants. These continuing or future effects could materially and adversely affect our business, financial condition, results of operations and growth prospects, and exacerbate the other risks and uncertainties described elsewhere in this ‘‘Risk Factors’’ section.
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If we are unable to manage our growth, there could be a material adverse impact on our business, financial condition and results of operations, and our prospects may be adversely affected.
We have experienced and expect to continue to experience growth in the number of our employees and in the scope of our operations.operations, in particular as we continue to expand the cabozantinib franchise into new indications and grow our pipeline of product candidates. This growth places significant demands on our management operational and financial resources, and our current and planned personnel facilities, systems, procedures and controlsoperating practices may not be adequate to support our growth. To effectively manage our growth, we must continue to improve existing, and implement new, facilities, operational and financial systems, and procedures and controls, and mustas well as expand, train and manage our growing employee base, and there can be no assurance that we will effectively manage our growth without experiencing operating inefficiencies or control deficiencies. We expect that we may needcontinue to increase our management personnel to oversee our expanding operations, and recruiting and retaining qualified individuals is difficult. If we are unable to manage our growth effectively, including as a result of the COVID-19 pandemic or otherwise, or we are unsuccessful in recruiting qualified management personnel, there could be a material adverse impact on our business, financial condition and results of operations, and our prospects may be adversely affected.operations.
The loss of key personnel or the inability to retain and, where necessary, attract additional personnel could impair our ability to operate and expand our operations.
We are highly dependent upon the principal members of our management, as well as clinical, commercial and scientific staff, the loss of whose services might adversely impact the achievement of our objectives. Also, we may not have sufficient personnel to execute our business plans. Retaining and, where necessary, recruiting qualified clinical, commercial, scientific and scientificpharmaceutical operations personnel will be critical to support activities related to advancing the development program for the cabozantinib franchise and our other compounds,product candidates, successfully executing upon our commercialization plan for the cabozantinib franchise and our internal proprietary research and development efforts. Competition is intense for experienced clinical, commercial, scientific and scientificpharmaceutical operations personnel, and we may be unable to retain or recruit such personnel with the expertise or experience necessary to allow us to successfully develop and commercialize our products. Further, all of our employees are employed “at will” and, therefore, may leave our employment at any time.
Risks Related to Environmental and Product Liability
We use hazardous chemicals and biological materials in our business. Any claims relating to improper handling, storage or disposal of these materials could be time consuming and costly.
Our research and development processes involve the controlled use of hazardous materials, including chemicals and biological materials. Ourmaterials, and our operations can produce hazardous waste products. We cannot eliminate the risk of accidental contamination or discharge, andor any resultant injury from these materials. Federal, statematerials, and local laws and regulations govern the use, manufacture, storage, handling and disposal of hazardous materials. Wewe may face liability under applicable laws for any injury or contamination that results from our use or the use by our collaboration partners or other third parties of these materials, and suchmaterials. Such liability may exceed our insurance coverage and our total assets. Complianceassets, and in addition, we may be required to indemnify our collaboration partners against all damages and other liabilities arising out of our development activities or products produced in connection with our collaborations with them. Moreover, our continued compliance with environmental laws and regulations may be expensive, and current or future environmental regulations may impair our research, development and production efforts.
We face potential product liability exposure far in excess of our limited insurance coverage.
We may be held liable if any product we or our collaboratorscollaboration partners develop or commercialize causes injury or is found otherwise unsuitable during product testing, manufacturing, marketing or sale. Regardless of merit or eventual outcome, product liability claims could result in decreased demand for our products and product candidates, injury to our reputation, withdrawal of patients from our clinical trials, product recall, substantial monetary awards to third parties and the inability to commercialize any products that we may develop in the future. These claims might be made directly by consumers, health care providers, pharmaceutical companies or others selling or testing our products. We have obtainedmaintain limited product liability insurance coverage for our clinical trials and commercial activities for cabozantinib in the amount of $20.0 million per occurrence and $20.0 million in the aggregate.cabozantinib. However, our insurance may not reimburse us or may not be sufficient to reimburse us for expenses or losses we may suffer. Moreover, if insurance coverage becomes more expensive, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses due to liability. On occasion, juries have awarded large judgments in class action lawsuits for claims based on drugs that had unanticipated side effects. In addition, the pharmaceutical, biopharmaceutical and biotechnology industries, in general, have been subject to significant medical malpractice litigation. A successful product liability claim or series
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Risks Related to Our Common Stock
Our stock price has been and may in the future be highly volatile.
The trading price of our common stock has been highly volatile, and we believe the trading price of our common stock willit may remain highly volatile and mayor fluctuate substantially due to factors such as the following, many of which we cannot control:
•the announcement of FDA or other regulatory approval or non-approval, or delays in the FDA or other regulatory review process with respect to cabozantinib, our collaborators’collaboration partners’ product candidates being developed in combination with cabozantinib, or our competitors’ product candidates;
•the commercial successperformance of both CABOMETYX and COMETRIQ and the revenues we generate from those approved products;products, including royalties paid under our collaboration and license agreements;
•adverse or inconclusive results or announcements related to our or our collaboration partners’ clinical trials or delays in those clinical trials;
•the timing of achievement of our clinical, regulatory, partnering, commercial and other milestones such asfor the commencement of clinical development, the completion of a clinical trial, the filing for regulatory approval or the establishment of collaborative arrangements for cabozantinib franchise or any of our other programs or compounds;product candidates;
•our ability to make future investments in the expansion of our pipeline through drug discovery, including future research collaborations, in-licensing arrangements and other strategic transactions;
•our ability to obtain the materials and services, including an adequate product supply for any approved drug product, from our third-party vendors or do so at acceptable prices;
•the timing and amount of expenses incurred for clinical development and manufacturing of cabozantinib;
•actions taken by regulatory agencies, both in the U.S. and abroad, with respect to cabozantinib or our clinical trials for cabozantinib;
•unanticipated regulatory actions taken by the FDA as a result of changing FDA standards and practices concerning the review of product candidates, including approvals at earlier stages of clinical development or with lesser developed data sets and expedited reviews;
•the announcement of new products or clinical trial data by our competitors;
•the announcement of regulatory applications, such as MSN’s and Teva’s respective ANDAs, seeking a path to U.S. approval of generic versions of our marketed products;
•quarterly variations in our or our competitors’ results of operations;
•the announcement of an in-licensed product candidate or strategic acquisition;
•litigation, including intellectual property infringement and product liability lawsuits, involving us;
•changes in earnings estimates or recommendations by securities analysts;analysts, or financial guidance from our management team, and any failure to achieve the operating results projected by securities analysts or by our management team;
•the entry into new financing arrangements;
•developments in the biotechnology, biopharmaceutical or pharmaceutical industry;
•sales of large blocks of our common stock or sales of our common stock by our executive officers, directors and significant stockholders;
•additions and departures of key personnel or board members;
•the extent to which coverage and adequate reimbursement is available for both CABOMETYX and COMETRIQ from government and health administration authorities, private health insurers, managed care programs and other third-party payers;
disposition of any of our technologies or compounds; and
•general market, economic and political conditions and other factors, including factors unrelated to our operating performance or the operating performance of our competitors.
