UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the fiscal year ended December 31 2020, 2022

OR

☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the transition period from to

Commission File Number 001-39756

Silverback Therapeutics, Inc.

ARS Pharmaceuticals, Inc.

(Exact name of Registrant as specified in its Charter)

Registrant’s telephone number, including area code: (206) (206) 456-2900

Securities registered pursuant to Section 12(b) of the Act:

Securities registered 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  Yes ☐    NO  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  Yes ☐    NO  No☒

Indicate by check mark whether the Registrant: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 Registrantregistrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. YES  Yes☒    NO   No ☐

Indicate by check mark whether the Registrantregistrant 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 Registrantregistrant was required to submit such files). YES  Yes☒    NO   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 an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Act:

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

Indicate by check mark whether the registrant 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. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

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

TheAs of March 17, 2023 there were 94,403,028 shares of registrant’s common stock, $0.0001 par value per share, outstanding.

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant was not publicly tradedapproximately $102.9 million as of theJune 30, 2022 (the last businesstrading day of the registrant’s most recently completed second fiscal quarter.quarter) based on the closing price of $4.24 as reported on the Nasdaq Global Market on such date. Shares of the registrant’s common stock held by executive officers, directors, and their affiliates have been excluded from this calculation. This determination of affiliate status is not necessarily a conclusive determination for other purposes.

The number of shares of Registrant’s Common Stock outstanding as of March 26, 2021 was 34,903,497.

DOCUMENTS INCORPORATED BY REFERENCE

Table of Contents

PART I

Special Note Regarding Forward-Looking Statements

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K and the information incorporated herein by reference contain (this “Annual Report”) contains forward-looking statements that involve a number of risks and uncertainties, many of which are beyond our control. Although ouruncertainties. We make such forward-looking statements reflectpursuant to the good faith judgment of our management, these statements can only be based on facts and factors currently known by us. Consequently, these forward-looking statements are inherently subject to risks and uncertainties, and actual results and outcomes may differ materially from results and outcomes discussed in the forward-looking statements as a result of various factors, including those set forth below under the caption “Risk Factors.”

Forward-looking statements include, but are not limited to, statements regarding:

forward-looking statements. In some cases, you can identify forward-looking statements by terminologywords such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “project,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends,“would,” or the negative of these termswords or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

Any forward-looking statements in this Annual Report reflect our current views with respect to future events or to our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by these forward-looking statements. Factors that may cause actual results to differ materially from current expectations include, among other things, those listed under Part I, Item 1A, “Risk Factors” of this Annual Report. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These forward-looking statements are subjectbased upon information available to a numberus as of known and unknown risks, uncertainties and assumptions described in the sectionsdate of this Annual Report on Form 10-K titled “Risk Factors”report, and “Management’s Discussionwhile we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and Analysis of Financial Condition and Results of Operations” and elsewhere in this report. We discuss many of the risks associated with the forward-lookingour statements in this Annual Report on Form 10-K in greater detail under the heading “Risk Factors.” Moreover,should not be read to indicate that we operate in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impacthave conducted an exhaustive inquiry into, or review of, all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-lookingpotentially available relevant information. These statements we may make. You should be aware that the occurrence of any of the events discussed under the caption “Risk Factors” and elsewhere in this report could substantially harm our business, results of operations and financial condition and that if any of these events occurs, the trading price of our common stock could declineare inherently uncertain and you could lose all or a part of the value of your shares of our common stock.

The cautionary statements made in this report are intended to be applicable to all related forward-looking statements wherever they may appear in this Annual Report on Form 10-K. We urge youcautioned not to unduly rely upon these statements. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report on Form 10-K. For all forward-looking statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.statements. Except as required by law, we assume no obligation to update ouror revise these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated infor any forward-looking statements, whether as a result ofreason, even if new information future events or otherwise.

This Annual Report on Form 10-K also contains estimates, projections and other information concerning our industry, our business, and the markets for our product candidates, including data regarding the estimated size of markets for oncology therapeutics and the incidence of certain medical conditions, statements that certain drugs, classes of drugs, or dosages are widely prescribedbecomes available in the United States or other markets, statements regarding the perceptions and preferencesfuture.

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SUMMARY OF RISKS ASSOCIATED WITH OUR BUSINESS

An investment in shares of patients and physicians regarding certain therapies and other prescription, prescriber and patient data, as well as data regarding market research, estimates and forecasts prepared by our management. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties, and actual events or circumstances may differ materially from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained this industry, business, market and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources.

You should read the following together with the more detailed information regarding our company, our common stock and our financial statements and notes to those statements appearing elsewhere in this report or incorporated by reference. The Securities and Exchange Commission, or SEC, allows us to “incorporate by reference” information that we file with the SEC, which means that we can disclose important information to you by referring you to those documents. The information incorporated by reference is considered to be partinvolves a high degree of this report.

Risk Factors Summary

risk. Below is a summarylist of the material factors that make an investment inmore significant risks associated with our common stock speculative or risky.business. This summary does not address all of the risks that we face. Additional discussion of the risks summarizedlisted in this risk factor summary, andas well as other risks that we face, can be found below under the heading “Risk Factors”are set forth under Part I, Item 1A, of this Annual Report and should be carefully considered, together with other information“Risk Factors” in this Annual Report before making investment decisions regarding our common stock.

Item 1. Business.

As used in this Annual Report, on Form 10-K, unless the context indicates or otherwise requires, “Silverback,“ARS,” “our company,the “company,” “we,” “us,” “our,” and “our”other similar terms refer to Silverback Therapeutics,ARS Pharmaceuticals, Inc., a Delaware corporation.corporation and its consolidated subsidiaries.