These and other factors as well as general economic, political and market conditions, may materially adversely affectcould have material adverse impact on the market price of our common stock. In addition, the stock markets in general, and the markets for biotechnology and pharmaceutical stocks in particular, have historically experienced significant volatility that has often been unrelated or disproportionate to the operating performance of particular companies. For example, negative publicity regarding drug pricing and price increases by pharmaceutical companies has negatively impacted, and may continue to negatively impact,
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markets for biotechnology and pharmaceutical stocks. These broad market fluctuations have adversely affected and may in the future adversely affect the trading price of our common stock. Excessive volatility may continue for an extended period of time following the date of this report.
In the past, following periods of volatility in the market price of a company’s securities, securities class action litigation has often been instituted.initiated. A securities class action suit against us could result in substantial costs and divert management’sthe attention and resources,of management, which could have a material adverse impact on our business, financial condition and results of operations.
Anti-takeover provisions in our charter documents and under Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more difficult and may prevent or deter attempts by our stockholders to replace or remove our current management, which could cause the market price of our common stock to decline.
Provisions in our corporate charter and bylaws may discourage, delay or prevent an acquisition of us, a change in control, or attempts by our stockholders to replace or remove members of our current Board of Directors. Because our Board of Directors is responsible for appointing the members of our management team, these provisions could in turn affect any attempt by our stockholders to replace current members of our management team. These provisions include:
•a prohibition on actions by our stockholders by written consent;
•the ability of our Board of Directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our Board of Directors; and
•advance notice requirements for director nominations and stockholder proposals.
Moreover, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which prohibits a person who owns in excess of 15% of our outstanding voting stock from merging or combining with us for a period of three years after the date of the transaction in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or combination is approved in a prescribed manner.
Item 1B. Unresolved Staff Comments
None.
Item 2. Properties
Item 3. Legal Proceedings
In September 2019, we received a notice letter regarding an ANDA submitted to the FDA by MSN, requesting approval to market a generic version of CABOMETYX tablets. MSN’s initial notice letter included a Paragraph IV certification with respect to our U.S. Patent Nos. 8,877,776 (salt and polymorphic forms), 9,724,342 (formulations), 10,034,873 (methods of treatment) and 10,039,757 (methods of treatment), which are listed in the Orange Book for CABOMETYX. MSN’s initial notice letter did not provide a Paragraph IV certification against the ’473 Patent (composition of matter) or U.S. Patent No. 8,497,284 (methods of treatment), each of which is listed in the Orange Book. On October 29, 2019, we filed a complaint in the Delaware District Court for patent infringement against MSN asserting infringement of U.S. Patent No. 8,877,776 arising from MSN’s ANDA filing with the FDA. On November 20, 2019, MSN filed its response to the complaint, alleging that the asserted claims of U.S. Patent No. 8,877,776 are invalid and not infringed. On May 5, 2020, we received notice from MSN that it had amended its ANDA to include additional Paragraph IV certifications. In particular, the ANDA requested approval to market a generic version of CABOMETYX tablets prior to expiration of two previously unasserted CABOMETYX patents: the ‘473 Patent and U.S. Patent No. 8,497,284. On May 11, 2020, we filed a complaint in the Delaware
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District Court for patent infringement against MSN asserting infringement of the ‘473 Patent and U.S. Patent No. 8,497,284 arising from MSN’s amended ANDA filing with the FDA. Neither of our complaints have alleged infringement of U.S. Patent Nos. 9,724,342, 10,034,873 and 10,039,757. On May 22, 2020, MSN filed its response to the complaint, alleging that the asserted claims of the ‘473 Patent and U.S. Patent No. 8,497,284 are invalid and not infringed. On March 23, 2021, MSN filed its First Amended Answer and Counterclaims (amending its prior filing from May 22, 2020), seeking, among other things, a declaratory judgment that U.S. Patent No. 9,809,549 is invalid and would not be infringed by MSN if its generic version of CABOMETYX tablets were approved by the FDA. U.S. Patent No. 9,809,549 is not listed in the Orange Book. On April 7, 2021, we filed our response to MSN’s First Amended Answer and Counterclaims, denying, among other things, that U.S. Patent No. 9,809,549 is invalid or would not be infringed.
On October 1, 2021, pursuant to a stipulation between us and MSN, the Delaware District Court entered an order that (i) MSN’s submission of its ANDA constitutes infringement of certain claims relating to the ‘473 Patent and U.S. Patent No. 8,497,284, if those claims are not found to be invalid, and (ii) upon approval, MSN’s commercial manufacture, use, sale or offer for sale within the U.S., and importation into the U.S., of MSN’s ANDA product prior to the expiration of the ‘473 Patent and U.S. Patent No. 8,497,284 would also infringe certain claims of each patent, if those claims are not found to be invalid. Then, on October 12, 2021, pursuant to a separate stipulation between us and MSN, the Delaware District Court entered an order dismissing MSN’s counterclaims with respect to U.S. Patent No. 9,809,549. In our complaints, we are seeking, among other relief, an order that the effective date of any FDA approval of MSN’s ANDA be a date no earlier than the expiration of all of the ‘473 Patent, U.S. Patent No. 8,497,284 and U.S. Patent No. 8,877,776, the latest of which expires on October 8, 2030, and equitable relief enjoining MSN from infringing these patents. A bench trial has been scheduled for May 2022.
On January 11, 2022, we received notice from MSN that it had further amended its ANDA to assert additional Paragraph IV certifications. The ANDA now requests approval to market a generic version of CABOMETYX tablets prior to expiration of four previously-unasserted CABOMETYX patents that are now listed in the Orange Book: U.S. Patent Nos. 11,091,439 (salt and polymorphic forms) 11,091,440 (formulations) and 11,098,015 (methods of treatment). We have 45 days from the receipt of the January 11, 2022 notice to file a patent infringement claim against MSN relating to the newly challenged patents.
In May 2021, we received notice letters from Teva regarding an ANDA Teva submitted to the FDA, requesting approval to market a generic version of CABOMETYX tablets. Teva’s notice letters included a Paragraph IV certification with respect to our U.S. Patent Nos. 9,724,342 (formulations), 10,034,873 (methods of treatment) and 10,039,757 (methods of treatment), which are listed in the Orange Book and expire in 2033, 2031 and 2031, respectively. Teva’s notice letters did not provide a Paragraph IV certification against any additional CABOMETYX patents. On June 17, 2021, we filed a complaint in the Delaware District Court for patent infringement against Teva, along with Teva Parent, asserting infringement of U.S. Patent Nos. 9,724,342, 10,034,873 and 10,039,757 arising from Teva’s ANDA filing with the FDA. On August 27, 2021, Teva filed its answer and counterclaims to the complaint, alleging that the asserted claims of U.S. Patent Nos. 9,724,342, 10,034,873 and 10,039,757 are invalid and not infringed, and on August 23, 2021, we and Teva entered into a stipulation wherein Teva Parent was dismissed without prejudice from this lawsuit and agreed to be bound by any stipulation, judgment, order or decision rendered as to Teva, including any appeals and any order granting preliminary or permanent injunctive relief against Teva. On September 17, 2021, we filed an answer to Teva’s counterclaims. We are notseeking, among other relief, an order that the effective date of any FDA approval of Teva’s ANDA be a partydate no earlier than the expiration of all of U.S. Patent Nos. 9,724,342, 10,034,873 and 10,039,757, the latest of which expires on July 9, 2033, and equitable relief enjoining Tevafrom infringing these patents. On February 8, 2022, the parties filed a stipulation to any material legal proceedings. stay all proceedings, which was granted by the Delaware District Court on February 9, 2022. The stipulation and order were filed under seal.