Overview

Overview

Company Summary

We are a clinical-stage biopharmaceutical company with onefocused on the development of our novel, potentially first-in-class product candidate, neffy® (previously referred to as ARS-1) for the emergency treatment of Type I allergic reactions, including anaphylaxis. neffy is a proprietary composition of epinephrine with an innovative absorption enhancer called Intravail®, which allows neffy to provide injection-like absorption of epinephrine at a low dose, in a Phase 1/1b clinical trial,small, easy-to-carry, easy-to-use, rapidly administered and reliable nasal spray.

Type I severe allergic reactions are serious and potentially life-threatening events that can occur within minutes of exposure to an allergen and require immediate treatment with epinephrine injection, the only FDA-approved medication for these reactions. While epinephrine injection devices have been shown to be highly effective, there are well published limitations that result in many patients and caregivers delaying or not administering treatment in an emergency situation. These limitations include fear of the needle, lack of portability, needle-related safety concerns, lack of reliability, and complexity of the devices. Delay in treatment can allow the allergic reaction to progress in severity leading to symptoms that seriously impact patient quality of life, to potential need for emergency services and/or hospitalizations, and to life-threatening symptoms or events.

There are approximately 25 to 40 million people in the United States who experience Type I allergic reactions. Of this group, approximately 16 million people have been diagnosed and experienced severe Type I allergic reactions that may lead to anaphylaxis, but only 3.3 million currently have an active epinephrine autoinjector prescription, and of those, only half consistently carry their prescribed autoinjector. Even if patients or caregivers carry an autoinjector, more than half either delay or do not administer the device when needed in an emergency. In aggregate, we estimate that 90% of patients prescribed an epinephrine device are focused on leveraging our proprietary ImmunoTAC technology platformnot achieving an optimal treatment outcome today.

We believe neffy’s “no needle, no injection” delivery that eliminates needle-related apprehension and injury concerns, with its small pocket size, ease of use, and high reliability would, if approved, increase prescriptions for epinephrine and make it more likely for patients and caregivers to develop systemically delivered, tissue targeted therapeutics foradminister epinephrine sooner, achieve more rapid symptom relief and prevent the treatment of cancer, chronic viral infections, and other serious diseases. Our platform enables us to strategically pair proprietary linker-payloads that modulate key disease-modifying pathways with monoclonal antibodies directed to specific disease sites. Initially, we are applying our platform to create a new class of targeted immuno-oncology agents that direct a myeloid cell activator to the tumor microenvironment (TME) in solid tumors to promote cancer cell killing. Our lead product candidate, SBT6050, is comprised of a TLR8 agonist linker-payload conjugatedallergic reaction from progressing to a HER2-directed monoclonal antibodylevel of severity that targets tumors such as certain breast, gastric and non-small cell lung cancers. SBT6050 is currently could lead to hospitalization or even death. Data from our studies of neffy in a Phase 1/1b clinical trial as a monotherapy and in combination with pembrolizumab, in patients with advanced or metastatic HER2-expressing solid tumors. In this trial, we have observed changes in pharmacodynamic markers in the first dose cohort, and we anticipate providing an update on interim data from the Phase 1 single

agent dose-escalation cohorts in the second half of 2021. SBT6290 is our second product candidate, expanding on the potential of a TLR8 agonist as a payload. SBT6290 is a TLR8 linker-payload conjugated to a monoclonal antibody that targets Nectin4, which is expressed in certain bladder, triple negative breast, head and neck, and non-small cell lung cancers. We anticipate submitting an investigational new drug application (IND)Our NDA was accepted for SBT6290review by FDA in the fourth quarter of 2021. Our third TLR8 program, SBT8230,2022 with an anticipated mid-2023 PDUFA target action date, and if our NDA is comprisedapproved, we believe neffy will be the first “no needle, no injection” marketed epinephrine product for the emergency treatment of a TLR8 linker-payload conjugatedType I allergic reactions. However, the timing for regulatory approvals is outside of our control and may be delayed and is uncertain.

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Epinephrine and Allergic Reactions Background

Type I allergic reactions are potentially life-threatening hypersensitivity reactions that can occur within minutes of exposure to an ASGR1 monoclonal antibodyallergen and need to be treated immediately to relieve symptoms and prevent further progression. Initial symptoms significantly impact patient quality of life and include difficulty breathing, bronchospasms, hypotension, presyncope, itching, hives, swelling of eyes and lips, and abdominal pain and vomiting. If not treated immediately, more severe reactions known as anaphylaxis that involve constriction of the airways, swelling of the throat, rapid heart rate, severe hypotension and other respiratory and cardiac symptoms can develop and potentially present a medical and life-threatening emergency. Immediate administration of epinephrine is under developmentcurrently the only first-line treatment for Type I allergic reactions, including anaphylaxis. The only out-of-hospital delivery option today is an intra-muscular injectable product, typically offered as prefilled syringes or auto-injector devices, such as EpiPen®, which is marketed by Viatris Inc., and generic versions of EpiPen, marketed by Teva Pharmaceuticals, Inc. These intra-muscular auto-injection devices have several limitations that result in under-utilization by patients and may lead to serious complications and hospitalizations.

These limitations include:

As a result, many of the approximately 25 to 40 million patients at risk of severe Type I allergic reactions do not receive or fill prescriptions for intra-muscular injectables. Of 3.3 million patients that do fill their prescriptions, approximately half do not carry the intra-muscular injectable products with them on a regular basis, while many of the other half delay or hesitate treatment during a severe Type I allergic reaction. This may contribute to treatment postponement, prolonging troublesome symptoms, reducing quality of life and increasing the risk of complications or even death. In addition to the 3.3 million patients who currently fill their prescriptions for an epinephrine injectable device, we estimate that approximately 2.5 million patients received a prescription in the last 3 years, but either did not fill or renew it. We believe the advantages of neffy will be attractive to this group and lead to an increase in the number of patients filling their prescription as further described below. These patients are additive to the 3.3 million patients that do fill a prescription per year.

Notwithstanding their widespread lack of use, we estimate that net sales of intra-muscular injectable products approved for outpatient use in the United States was approximately $1 billion in 2021 among the approximately 3.3 million patients who filled a prescription.

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Our Approach

neffyTM is an investigational drug currently in clinical trials for the emergency treatment of chronic hepatitis B virus infection (cHBV). We are also developing agents that localize therapies to modulate important pathways in additional oncology and fibrosis indications using TLR8 andallergic reactions (type I) including anaphylaxis. neffyTM is not approved by the FDA, EMA or other linker-payloads.health authorities.

Our ImmunoTAC Platform

Our ImmunoTAC platform is the result of a focused effort to discover ways to systemically deliver disease-modifying small molecules in a directed fashion to sites of disease. Many potentially promising systemic therapies fail to maximize their therapeutic potential due to toxicities in healthy tissues. Our approach7

neffy is designed to increaseaddress the therapeutic windowshortcomings of intra-muscular injectable devices. neffy is a convenient “no needle, no injection,” solution designed to be easier to carry, more reliable and avert unacceptable toxicities by directly targeting specific disease sites where our therapeutics are locally active.easier to administer, without the aversion, safety concerns and fear and pain of needles associated with intra-muscular injectables. Based on the factors set forth below, we believe that neffy can transform the paradigm of epinephrine delivery from cumbersome, unreliable, intra-muscular injectable devices to an intranasal delivery method that makes patients more likely to administer epinephrine sooner, thus achieving more rapid symptom relief and preventing symptoms from becoming serious or life-threatening.

As shown8

Our Management Team, Financing History and Investors

We were created to innovate, develop and commercialize neffy, a novel, potentially first-in-class treatment that addresses Type I allergy patients’ desire and need for a no needle, no injection, easy-to-use, portable and reliable solution for delivering epinephrine. To achieve this goal, we have assembled a management team with extensive experience in the figure below,development and commercialization of drugs, such as recently approved nasal sprays NARCAN (naloxone nasal spray) and VALTOCO (diazepam nasal spray).

Our company was founded by Richard Lowenthal, M.S., MSEL, Robert Bell, Ph.D. and Sarina Tanimoto, M.D., M.B.A. Pratik Shah, Ph.D. was our ImmunoTAC platformfirst external investor.

Mr. Lowenthal, our Co-Founder and Chief Executive Officer, has more than 25 years of biotechnology and pharmaceutical development experience including leading the regulatory approvals of VALTOCO (diazepam nasal spray) and NARCAN (naloxone nasal spray). Dr. Bell, our Co-Founder and Chief Scientific Officer, has more than 25 years of product development experience including leading R&D at Barr Laboratories, Somerset Pharmaceuticals and UDL Laboratories. Dr. Tanimoto, our Co-Founder and Chief Medical Officer, has more than 20 years of pharmaceutical experience in clinical drug development including supporting the approval of multiple nasal spray products such as VALTOCO and NARCAN. Dr. Shah, our Chairman, has more than 30 years of experience founding and leading biopharmaceutical companies and healthcare investment decisions including his role as Executive Chairman of Design Therapeutics, former Chairman of Synthorx (now part of Sanofi) and former Chief Executive Officer of Auspex Pharmaceuticals (now part of Teva Pharmaceuticals).

Our commercial team is comprisedled by Eric Karas, Chief Commercial Officer, who has more than 25 years of three components:sales, marketing, market access and strategic planning experience across multiple specialty products, including leading commercial initiatives for NARCAN® nasal spray at Emergent BioSolutions and Adapt Pharmaceutical (now part of Emergent BioSolutions). Harris Kaplan, Executive Vice President, Commercial Strategy has been involved in the development and launch of 125 new products totaling more than $300 billion in peak revenues, and Dan Relovsky, Senior Vice President of Marketing, has extensive and relevant launch experience across a number of therapeutic categories.

The other key members of the ARS team bring extensive finance, business development and commercial operations experience and include Kathleen Scott, Chief Financial Officer; Justin Chakma, Chief Business Officer; Brian Dorsey, Chief Operating Officer and Alex Fitzpatrick, Chief Legal Officer.

Since our inception, we have raised over $360 million in proceeds, including equity financing from a syndicate of leading life sciences investors that include, among others, RA Capital, SR One and Deerfield, from our licensing and collaboration agreements and from our reverse merger with Silverback Therapeutics, Inc. We have builtentered into licensing and collaboration agreements for neffy with Alfresa Pharma for Japanese rights, and Pediatrix Therapeutics (founded by F-Prime Capital, Eight Roads and Creacion Ventures) for Chinese rights. We previously entered into a library of proprietary small molecule linker-payloadslicensing and antigen binding domains that allows us to mixcollaboration agreement with Recordati for development and match these components to strategically pair and create new therapeutic agents.

Our ImmunoTAC Platform Strategically Pairs Antigen Binding Domains with Linker-Payloads to Modulate Pathways Underlying Difficult-to-Treat Diseases

Our Development Pipeline

Our ImmunoTAC platform drives our development pipeline of tissue targeted therapeutic candidates as summarizedcommercialization rights in the chart below:European Union (“EU”), Iceland, Liechtenstein, Norway, Switzerland, the United Kingdom, Russia/CIS, Turkey, the Middle East and French-speaking African countries. In the first quarter of 2023, we entered into an agreement with Recordati to terminate our prior agreement with it and reacquire Recordati’s rights to develop and commercialize neffy.