We may also from time to time become a party or subject to various other legal proceedings and claims, either asserted or unasserted, which arise in the ordinary course of business. Some of these proceedings have involved, and may involve in the future, claims that are subject to substantial uncertainties and unascertainable damages.
Item 4. Mine Safety Disclosures
Not applicable.
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PART II
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
Our common stock has traded on the Nasdaq Global Select Market under the symbol “EXEL” since April 11, 2000.
Holders
On February 12, 2019,7, 2022, there were 398347 holders of record of our common stock. The number of record holders is based upon the actual number of holders registered on our books at such date and does not include holders of shares in “street names” or persons, partnerships, associations, corporations or other entities identified in security position listings maintained by depository trust companies.
Dividends
Since inception, we have not paid dividends on our common stock. We currently intend to retain all future earnings, if any, for use in our business and currently do not plan to pay any cash dividends in the foreseeable future. Any future determination to pay dividends will be at the discretion of our Board of Directors.
Unregistered Sales of Equity Securities
There were no unregistered sales of equity securities by us during the year ended December 31, 2018.2021.
Equity Securities
There were no repurchases of our common stock during the year ended December 31, 2021.
Performance
This performance graph shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities under that Section and shall not be deemed to be incorporated by reference into any filing of ours under the Securities Act of 1933, as amended.
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The following graph compares, for the five yearfive-year period ended December 31, 2018,2021, the cumulative total stockholder return for our common stock, the Nasdaq Composite Index and the Nasdaq Biotechnology Index. The graph assumes that $100 was invested on December 31, 20132016 in each of our common stock, the Nasdaq Composite Index and the Nasdaq Biotechnology Index and assumes reinvestment of any dividends. The stock price performance on the following graph is not necessarily indicative of future stock price performance.
| Year Ended December 31, | |||||||||||||||||||||||||||||||||||
| 2016 | 2017 | 2018 | 2019 | 2020 | 2021 | ||||||||||||||||||||||||||||||
| Exelixis, Inc. | 100 | 204 | 130 | 114 | 135 | 123 | |||||||||||||||||||||||||||||
| Nasdaq Composite Total Return | 100 | 130 | 125 | 173 | 250 | 305 | |||||||||||||||||||||||||||||
| Nasdaq Biotechnology Total Return | 100 | 122 | 109 | 136 | 175 | 175 | |||||||||||||||||||||||||||||
Item 6. Reserved
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| December 31, | |||||||||||||||||
| 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | ||||||||||||
| Exelixis, Inc. | 100 | 28 | 95 | 251 | 513 | 328 | |||||||||||
| Nasdaq Composite Index | 100 | 114 | 120 | 130 | 166 | 158 | |||||||||||
| Nasdaq Biotechnology Index | 100 | 136 | 150 | 117 | 142 | 127 | |||||||||||
| Year Ended December 31, | |||||||||||||||||||
| 2018 | 2017 | 2016 | 2015 | 2014 | |||||||||||||||
| (In thousands, except per share data) | |||||||||||||||||||
| Consolidated Statements of Operations Data: | |||||||||||||||||||
| Revenues | $ | 853,826 | $ | 452,477 | $ | 191,454 | $ | 37,172 | $ | 25,111 | |||||||||
| Operating expenses: | |||||||||||||||||||
| Cost of goods sold | 26,348 | 15,066 | 6,552 | 3,895 | 2,043 | ||||||||||||||
| Research and development | 182,257 | 112,171 | 95,967 | 96,351 | 189,101 | ||||||||||||||
| Selling, general and administrative | 206,366 | 159,362 | 116,145 | 57,305 | 50,829 | ||||||||||||||
| Restructuring (recovery) charge | — | (32 | ) | 914 | 1,042 | 7,596 | |||||||||||||
| Total operating expenses | 414,971 | 286,567 | 219,578 | 158,593 | 249,569 | ||||||||||||||
| Income (loss) from operations | 438,855 | 165,910 | (28,124 | ) | (121,421 | ) | (224,458 | ) | |||||||||||
| Other income (expenses), net | 13,237 | (7,333 | ) | (42,098 | ) | (40,268 | ) | (37,021 | ) | ||||||||||
| Income (loss) before income taxes | 452,092 | 158,577 | (70,222 | ) | (161,689 | ) | (261,479 | ) | |||||||||||
| Income tax benefit (provision) | 237,978 | (4,350 | ) | — | (55 | ) | 182 | ||||||||||||
| Net income (loss) | $ | 690,070 | $ | 154,227 | $ | (70,222 | ) | $ | (161,744 | ) | $ | (261,297 | ) | ||||||
| Net income (loss) per share, basic | $ | 2.32 | $ | 0.52 | $ | (0.28 | ) | $ | (0.77 | ) | $ | (1.34 | ) | ||||||
| Net income (loss) per share, diluted | $ | 2.21 | $ | 0.49 | $ | (0.28 | ) | $ | (0.77 | ) | $ | (1.34 | ) | ||||||
| Shares used in computing net income (loss) per share, basic | 297,892 | 293,588 | 250,531 | 209,227 | 194,299 | ||||||||||||||
| Shares used in computing net income (loss) per share, diluted | 312,803 | 312,003 | 250,531 | 209,227 | 194,299 | ||||||||||||||
| December 31, | |||||||||||||||||||
| 2018 | 2017 | 2016 | 2015 | 2014 | |||||||||||||||
| (In thousands) | |||||||||||||||||||
| Consolidated Balance Sheet Data: | |||||||||||||||||||
| Cash and investments | $ | 851,621 | $ | 457,176 | $ | 479,554 | $ | 253,310 | $ | 242,760 | |||||||||
| Working capital (deficit) | $ | 791,544 | $ | 369,704 | $ | 200,215 | $ | 126,414 | $ | (3,188 | ) | ||||||||
| Total assets | $ | 1,422,286 | $ | 655,294 | $ | 595,739 | $ | 332,223 | $ | 323,256 | |||||||||
| Long-term obligations | $ | 29,361 | $ | 255,163 | $ | 237,635 | $ | 420,897 | $ | 312,163 | |||||||||
| Accumulated deficit | $ | (880,363 | ) | $ | (1,829,172 | ) | $ | (1,983,147 | ) | $ | (1,912,925 | ) | $ | (1,751,181 | ) | ||||
| Total stockholders’ equity (deficit) | $ | 1,287,453 | $ | 284,961 | $ | 89,318 | $ | (140,806 | ) | $ | (159,324 | ) | |||||||
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations
Some of the statements under in this “Management’s Discussion and Analysis of Financial Condition and Results of Operations” are forward-looking statements. These statements are based on our current expectations, assumptions, estimates and projections about our business and our industry and involve known and unknown risks, uncertainties and other factors that may cause our company’s or our industry’s results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied in, or contemplated by, the forward-looking statements. Our actual results and the timing of events may differ significantly from the results discussed in the forward-looking statements. Factors that might cause such a difference include those discussed in “Item 1A. Risk Factors” as well as those discussed elsewhere in this Annual Report on Form 10-K. These and many other factors could affect our future financial and operating results. We undertake no obligation to update any forward-looking statement to reflect events after the date of this report.
Overview
We are an oncology-focused biotechnology company that aimsstrives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. SinceUsing our considerable drug discovery, development and commercialization resources and capabilities, we were founded in 1994,have invented and brought to market innovative therapies that appropriately balance patient benefits and risks; we will continue to build on this foundation as we strive to provide cancer patients with new treatment options that improve upon current standards of care.
Today, four products resulting from our discovery efforts have progressed through clinical development and received regulatory approval; three have a growing commercial presencethat originated in markets worldwide, and we expect that the fourth will soon enter the marketplace in Japan. TwoExelixis laboratories are derived from cabozantinib,available to be prescribed to patients. Sales related to our flagship molecule, cabozantinib, account for the large majority of our revenues. Cabozantinib is an inhibitor of multiple tyrosine kinases including MET, AXL, VEGF receptors and RET. These are:RET and has been approved by the FDA and in 61 other countries as: CABOMETYX tablets approved for advanced RCC, both alone and in combination with OPDIVO, for previously treated HCC and, currently by the FDA, for previously treated, RAI-refractory DTC; and COMETRIQ capsules approved for progressive metastatic MTC. For these types of cancer, cabozantinib has become or is becoming an important drug in their selection of effective therapies.
The other two other products resulting from our discovery efforts are: COTELLIC, an inhibitor of MEK, approved as part of amultiple combination regimenregimens to treat specific forms of advanced melanoma and marketed under a collaboration with Genentech; and MINNEBRO, an oral, non-steroidal, selective blocker of the MRmineralocorticoid receptor, approved for the treatment of hypertension in Japan and licensed to Daiichi Sankyo. For additional information about these products, see “Business—Collaborations and Business Development Activities—Other Collaborations” in Part I, Item 1 of this Annual Report on Form 10-K.
Cabozantinib Franchise
On January 22, 2021, the FDA approved CABOMETYX in combination with OPDIVO as a first-line treatment of patients with advanced RCC. This regulatory milestone expands upon the FDA’s prior approvals of CABOMETYX as a monotherapy for previously treated patients with advanced RCC in April 2016 and then in December 2017, approximately two months ahead of the assigned PDUFA action date, the FDA expanded CABOMETYX’s approval in this indication to includefor previously untreated patients with advanced RCC.RCC in December 2017. Additionally, in January 2019, the FDA approved CABOMETYX as afor the treatment forof patients with HCC who have been previously treated with sorafenib. Thissorafenib, and most recent approval was basedrecently, on results from CELESTIAL, our phase 3 pivotal trial evaluating cabozantinib inSeptember 17, 2021, the FDA approved CABOMETYX for the treatment of adult and pediatric patients 12 years of age and older with previously treated HCC, which demonstrated a statistically significantlocally advanced or metastatic DTC that has progressed following prior VEGF receptor-targeted therapy and clinically meaningful improvement in OS versus placebo. Wewho are highly focused on optimizing the execution of this commercial launch in HCC in the U.S. through our commercial and medical affairs organizations and established distribution network.RAI-refractory or ineligible.
To develop and commercialize CABOMETYX and COMETRIQ outside the U.S., we have entered into license agreements with Ipsen and Takeda. We granted to Ipsen has been grantedthe rights to develop and commercialize cabozantinib outside of the U.S. and Japan, and to Takeda has been grantedthe rights to develop and commercialize cabozantinib in Japan. Both partnersIpsen and Takeda also contribute financially and operationally to the further global development and commercialization of the cabozantinib franchise in other potential indications, and we continue to work closely with them on these activities. Utilizing its regulatory expertise and established international oncology marketing network, since the initiation of our collaboration Ipsen has continued to execute on its
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commercialization plans most recently receivingfor CABOMETYX, having received regulatory approval fromapprovals and launched in multiple territories outside of the EC for CABOMETYXU.S., including in the EU, the U.K. and Canada, as a treatment for advanced RCC and for HCC in adults who have previously been treated with sorafenib,sorafenib. In addition, in March 2021, Ipsen and Takeda continues to conduct clinical development activitiesBMS received regulatory approval from the EC for CABOMETYX in bothcombination with OPDIVO as a first-line treatment for patients with advanced RCC, and HCC,both Ipsen and BMS plan to submit applications to approve the combination in other territories beyond the EU. Ipsen also submitted a variation application to the EMA to approve CABOMETYX as a treatment for patients with previously treated, RAI-refractory DTC, with the goalEMA validating the variation and beginning its centralized review process in August 2021. With respect to the Japanese market, Takeda received Manufacturing and Marketing Approvals in 2020 from the Japanese MHLW of supporting future regulatory filingsCABOMETYX as a treatment of patients with curatively unresectable or metastatic RCC and as a treatment of patients with unresectable HCC who progressed after cancer chemotherapy. Most recently, in Japan.August 2021, Takeda and Ono Pharmaceutical Co., Ltd. (Ono), BMS’ development and commercialization partner in Japan, received Manufacturing and Marketing Approval from the Japanese MHLW of CABOMETYX in combination with OPDIVO as a treatment for unresectable or metastatic RCC.
In addition to our regulatory and commercialization efforts in the U.S. and the support provided to our collaboration partners for rest of worldrest-of-world regulatory and commercialization activities, we are also focused on the next wave of cabozantinib’s clinical development program, pursuing other indications for cabozantinib that have the potential to expandincrease the number of cancer patients who could potentially benefit from this medicine. We are evaluatingcontinue to evaluate cabozantinib, both as a single agent and in combination with other
To expand our exploration of combinations with ICIs, we have also initiated COSMIC-312, a phase 3 pivotal trialmultiple trials evaluating cabozantinib in combination with Roche’s ICI, atezolizumab, versus sorafenib in previously untreated advanced HCC, andatezolizumab. COSMIC-021 is a broad phase 1b dose escalation study evaluating the safety and tolerability of cabozantinib in combination with atezolizumab in patients with a wide variety of locally advanced or metastatic solid tumors. The COSMIC-021 study comprises eighteen tumor expansion cohorts, including multiple therapeutic settings of RCC, UC,Based on encouraging efficacy and NSCLC and single therapeutic settings of HCC, CRPC, TNBC, EOC, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, DTC and head and neck cancer of squamous cell histology, and is currently enrolling. Findingssafety data that has emerged from the dose escalation stage oftrial, certain cohorts have been expanded, including Cohort 6 evaluating patients with mCRPC who have been previously treated with enzalutamide and/or abiraterone acetate and experienced radiographic disease progression in soft tissue and another cohort evaluating patients with NSCLC who have been previously treated with an ICI. We announced data from Cohort 6 in May 2021 and presented more detailed results from Cohort 6 at the study demonstrate thatESMO 2021 Congress in September 2021.