Our Pipeline: Suite of neffy Programs

SBT6050

Our lead product candidate, SBT6050,We are focused on advancing neffy through regulatory approvals for the emergency treatment of Type I allergic reactions, including anaphylaxis, and commercialization. neffy is comprisedan intranasal composition of a TLR8 agonist linker-payload conjugated to a HER2-directed monoclonal antibody andepinephrine that is designed to activate myeloid cellsaddress the limitations of epinephrine intra-muscular injectable products that are available on the market today.

We submitted our NDA for the 2.0 mg neffy dose for adults and children greater than 30 kg in tumors expressing moderateweight to high levels of HER2. TLR8 is expressed in myeloid cell types prevalent in human tumors and TLR8 agonism can activate a broad spectrum of anti-tumor immune mechanisms. Therefore, we believe that TLR8 is the optimal target for activating human myeloid cell typesFDA in the TME.

Myeloid cells are a classthird quarter of innate immune cells that develop from common monocyte-dendritic cell progenitor cells and are comprised of both immunosuppressive and pro-inflammatory subpopulations. Tumors are permeated with myeloid cells, which can comprise between 5% and 10% of the tumor. Activation of myeloid cells, either2022. Our NDA was accepted for review by reprogramming immunosuppressive myeloid cells towards a more pro-inflammatory phenotype or stimulating other myeloid cells that have been silenced (e.g., dendritic cells), results in direct tumor killing and recruitment of immune cells. Further, activated myeloid cells can prime and amplify T cell and natural killer (NK) cell responses, bridging the innate and adaptive immunity to elicit broad, durable anti-tumor responses.

SBT6050 utilizes HER2 to localize and facilitate the delivery of the TLR8 agonist conjugate into myeloid cells in the TME. Therefore, unlike HER2 targeted therapies that have been approved by the U.S. Food and Drug Administration (FDA) such as Herceptin (trastuzumab), SBT6050 does not require HER2 to be an oncogenic driver to elicit anti-tumor activity. Furthermore, SBT6050 recognizes the HER2 sub-domain II, the pertuzumab epitope, and does not cross-block trastuzumab, allowing for potential combinations with trastuzumab-based agents, which are standard of care therapies in some HER2-expressing cancers.

We are currently evaluating the safety and tolerability of SBT6050 in a Phase 1 dose-escalation trial in patients with advanced or metastatic HER2-expressing solid tumors. Changes in pharmacodynamic markers have been observed in the first dose-escalation cohort of this trial. We anticipate providing an update on interim data from the Phase 1 single agent dose-escalation cohorts in the second half of 2021.

SBT6290

SBT6290 is our second product candidate, expanding on the potential of a TLR8 agonist as a payload. The same TLR8 linker-payload used in SBT6050 is conjugated to a monoclonal antibody that targets Nectin4. Nectin4 is expressed in subsets of solid tumors including bladder, triple negative breast, head and neck, and non-small cell lung cancers, and has been clinically validated through the approval of the antibody-drug conjugate enfortumab vedotin (Padcev). We anticipate submitting the IND for SBT6290FDA in the fourth quarter of 2021.

SBT8230

SBT8230,2022 with an ASGR1-TLR8 ImmunoTAC therapeutic, isanticipated mid-2023 PDUFA target action date. In the EU, our third TLR8 program. SBT8230 is engineered to potently activate human myeloid cells in the liverMAA for the treatment of cHBV. Selgantolimod (GS-9688), an existing untargeted, orally administered TLR8 agonist being developed2.0 mg neffy dose for subjects greater than 30 kg in weight was filed and validated for review by Gilead Sciences, generated anti-viral immune responses in a cHBV animal model. The clinical development of this untargeted TLR8 agonist has shown promise, but we believe that toxicity prevented the use of a sufficient dose to elicit optimal clinical activity. We believe liver- localized TLR8 agonism could better realize the potential for effective therapy and potentially lead to functional cures, which is defined as sustained loss of hepatitis B surface antigen (HBsAg) in the blood, in patients suffering from cHBV. We selected a development candidate for this programEMA in the fourth quarter of 2020,2022. We have also entered into partnerships for the development and commercialization of neffy in regions outside of the U.S., including our partnerships with Alfresa Pharma in Japan and Pediatrix Therapeutics in China to develop and commercialize neffy in those countries.

Furthermore, we also plan to pursue additional expansion in our pediatric labeling with neffy and are conducting a single-arm pharmacokinetic study in subjects 4 to 18 years of age. The interim pediatric data including subjects greater than 30 kg in weight is included in our initial NDA. We plan to submit a supplemental NDA (“sNDA”) for neffy for children weighing 15 to 30 kilograms to the FDA in 2023. We also plan to submit a post-approval variation to EMA for 1.0 mg neffy following the potential approval of our MAA for the 2.0 mg neffy dose.

In addition, we believe neffy may be able to target other conditions in addition to Type I allergic reactions, and we anticipate initiating IND-enabling tox studieshave identified additional indications for further examination and potential future development.