Although, following our discussions with the FDA, we will not pursue a regulatory submission for the combination was well-toleratedregimen in mCRPC based solely on the Cohort 6 results, data from COSMIC-021 have been instrumental in guiding our clinical development strategy for cabozantinib in combination with ICIs, including supporting the initiation of COSMIC-312, a phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC, and showed encouraging anti-tumor activitythree phase 3 pivotal trials in collaboration with Roche, CONTACT-01, CONTACT-02 and CONTACT-03, evaluating the combination of cabozantinib with atezolizumab in patients with metastatic NSCLC, mCRPC and advanced RCC. Depending on theRCC, respectively. CONTACT-01 and CONTACT-03 are sponsored by Roche and co-funded by us; CONTACT-02 is sponsored by us and co-funded by Roche. In June 2021, we announced results from COSMIC-021,COSMIC-312. The trial met one of the primary endpoints, demonstrating significant improvement in BIRC assessed PFS at the planned primary analysis, reducing the risk of disease progression or death by 37% compared with sorafenib. The interim analysis for the second primary endpoint of OS, performed at the same time as the primary analysis for PFS, did not reach statistical significance. The trial is continuing as planned to the final analysis of OS, anticipated during the first quarter of 2022, and we may also evaluateintend to submit an sNDA to the FDA for the combination regimen if supported by the final OS analysis.
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For additional information on our cabozantinib clinical trials, see “Business—Exelixis Development Programs—Cabozantinib Development Program” in Part I, Item 1 of this combinationAnnual Report on Form 10-K.
Pipeline Activities
Our small molecule discovery programs are supported by a robust and expanding infrastructure, including a library of 4.6 million compounds. We have extensive experience in various other tumor types, including NSCLC. COSMIC-021 also includes two exploratory cohorts that will evaluate cabozantinib as a single-agent therapy in NSCLCthe identification and UC indications.
We also augment our small molecule discovery activities through research collaborations and in-licensing arrangements with other companies. The most advanced compounds to emerge from these arrangements are XL102 , the lead program targeting CDK7 under our collaboration with Aurigene, and XL114, Aurigene’s novel anti-cancer compound that inhibits the CBM complex. Based on encouraging preclinical data, we have exercised our exclusive options to license each of XL102 and XL114 from Aurigene and initiated a phase 1 clinical trial evaluating XL102 in January 2021; we plan to initiate a phase 1 clinical trial for XL114 in the first half of 2022.
Beyond small molecules, we have also launched rigorous efforts to discover and advance various biotherapeutics that have the potential to become anti-cancer therapies, such as bispecific antibodies, ADCs and other innovative treatments. ADCs in particular present a unique opportunity for new cancer treatments, given their capabilities to deliver anti-cancer payload drugs to targets with increased precision while minimizing impact on healthy tissues, and have been validated by the multiple regulatory approvals for the commercial sale of ADCs in the past several years. To facilitate the growth of these programs, we have established multiple research collaborations and in-licensing arrangements and entered into other strategic transactions that provide us with access to antibodies or other binders, which are the starting point for use with additional technology platforms that we employ to generate next-generation ADCs or multispecific antibodies. We have already made significant progress under these arrangements and believe we will continue to do so in 2022 and future years. For example, based on promising preclinical data for XB002, Iconic’s lead TF-targeting ADC program, we exercised our exclusive option to license XB002 in December 2020 and initiated a phase 1 clinical trial in June 2021. We have expanded our access to antibodies through arrangements with WuXi Bio, focused on leveraging WuXi Bio’s panel of mAbs against an undisclosed target for the development of ADC, bispecific and certain other novel tumor-targeting biotherapeutics, and through the execution of an asset purchase agreement with GamaMabs, under which we will, upon the closing of the asset purchase and subject to certain conditions, acquire all rights, title and interest in GamaMabs’ antibody program directed at AMHR2. These antibodies, as well as those originating from our collaboration with Invenra, which was expanded in August 2021 to include an additional 20 oncology targets, provide starting points for the construction of ADCs through our collaborations with NBE and Catalent, utilizing their site-specific conjugation technologies and payloads. In addition, our collaboration with Adagene, focused on using Adagene’s SAFEbody technology to develop novel masked ADCs or other innovative biotherapeutics, provides potential for developing ADCs or other biotherapeutics with improved therapeutic index. As a direct result of these arrangements, we designated XB010, our first ADC advanced internally, as a development candidate in late 2021. XB010, which targets the tumor antigen 5T4, incorporates antibodies sourced from Invenra and was constructed using and Catalent’s SMARTag site-specific bioconjugation platform.
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For additional information on these early-stage trials of our small molecule and biotherapeutic product candidates, see “Business—Exelixis Development Programs—Other Development Programs - Advancing Exelixis’ Future Cancer Therapy Candidates” in Part I, Item 1 of this Annual Report on Form 10-K. For additional information on our specific research collaborations, in-licensing arrangements and other strategic transactions related to our small molecule and biotherapeutics programs, see “Business—Collaborations and Business Development Activities—Research Collaborations, In-licensing Arrangements and Other Business Development Activities” in Part I, Item 1 of this Annual Report on Form 10-K.
As of the date of this Annual Report, we are currently advancing more than 10 discovery projects.programs and expect to progress up to five new development candidates into preclinical development during 2022. In addition, we will continue to engage in business development initiatives with the goal of acquiring and in-licensing promising oncology platforms and assets and then further characterize and develop them utilizing our established preclinical and clinical development infrastructure.
COVID-19 Update
As of the date of this Annual Report on Form 10-K, the COVID-19 pandemic continues to have a modest impact on our business operations, in particular with respect to our clinical trial and commercial activities. We have and continue to undertake considerable efforts to mitigate the various problems presented by this crisis, including as described below:
Clinical Trials. To varying degrees and at different rates across our global clinical trials, we experienced declines in screening and enrollment activity during the early days of the COVID-19 pandemic, as well as delays in new site activations and restrictions on the access to treatment sites that is necessary to monitor clinical study progress and administration. However, we and our collaboration partners, including principal investigators and personnel at clinical trial sites, have been successful overall in preventing material delays to our ongoing and planned clinical trials due to the COVID-19 pandemic. We have done this through ongoing assessment of the COVID-19 pandemic’s impact, which has included staffing and materials shortages and other operational disruptions at clinical trial sites, and wherever possible, we take proactive steps in compliance with guidance issued by the FDA, EMA and other regulatory agencies to support the safety of our patients and their access to treatment, as well as to maintain the high quality of our clinical trials. We recognize, however, that we may have to make further operational adjustments to our ongoing and planned clinical trials and that patient enrollment, and new clinical trial site initiations may again be slowed due to recurring COVID-19 outbreaks and potential reintroduction of certain restrictions intended to mitigate the spread of COVID-19.