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Our Strategy

Our strategy is focused on developing and commercializing neffy as a potentially first-in-class approved intranasal treatment for the approximately 16 million patients in the United States who have been diagnosed and experienced severe Type I allergic reactions and are at risk of anaphylaxis, in geographic regions outside of the United States and for other allergy indications. Key elements of our strategy include:

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Overview of Type I Allergic Reactions and Current Challenges

Overview of Type I Allergic Reactions

The immune system plays an important role in monitoring and protecting the body against microbial threats. However, this system can lead to overstated immune and inflammatory responses that results in adverse outcomes known as hypersensitivity reactions. Type I allergic reactions are potentially life-threatening hypersensitivity reactions that can occur within minutes following exposure to an allergen and need to be treated immediately to relieve troublesome symptoms, mitigate severity and avoid a potentially fatal event. These severe reactions are caused by exposure to a specific allergen, typically foods (most commonly, nuts, eggs, shellfish), drugs and venoms and are mediated by immunoglobulin E IgE antibodies that bind to mast cells causing the release of histamines. The histamines induce smooth muscle contraction in the airways and a wheal and flare response in the skin producing swelling and inflammation. At the same time, widespread activation of mast cells leads to systemic effects of circulatory shock, hypotension or vascular collapse, and in the most severe cases respiratory arrest and death. The severity of a Type I allergic reaction is a function of the speed of onset and the number of organ systems affected by the reaction. As such, early intervention within minutes is critical in order to provide symptom relief and to prevent severe allergic reactions, known as anaphylaxis.

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Table 1: Symptoms of Type I Allergic Reactions including Anaphylaxis

* Reprinted with permission from Dr. Pete Smith (Medical Media Kits) and Mary Johnson

Role of Epinephrine in Treating Type I Allergic Reactions

Epinephrine intra-muscular injectables are the only current out-of-hospital treatment for severe Type I allergic reactions and are recommended to be prescribed to all patients who have experienced a severe Type I allergic reaction and have either experienced anaphylaxis or are at risk of anaphylaxis. When properly used, these devices can allow for the early administration of epinephrine to stop or reduce the intensity of the systemic allergic reaction before refractory anaphylaxis develops. Even a few minutes delay in the administration of epinephrine can lead to the need for emergency services and/or hospitalizations, comorbidities and life-threatening symptoms or events, while also prolonging the significant negative impact on patient quality of life by delaying symptom relief.

EpiPen epinephrine autoinjector was first approved by the FDA for the emergency treatment of Type I hypersensitivity reactions, including anaphylaxis, in December 1987. Other FDA-approved epinephrine intra-muscular injection products include Twinject® approved in May 2003, Adrenaclick® approved in November 2009, and Auvi-Q® approved in August 2012. In June 2017, the FDA approved Symjepi™ epinephrine injection, which is a pre-filled syringe for the same indication. These injection devices were approved by the FDA without pharmacokinetic data based on an assumption that injections and devices were all effectively the same as the reference listed drug of intra-muscular injection with a needle and syringe. Intra-muscular injection with a needle and syringe is considered the gold standard, and is almost exclusively used in non-community use clinical settings. Although there are no known differences in efficacy or time to observed effect in clinical practice between these devices, current data indicates that different devices deliver an intra-muscular dose of epinephrine with a range of PKs. A single dose with either an intra-muscular injection with needle and syringe or an auto-injector device results in resolution of allergic reaction for approximately 90% of cases within 5 to 15 minutes.

Epinephrine works due to its agonistic effects on the body’s adrenergic receptors (alpha and beta receptors). By activating alpha-1 receptors, epinephrine prevents and relieves airway edema, hypotension and shock. By activating beta-1 receptors, epinephrine increases the rate and force of cardiac contractions. Lastly, epinephrine’s effect on beta-2 receptors leads to bronchodilation and decreased allergy causing mediator release by mast cells.

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Treatment guidelines recommend that epinephrine be administered immediately at the first sign of a severe allergic reaction.Epinephrine is the only medication that can reverse severe allergic reactions and reduce hospitalization and death. Early administration of epinephrine is associated with better outcomes and decreased likelihood of hospitalizations. The sooner epinephrine is administered following allergen exposure, the less severe the systemic allergic reaction may become, and the less likely it will develop into an anaphylaxis event. A short delay of even a few minutes in the recognition and treatment of anaphylaxis can lead to more serious symptoms, including potential hypoxia or death. Additionally, accompanying symptoms of even non-life-threatening allergic reactions can adversely impact health-related quality of life and can lead to loss of productivity, negatively impact social life, as well as lead to depression and anxiety and feelings of fear, frustration, worry and lack of control. A second dose of epinephrine is required for adequate treatment in about 10% of cases, irrespective of whether epinephrine was dosed using an auto-injector such as EpiPen or needle and syringe.

While antihistamines such as diphenhydramine, also known as Benadryl® (marketed by Johnson & Johnson), can sometimes relieve the dermatological symptoms and pruritus associated with severe Type I allergic reactions, treatment guidelines state that antihistamines should never be administered instead of epinephrine because they do not reverse the cardiovascular symptoms such as hypotension and shock, or respiratory distress. Instead, antihistamines can potentially mask symptoms and allow the disease to continue to progress silently.

In the United States, dosing recommendations for epinephrine use by intra-muscular injection are from 0.1 mg to 0.5 mg depending on weight with repeat dosing administered as needed to control a severe allergic reaction. 0.1 mg, 0.15 mg and 0.3 mg are the approved doses for the epinephrine auto-injectors. Approximately 80% of epinephrine auto-injectors prescribed in the United States for outpatient use are the 0.3 mg dose level for persons greater than 30 kg in weight, approximately 15% contain doses of 0.15 mg for persons between 15 to 30 kg and less than 5% contain 0.1 mg doses for persons less than 15 kg. A low dose of epinephrine is important for safety as overexposure to epinephrine can lead to adverse events.

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Limitations of Existing Epinephrine Products

* Reprinted from RECAPEM (image described in the public-domain and freely available).