Drug Discovery and Preclinical Development. We have fully resumed drug discovery in our laboratories following a temporary suspension of these activities while we observed the shelter in place orders issued by the State of California and Alameda County. While this temporary suspension combined with interruptions in the portion of drug discovery work outsourced to third-party contractors in regions first impacted by COVID-19 caused us to experience modest delays in the advancement of certain of our early-stage programs, we continued to substantially progress our product pipeline despite the COVID-19 pandemic, including the submission of INDs for XB002, XL102 and XL114.
Commercial Activities. Despite the challenges posed by the COVID-19 pandemic, including requiring us to temporarily shift to telephonic and virtual interactions with healthcare professionals, we believe our commercial business was only modestly impacted. Our field employees have now partially resumed their in-person promotional activities while supplementing these activities with telephonic and virtual interactions and we believe they are well-positioned to execute on our commercial objectives.
Supply Chain. We have not experienced significant production delays or seen any significant impairment to our supply chain as a result of the COVID-19 pandemic. In addition, we continue to maintain sufficient safety stock inventories for our commercial drug substance and drug products. We continue to work closely with our third-party contract manufacturers, distributors, suppliers, comparator drug sourcing vendors and collaboration partners to safeguard both the timely production and delivery of our products.
General Business Operations. We have taken numerous precautions, some temporary and others still in place, to help mitigate the risk of transmission of the virus in the workplace, including: initially reducing the number of our employees working on-site at our Alameda headquarters; implementing a vaccination mandate and maintaining enhanced safety and social distancing protocols for those employees who have returned to working on-site, as well as initiating an on-site COVID-19 testing program and limiting certain non-essential business travel for our employees. While most of our employees worked remotely during much of 2020 and early 2021, our Alameda-based workforce has largely returned to working on-site at our headquarters consistent with the policies in place
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prior to the COVID-19 pandemic. As of the date of this Annual Report on Form 10-K, the COVID-19 pandemic has only had a modest impact on our productivity and has not caused significant interruptions in our general business operations. For a discussion of workplace safety measures we have taken as a result of the COVID-19 pandemic, see “Business—Environmental, Health and Safety—Workplace Safety Measures in Response to COVID-19” in Part I, Item 1 of this Annual Report on Form 10-K.
The circumstances and public health requirements surrounding the COVID-19 pandemic continue to be subject to rapid change, and we will continue to monitor new developments that could pose additional risks for us, including the spread of the Delta and Omicron variants in the U.S. and other countries and the potential emergence of other SARS-CoV-2 variants that may prove especially contagious or virulent. Despite our mitigation efforts, we may experience delays or an inability to execute on our clinical and preclinical development plans, reduced revenues or other adverse impacts to our business, which are described in more detail in “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K. We recognize that this pandemic will continue to present unique challenges for us throughout 2022, and potentially into 2023.
For additional information regarding our business, see “Business” in Part I, Item 1 of this Annual Report on Form 10-K.
During 2018,2021, we continued to execute on our commercial, development and financialbusiness objectives, generating significant revenuerevenues from operations and enabling the businessus to continue to seek to maximize the clinical and commercial potential of our CABOMETYX and our other internally discovered, commercially available products and to expand theour product pipeline. Significant business updates and financial highlights for 20182021 and subsequent to year endyear-end include:
Business Updates
•In January 2021, the FDA approved the combination of CABOMETYX and June 2018,OPDIVO as a first-line treatment of patients with advanced RCC, and we commenced the commercial launch of the combination upon such approval.
•In January 2021, we announced amendments to the protocol for COSMIC-021, theinitiation of a phase 1b1 clinical trial of cabozantinibevaluating XL102, both as a single agent and in combination with atezolizumabother anti-cancer therapies in patients with inoperable, locally advanced or metastatic solid tumors.
•In February 2021, we announced a collaboration and license agreement with Adagene to utilize Adagene’s SAFEbody technology platform to generate masked versions of mAbs from our growing preclinical pipeline for the development of ADCs or other innovative biotherapeutics.
•In February 2021, cabozantinib was the subject of multiple data presentations in forms of RCC and other genitourinary cancers at the virtual 2021 ASCO Genitourinary Cancers Symposium.
•In March 2021, we announced an exclusive license agreement with WuXi Bio for a panel of mAbs, which were discovered based on WuXi Bio’s integrated technology platforms for the development of ADC, bispecific and certain other novel tumor-targeting biotherapeutic applications.
•In March 2021, we announced a clinical trial collaboration and supply agreement with Merck KGaA and Pfizer to evaluate XL092 in combination with avelumab in patients with locally advanced or metastatic solid tumors, to add new expansion cohorts toUC as part of the trial (for an aggregate of eighteen cohorts), which now includes patients with RCC, UC, NSCLC, CRPC, HCC, TNBC, EOC, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, DTC and head and neck cancer of squamous cell histology.ongoing STELLAR-001 phase 1b dose escalation study.
•In January 2018, we entered into an exclusive collaboration and license agreement with StemSynergy for the discovery and development of novel oncology compounds aimed to inhibit tumor growth by targeting CK1α.
•In March 2021 and metastatic RCC cohorts.
•In April 2021, we announced the FDA’s acceptance of the IND for XB002 and initiated a phase 1 trial evaluating the ADC in patients with advanced solid tumors in June 2021.
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•In May 2021, we announced an asset purchase agreement with GamaMabs to acquire GamaMabs’ antibody program directed at AMHR2.
•In June 2021, cabozantinib was the subject of multiple data presentations in forms of RCC and DTC at the 2021 ASCO Annual Meeting.
•In June 2021, we filed a patent lawsuit against Teva, following receipt of two Paragraph IV certification notice letters from Teva informing us that it had filed an ANDA with the FDA requesting approval to market a generic version of CABOMETYX was basedtablets. For a more detailed discussion of this litigation matter, see “Legal Proceedings” in Part I, Item 3 of this Annual Report on Form 10-K.
•In June 2021, we announced results from CABOSUN, a randomizedthe phase 23 COSMIC-312 trial, comparingin which the combination of cabozantinib with sunitiniband atezolizumab met one of the primary endpoints, demonstrating significant improvement in PFS versus sorafenib in patients with previously untreated advanced RCC with intermediate- or poor-risk disease that demonstratedHCC at the planned primary analysis. The interim OS analysis performed at the same time as the primary analysis for PFS did not demonstrate a statistically significant benefit for the combination. Detailed results from COSMIC-312 were later presented at the ESMO Asia Virtual Oncology Week in November 2021. The trial is continuing as planned to the final analysis of OS, anticipated during the first quarter of 2022, and clinically meaningful improvement in PFS and ORR versus sunitinib.we intend to submit an sNDA to the FDA for the combination regimen if supported by the final OS analysis.