Epinephrine intra-muscular injectables have been proven to be highly effective if they are administered timely and effectively, and work as intended, but the limitations of these products include painful application, inconvenient size and a complicated mechanism of administration. These limitations discourage patients and caregivers from carrying these devices and administering epinephrine in a timely manner. Both uptake and use of intra-muscular injection devices has been limited among eligible patients with severe Type I allergic reactions at risk of anaphylaxis. Of the approximately 16 million people in the United States who have been diagnosed and experienced Type I severe allergic reactions, only 3.3 million currently have an active and filled epinephrine autoinjector prescription.

In studies published in peer-reviewed journals, only 23% to 48% of patients self-administered with an auto-injector during a severe Type I allergic reaction, likely due to less than half of patients actually carrying their prescribed injection device, and only half administering even if the device was available. Across our market research studies, approximately 40% to 60% of patients reported using an antihistamine first, which is not known to be effective, and if carrying an intra-muscular injectable, waited an average of 8 to 18 minutes to administer the device. The principal device-related reasons for delay were presence of a needle, concern about serious cardiac side effects, and potential pain. Patients, and particularly parents who administer to their child, perceive injection to be traumatic, which leads to a fear and avoidance of administering timely treatment. Further, the potentially life-threatening nature of a severe Type I allergic reaction is often accompanied with psychological stress and panic which can lead to delays or errors in proper intra-muscular injection, which can result in hospitalization or even death. In a meta-analysis of 32 studies evaluating epinephrine injectable administration techniques, 23% to 35% of participants failed to achieve the correct administration technique following training.

Further, there is variability in respect to whether auto-injector devices are able to reliably deliver a sufficient dose of epinephrine. The FDA has reported that EpiPen device failures lead to multiple deaths and dozens of hospitalizations annually.

The injection needle can be painful and dangerous not just due to the risk of skin lacerations and the possibility of the needle hitting a patient’s bone during administration, but also the risk of serious, sudden cardiovascular events resulting from accidental blood vessel injection. In our clinical studies, we observed instances of potential accidental blood vessel injection in approximately 14% of patients dosing themselves with EpiPen.

In comparison, neffy is perceived by patients and parents as a potentially “game changing” device that, if approved, could improve the management of severe Type I allergic reactions by addressing the current limitations of epinephrine intra-muscular injectable devices.

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Clinical Development of neffy

neffy is designed to provide injection-like absorption of epinephrine at a 1.0 or 2.0 mg dose comparable to 0.3 mg injection, in a small, easy-to-carry, easy-to-use, rapidly administered and reliable nasal spray. Based on our development work to date, we believe neffy’s “no needle, no injection” clinical profile supports differentiation over intra-muscular injections for the emergency treatment of Type I allergic reactions, including anaphylaxis.

We submitted our NDA to the FDA in the third quarter of 2022 and submittingbased on a rigorous clinical development program agreed upon during pre-NDA meeting discussion with the INDFDA in mid-2021. Our NDA was accepted for review by FDA in the second halffourth quarter of 2022.2022 with an anticipated mid-2023 PDUFA target action date. The FDA reference listed drug is intra-muscular needle-in-syringe injection products but there are several approved epinephrine intra-muscular injection products, including intra-muscular auto-injectors such as EpiPen, that establish a range of exposures that have indistinguishable efficacy, time to observed clinical effect and safety.

Additional Immuno-Oncology ProgramsDuring our pre-NDA meeting in mid-2021, FDA agreed that bracketing based on the primary parameters of Cmax, tmax and early partial AUCs from the range of PKs observed in listed epinephrine injection products was the best approach to ensure efficacy and safety, while bracketing by AUC0-t was considered an important parameter to ensure safety. PD measures of epinephrine activity such as systolic blood pressure and pulse rate were agreed to be supportive, and to be not meaningfully lower than injection. FDA also agreed that successfully demonstrating that neffy met these criteria in three primary studies described below would be sufficient to serve as a basis for our registration program for adults. Furthermore, FDA also agreed that a single study in pediatric subjects also described below would be sufficient to support our pediatric labeling.

We have completed three registrational clinical trials in adults using our 2.0 neffy dose for which we submitted our NDA to the FDA in the third quarter of 2022. The adult registrational program using the 2.0 mg neffy was intended to generate bioavailability, PDs and safety data in three primary studies: (i) during single and repeat dosing in healthy subjects (EPI-15), (ii) during self-administration by subjects with severe Type I allergies (EPI-17), and (iii) during rhinitis induced by a nasal challenge with an allergen (EPI-16). EPI-15 was conducted in the United States on behalf of ARS Pharma by WCCT Global, Inc., a third-party contract research organization, and selected for 59 healthy male or female volunteers between the ages of 18 to 55 years. EPI-16 was conducted in the United States on behalf of ARS Pharma by Altasciences Clinical Los Angeles, Inc., a third-party contract research organization, and selected 36 male or female volunteers between the ages of 18 to 55 years with a positive history of seasonal allergic rhinitis related to tree or grass allergens as demonstrated by skin prick test and nasal allergen challenge at screening. EPI-17 was conducted in the United States on behalf of ARS Pharma by Novum Pharmaceutical Research Services, a third party contract research organization, and selected 45 male or female volunteers between the ages of 18 to 55 years who had an ongoing history of Type I allergies. To support our proposed pediatric labeling, we are also conducting a single-arm pharmacokinetic study in subjects 4 to 18 years of age with either 1.0 mg or 2.0 mg of neffy depending on the subject’s weight (EPI-10). EPI-10 is being conducted in the United States by ARS Pharma and selected 42 male or female subjects between the ages of 4 and 18 years who have Type I allergies that required that the subject or caregiver been prescribed an epinephrine product. The interim results of this study from 57 subjects including 16 subjects dosed with 2.0 mg neffy were included in our initial NDA that was accepted for review by FDA in the fourth quarter of 2022.