•In May 2018,August 2021, we announced that IMblaze370, Genentech’s phase 3 pivotal trial evaluating the combinationexpansion of cobimetinibour discovery and licensing collaboration with atezolizumab in patients with CRC, did not meet its primary endpoint. However, Genentech continuesInvenra to pursueinclude an additional 20 oncology targets for multispecific antibody, ADC and other biotherapeutics candidate discovery and development.
•In August 2021, Takeda and Ono received regulatory approval from the cobimetinib development program, either as a single-agent orJapanese MHLW to manufacture and market CABOMETYX in combination studies.
•In September 2018, Ipsen received regulatory approval from Health Canada2021, the FDA approved CABOMETYX for CABOMETYX as athe treatment in Canada forof adult and pediatric patients with advanced RCC who have received prior VEGF-targeted therapy. Health Canada’s approval of CABOMETYX was based on results from METEOR, our phase 3 trial in which CABOMETYX provided
•In another poster presentation, data were presented from an analysis that evaluated the effect of PD-L1 expression on clinical outcomes with cabozantinib in advanced RCC from the CABOSUN and METEOR trials. This analysis showed that cabozantinib’s activity was independent of PD-L1 expression. Additionally, a separate retrospective analysis of RCC patients found thatSeptember 2021, cabozantinib was active following prior treatment with immune checkpoint inhibitor therapy either alone orthe subject of multiple data presentations in combination with VEGF-targeted or other prior therapy.
•In October 2021, we announced an exclusive collaboration and Drug Administrationlicense agreement with STORM to discover and develop inhibitors of novel RNA modifying enzymes, including ADAR1.
•In October 2021, we and Aurigene announced that we exercised our exclusive option for CABOMETYXXL114, Aurigene’s novel anti-cancer compound that inhibits the CBM complex, resulting in our assuming responsibility for all subsequent clinical development, manufacturing and commercialization of XL114. Following the FDA’s acceptance of the IND for XL114 in October 2021, we plan to initiate a phase 1 clinical trial evaluating XL114 as a treatment for patients with advanced RCC who have received prior anti-angiogenic therapy.
•In December 2018,November 2021, we initiated COSMIC-312,announced the completion of enrollment for CONTACT-01, a phase 3 pivotal trial evaluating cabozantinib in combination with atezolizumab versus sorafenibdocetaxel in patients with previously untreated advanced HCC. We are sponsoring COSMIC-312, and Ipsen will co-fund the trial. Ipsen will have access to the results to support potential future regulatory submissions outside of the U.S. and Japan. Roche is providing atezolizumab free of charge.
•In December 2021, we announced the initiation of STELLAR-002, a phase 1b clinical trial evaluating XL092 in combination with either nivolumab, nivolumab and ipilimumab, or nivolumab and bempegaldesleukin in patients with advanced solid tumors. Previously in June 2021, we announced a clinical trial collaboration and supply agreement with BMS pursuant to which BMS is providing nivolumab, ipilimumab and bempegaldesleukin for use in the trial.
•In December 2021, we appointed Jacqueline Wright to our Board of Directors. Ms. Wright currently serves as Corporate Vice President & Chief Digital Officer, U.S. Business at Microsoft Corporation.
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•In January 2022, we appointed Vicki L. Goodman, M.D., as Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer. Dr. Goodman had previously served as Vice President, Clinical Research and Therapeutic Area Head, Late Stage Oncology at Merck & Co.
•In January 2022, we announced the completion of enrollment for CONTACT-03, a phase 3 pivotal trial evaluating the efficacy and safety of cabozantinib in combination with atezolizumab versus cabozantinib alone in patients with locally advanced or metastatic RCC who progressed during or following treatment with an ICI as the immediate preceding therapy. Based on current event rates, we anticipate announcing results of PFS and the first interim OS analysis in the second half of 2022.
•In January 2022, we announced an amendment to our exclusive option and license agreement with Iconic to acquire broad rights to use the anti-TF antibody incorporated into XB002 for any application, including conjugated to other payloads, as well as rights within oncology to a number of other anti-TF antibodies developed by Iconic, including for use in ADCs and multispecific biotherapeutics.
•In January 2022, we presented encouraging data from two early-stage studies evaluating cabozantinib in combination with ICIs in patients with previously treated HCC, which demonstrated a statistically significantCRC at the 2022 ASCO Gastrointestinal Cancers Symposium: cohort 16 from COSMIC-021, evaluating cabozantinib in combination with atezolizumab in patients with metastatic CRC who were previously treated with fluoropyrimidine-containing chemotherapy; and clinically meaningful improvementcohort 2 from CAMILLA, the phase 2 IST evaluating cabozantinib in OS versus placebo.
•In February 2022, cabozantinib will be the primary objectivesubject of determining a dose for daily oral administrationmultiple data presentations in forms of XL092 suitable for further evaluation.RCC and other genitourinary cancers at the 2022 ASCO Genitourinary Cancers Symposium.
•Net product revenues for 2018 increased to $619.32021 were $1,077.3 million,, compared to $349.0$741.6 million for 2017.
2020.•Total revenues for 2021 were $1,435.0 million, compared to $987.5 million for 2020.
•Research and development expenses for 2018 increased to $182.32021 were $693.7 million,, compared to $112.2$547.9 million for 2017.
2020.•Selling, general and administrative expenses for 2018 increased to $206.42021 were $401.7 million,, compared to $159.4$293.4 million for 2017.
2020.•Provision for income taxes for 2021 was $63.1 million, compared to $19.1 million for 2020.
•Net income for 2021 was $231.1 million, or $0.73 per share, basic and $0.72 per share, diluted, compared to $111.8 million, or $0.36 per share, basic and $0.35 per share diluted, for 2020.
•Cash and investments increased to $851.6 million$1.9 billion at December 31, 2018,2021, compared to $457.2 million$1.5 billion at December 31, 2017.
2020.See “Results of Operations” below for a discussion of the detailed components and analysis of the amounts above.