In addition, we have completed two proof of concept clinical studies that evaluated the bioavailability of our 2.0 mg neffy dose. These two earlier-stage studies were conducted in the United States on behalf of ARS Pharma by WCCT Global, Inc. and Altasciences Clinical Los Angeles, Inc, respectively, and selected a total of 26 healthy male or female volunteers between the ages of 18 to SBT605055 years, and SBT6290, we42 male or female volunteers between the ages of 18 to 55 years who had an ongoing history of type I allergies.

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2.0 mg neffy is intended to be the dose that is comparable to approved 0.3 mg epinephrine intra-muscular injection products for persons greater than 30 kg in weight, which represents approximately 80% of the prescriptions in the United States. 1.0 mg neffy is intended to be the dose for persons 15 to 30 kg in weight. Our NDA for the 2.0 mg dose of neffy for adults and children 30 kg and greater in weight was accepted for review by FDA in the fourth quarter of 2022 with an anticipated mid-2023 PDUFA target action date. We plan to submit a supplemental NDA for the 1.0 mg dose of neffy in 2023 for subjects 15 to 30 kg in weight.

In our clinical studies in both adults and children, 2.0 mg neffy gave comparable epinephrine exposures that were within the range of approved intra-muscular injection products (needle-in-syringe products and EpiPen) on key pharmacokinetic parameters (Cmax, tmax, early partial AUCs, AUC0-t). The integrated data analysis summarizing the key outcomes for registration are evaluating other solid tumor targetsshown below.

The hemodynamic response, measured by systolic blood pressure and heart rate, after administration of neffy was comparable to leveragesome injection products including EpiPen, and was greater than 0.3 mg intra-muscular needle-with-syringe. These hemodynamic responses were within normal physiologic ranges that are typically experienced during exercise or climbing stairs.

Across all the TLR8 linker-payload pairedclinical trials, a total of more than 600 subjects have been exposed to neffy. All doses of neffy ranging from 0.5 mg to 2.0 mg single doses, as well as repeat doses up to 4 mg within 10 minutes, were well-tolerated by patients. There is no meaningful pain upon administration of neffy with additional tumor directed antibodies. These targets are differentially expressedaverage scores of 5 to 8 as assessed on tumors compareda 100 mm visual analogue scale, across studies. There was no irritation observed based on formal scoring in all studies. There were no serious treatment-related adverse events, and adverse events reported have generally not resulted in side effects more severe than grade 1, and were comparable to normal tissue.injection products. Since neffy is given without needle, there was also no needle-related injuries or accidental blood vessel injections.

ASGR1-TGFß Receptor Antagonist—Fibrosis ProgramIn contrast, for patients self-administering devices, which involved 132 subjects dosed for each of EpiPen and Symjepi, approximately 14% of subjects dosed with EpiPen (auto-injector) and 2% of subjects dosed with Symjepi (pre-filled needle-in-syringe) experienced a potential blood vessel injection leading to a rapid bolus dose of epinephrine, which could lead to serious side effects including cardiovascular events and cerebral hemorrhage according to the FDA EpiPen label. No subjects dosed with neffy experienced a blood vessel injection since it is not possible via the nasal route of administration.

TGFß signaling is a key mediatorFurthermore, our registrational self-administration study of fibrosis2.0 mg neffy by adults with severe Type I allergies (EPI-17) showed no critical dosing errors with neffy as evaluated by human factors professionals. Furthermore, neffy also showed zero dosing errors in two human factor validation studies involving 150 subjects when used by trained adults or trained children across multiple organ systems, including the liver. In the liver, TGFß drives fibrosis initiation and progression through multiple mechanisms, including hepatocyte apoptosis, hepatic stellate cell transdifferentiation to myofibroblasts, and pro-fibrotic macrophage activation. Our ASGR1-TGFßR1 antagonist conjugate pairs the ASGR1 antibodydemographic groups, as well as when used by passers-byers with no prior experience or training with an epinephrine device.

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Key features of neffy demonstrated in SBT8230 with a proprietary TGFßR1 antagonist to achieve liver-localized inhibition of TGFß signaling to treat fibrosis. Our tissue-directed approach has been designed to prevent toxicities associated with untargeted systemically distributed TGFßR1 antagonist agents. Our ASGR1-TGFßR1 antagonist conjugates are currently in preclinical testing and have demonstrated potent inhibition of TGFß signaling in vitro. We are currently evaluating conjugates in vivo in mouse disease models.our clinical, human factors or stability studies include:

Our Strategy

Our goal is to transform the treatment of cancer and other serious diseases with unmet need using our ImmunoTAC platform to deliver a new class of systemically delivered, tissue-directed, and locally active therapies. The key elements of our business strategy are to:

Planned Clinical Trials in Additional Indications

Epinephrine has been used empirically by physicians and included in treatment guidelines for multiple allergy conditions that do not fall under the emergency treatment of Type I allergic reactions indication that epinephrine auto-injectors are labelled for. The needle-free, portable, easy-to-use and potentially safer clinical profile of neffy supported by pharmacokinetic and pharmacodynamic data could enable the broader adoption of epinephrine in the outpatient setting for these other indications. We are conducting proof of concept studies evaluating neffy in additional allergy indications where neffy could potentially be used multiple times a year to treat acute episodes.