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Outlook, Challenges and Risks
We will continue to face a number of challenges and risks to our business that may impact our ability to execute on our 20192022 business objectives.objectives, and some of these risks to our business have been or may be exacerbated by the COVID-19 pandemic. In particular, we anticipate that for the foreseeable future, we expect our ability to maintain or meaningfully increase unrestrictedgenerate sufficient cash flow to fund our commercialbusiness operations and our development and discovery programsgrowth will be dependentdepend upon the continued successful commercializationcommercial success of CABOMETYX, both alone and in combination with other therapies, as a treatment for the treatment of RCC and HCC, in each case in territories wherehighly competitive indications for which it has beenis approved, and according to the terms of such regulatory approvals, and in potentialpossibly for other indications for which cabozantinib has been or is currently being evaluated in potentially label-enabling clinical trials, if warranted by the data generated from these trials. However, we cannot be certain that the clinical trials we and our collaboration partners are conducting will demonstrate adequate safety and efficacy in late-stage development, such as previously treated RAI-refractory DTC. Thethese additional indications to receive regulatory approval in the major commercial opportunity for CABOMETYX as a treatment of RCC and HCC remains subject to a variety of factors, most importantly, CABOMETYX’s perceived benefit/risk profile as compared to the benefit/risk profiles of other treatments available or currently in development for the treatment of these conditions. Our ability to maintain or meaningfully increase product revenues frommarkets where CABOMETYX is also affected by a number of other factors, includingapproved. Even if we and our collaboration partners receive the highly competitive marketsrequired regulatory approvals to market cabozantinib for whichadditional indications, we intendand our collaboration partners may not be able to pursue regulatory approval of cabozantinibcommercialize CABOMETYX effectively and successfully in these additional indications. In addition, CABOMETYX will only continue to be commercially successful if private third-party and government payers continue to provide coverage and reimbursement. However, as is the prospectcase for new competitiveall innovative pharmaceutical therapies, obtaining and generic competition, and the extent to whichmaintaining coverage and reimbursement for CABOMETYX is available from governmentbecoming increasingly difficult, both within the U.S. and other third-party payers. Obtaining and maintaining appropriate coverage and reimbursement for CABOMETYX is increasingly challenging due to, among other things, the focusin foreign markets, because of growing concerns over healthcare cost containment and other potential austerity measures being discussed incorresponding policy initiatives and activities aimed at expanding access to, and restricting the U.S. and worldwide, as well as increasing interest amongst legislators and policymakers in the U.S. in restricting drug prices through the imposition of, pharmaceutical drug price controls. Our ability to fulfill the commercial potential of cabozantinib also depends on whether data generated by our clinical development activities will support regulatory approval of cabozantinib in additional indications. pharmaceuticals.
Achievement of our 20192022 business objectives will also depend on our ability to maintain a competitive position with respect to the shifting landscape of therapeutic strategy for the treatment of cancer, which we may not be able to do. While we have had success in adapting our development strategy for the cabozantinib franchise and other product candidates to address the competitive landscape, including through evaluation of therapies that combine ICIs with other targeted agents, it is uncertain whether current and future clinical trials will lead to regulatory approvals, or whether physicians will prescribe regimens containing our products instead of competing product combinations in approved indications. Moreover, the complexities of this development strategy have required and are likely to continue to require collaboration with some of our developmentcompetitors. In the longer term, we may eventually face competition from potential manufacturers of generic versions of our marketed products, including the proposed generic versions of CABOMETYX tablets that are the subject of ANDAs submitted to the FDA by MSN and commercialization strategy formulated to navigate increased competition, including thatTeva, and the approval of either MSN’s or Teva’s ANDA could significantly decrease our revenues derived from but not limited to, ICIs, as well as the useU.S. sales of combination therapy to treat cancer. Furthermore,CABOMETYX and thereby materially harm our business, financial condition and results of operations. Separately, our research and development objectives may be impeded as we work to scaleby the challenges of scaling our organization to meet the demands of expanded drug development, unanticipated delays in clinical testing and the inherent risks and uncertainties associated with drug discovery activities.operations, all of which may be increased as a result of the COVID-19 pandemic. In connection with efforts to expand our product pipeline, we may be unsuccessful in discovering new drug candidates or we may not be able to successfully identifyidentifying appropriate candidates for in-licensing or acquisition.
Some of these challenges and risks are specific to our business, and others are common to companies in the pharmaceuticalbiopharmaceutical industry with development and commercial operations. As described under “—COVID-19 Update” above, these risks have been or may be exacerbated by the COVID-19 pandemic. For a completemore detailed discussion of challenges and risks we face, including those relating to the COVID-19 pandemic, see “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K.
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Results of Operations
We have adopted a 52- or 53-week fiscal year policy that ends on the Friday closest to December 31st. Fiscal 2021, which was a52-week fiscal year, ended December 31, 2021 and fiscal year 2020, which was a 52-week fiscal year, ended January 1, 2021. For convenience, references in this report as of and for the fiscal year ended January 1, 2021 are indicated as being as of and for the year ended December 31, 2020.
This discussion and analysis generally addresses 2021 and 2020 items and year-over-year comparisons between 2021 and 2020. Discussions of 2019 items and year-over-year comparisons between 2020 and 2019 that are not included in this Annual Report on Form 10-K can be found in “Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2020, submitted to the U.S. Securities and Exchange Commission (SEC) on February 10, 2021.
Revenues
Revenues by category were as follows (dollars in thousands):
| Year Ended December 31, | Percentage Change - 2018 v. 2017 | Percentage Change - 2017 v. 2016 | |||||||||||||||
| 2018 | 2017 | 2016 | |||||||||||||||
| Net product revenues | $ | 619,279 | $ | 349,008 | 135,375 | 77 | % | 158 | % | ||||||||
| Collaboration revenues | 234,547 | 103,469 | 56,079 | 127 | % | 85 | % | ||||||||||
| Total revenues | $ | 853,826 | $ | 452,477 | $ | 191,454 | 89 | % | 136 | % | |||||||
| Year Ended December 31, | Percent Change | ||||||||||||||||||||||||||||||||||||||||
| 2021 | 2020 | ||||||||||||||||||||||||||||||||||||||||
| Net product revenues | $ | 1,077,256 | $ | 741,550 | 45 | % | |||||||||||||||||||||||||||||||||||
| License revenues | 249,956 | 167,295 | 49 | % | |||||||||||||||||||||||||||||||||||||
| Collaboration services revenues | 107,758 | 78,693 | 37 | % | |||||||||||||||||||||||||||||||||||||
| Total revenues | $ | 1,434,970 | $ | 987,538 | 45 | % | |||||||||||||||||||||||||||||||||||
Net Product Revenues
Gross product revenues, discounts and allowances, and net product revenues were as follows (dollars in thousands):
| Year Ended December 31, | Percent Change | ||||||||||||||||||||||||||||||||||||||||
| 2021 | 2020 | ||||||||||||||||||||||||||||||||||||||||
| Gross product revenues | $ | 1,452,913 | $ | 962,591 | 51 | % | |||||||||||||||||||||||||||||||||||
| Discounts and allowances | (375,657) | (221,041) | 70 | % | |||||||||||||||||||||||||||||||||||||
| Net product revenues | $ | 1,077,256 | $ | 741,550 | 45 | % | |||||||||||||||||||||||||||||||||||
Net product revenues by product were as follows (dollars in thousands):
| Year Ended December 31, | Percentage Change - 2018 v. 2017 | Percentage Change - 2017 v. 2016 | Year Ended December 31, | Percent Change | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 2018 | 2017 | 2016 | 2021 | 2020 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CABOMETYX | $ | 599,946 | $ | 324,000 | $ | 93,481 | 85 | % | 247 | % | CABOMETYX | $ | 1,054,050 | $ | 718,687 | 47 | % | |||||||||||||||||||||||||||||||||||||||||
| COMETRIQ | 19,333 | 25,008 | 41,894 | (23 | )% | (40 | )% | COMETRIQ | 23,206 | 22,863 | 2 | % | ||||||||||||||||||||||||||||||||||||||||||||||
| Net product revenues | $ | 619,279 | $ | 349,008 | $ | 135,375 | 77 | % | 158 | % | Net product revenues | $ | 1,077,256 | $ | 741,550 | 45 | % | |||||||||||||||||||||||||||||||||||||||||