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Development outside the United States

In Europe, our MAA was filed and validated for review by EMA in the fourth quarter of 2022.In the Day 120 comments, we received during EMA’s review of our prior 1.0 mg dose neffy MAA submission, EMA required a preclinical dog anaphylaxis study, which we completed with data showing no meaningful differences in epinephrine absorption of neffy in dogs in a normal state or an anaphylactic state. In April 2022, we voluntarily withdrew our 1.0 mg neffy MAA submission to re-submit a 2.0 mg neffy MAA submission and allow EMA to review both our 2.0 mg neffy and preclinical dog anaphylaxis study results.

We are also pursuing pediatric approval of neffy in Europe based on the same US pediatric study. We plan to submit a post-approval variation to EMA for the 1.0 mg neffy following the potential approval of the 2.0 mg neffy dose.

Our partners in Japan and China expect that they will file for regulatory approval in their respective regions at end of 2023 or early 2024 following our anticipated FDA approval of neffy.

Commercialization Opportunity and Commercialization Plan

Type I Allergy Market Overview

neffy is a needle-free, low-dose intranasal epinephrine nasal spray in clinical development for use as a rescue medication for people with Type I severe allergic reactions including anaphylaxis. neffy was designed to provide injection-like absorption of epinephrine, in a small, easy-to-carry, easy-to-use, rapidly administered, and reliable nasal spray device.

All systemic allergic reactions have the potential of progressing to anaphylaxis and becoming life-threatening. These reactions can be unpredictable and progress quickly to develop severe symptoms within a few minutes after exposure and can progress to a life-threatening event if not treated immediately. Patient and caregiver preparedness to act quickly and confidently during a severe allergic reaction is imperative. Hesitation can lead to worse clinical outcomes and can be fatal.

Epinephrine is the first-line treatment for the emergency treatment of Type I allergic reactions including anaphylaxis. Epinephrine needs to be given as soon as symptoms occur because it is the only medication proven to stop a potentially life-threatening allergic reaction.

Needle-free and easy-to-use neffy may allow for improved patient and caregiver preparedness to give epinephrine quickly, confidently, and without hesitation that is caused by fear of the needle. Intended for use at the first signs of an allergic response, neffy is designed to provide patients and their families with a new option to rapidly resolve symptoms and prevent progression to severe anaphylaxis.

If approved for use, we believe our first-in-class nasal spray may transform the way we think about and use life-saving epinephrine.

Existing US Market Opportunity

We estimate approximately 25 to 40 million people in the United States have experienced Type I allergic reactions. Of this group, approximately 16 million people have been diagnosed and experienced severe Type I allergic reactions that may lead to anaphylaxis, but only about 3.3 million of them filled a prescription in 2021 for an epinephrine intra-muscular injectable device, including auto-injectors, equating to approximately 10 million devices.

Of those 3.3 million people, roughly half don’t carry these devices due to many drawbacks that can result in patient and caregiver injury, hesitation, and delays in administration principally because of apprehension and pain of needles. In turn, the failure or delay of epinephrine delivery can allow the allergic reaction to progress in severity causing life-threatening symptoms or events that potentially require emergency services and/or hospitalization.

We believe neffy could address the needs of not only the approximately 3.3 million patients in the United States who currently fill intra-muscular injectable prescriptions, but also the more than 22 million eligible Type I allergy patients in the United States who are at risk of severe allergic reactions that are not prescribed or do not fill their epinephrine prescriptions, including approximately 2.5 million former injectable patients in the United States in the last three years that either refused to fill, or did not renew an intramuscular injectable device prescription.

Based on market access research and data from IQVIA, we estimate that 2021 U.S. net sales for intra-muscular injectable devices were approximately $1 billion. Approximately 80% of the epinephrine intra-muscular injectables sold in the United States in 2021 were for the 0.3 mg dose for adults and children greater than 30 kg in weight.

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We have conducted multiple market research studies with caregivers, generally parents, and patients with severe Type I allergic reactions in the United States to evaluate potential market perceptions of neffy and currently available epinephrine delivery devices. Based on two independent quantitative market research studies including a total of 350 patients and 75 allergists, pediatricians and primary care physicians, approximately 80% of patients with a current epinephrine auto-injector prescription stated that they would prefer neffy. Furthermore, 100% of the physicians surveyed stated they would prescribe if their patient asked for neffy, indicating that neffy prescriptions would likely be highly driven by patient preference and awareness of neffy.

In our market research, parents and people with current or prior epinephrine auto-injector prescriptions were asked if and when they would adopt a new nasal spray device product such as neffy.

These data suggest thatneffy has the potential to be rapidly adopted by most of the approximately 3.3 million patients in the United States today who fill their epinephrine auto-injector prescription, if approved. These patients serve as our base estimate for the current epinephrine market for neffy.

Key potential growth levers for neffy within the existing epinephrine market for the emergency treatment of Type I allergic reactions, which currently consists of only intra-muscular injectable products include:

Our Team

We have assembled an accomplished management team

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US Market Expansion Opportunity

While we believe the existing epinephrine intra-muscular injectables market is a large commercial opportunity for neffy with a proven track record of therapeutic development expertise and of generating meaningful shareholder value. The members of our team have deep experience in discovering, developing, and commercializing therapeutics with a particular focus on cancer, having worked at companies such as Synthorx (acquired by Sanofi), Juno Therapeutics (acquired by Celgene), Cascadian Therapeutics (acquired by Seagen (formerly Seattle Genetics)), Acerta Pharma (acquired by AstraZeneca), Ignyta (acquired by Roche), Roche/Genentech, Seagen (formerly Seattle Genetics), SUGEN (acquired by Pharmacia), and Trubion Pharmaceuticals (acquired by Emergent Biosolutions).

Lead Product Candidate SBT6050: TLR8 Agonist Conjugated to a HER2 Antibody

SBT6050 is our lead product candidate, engineered using our ImmunoTAC platform. SBT6050 is comprised of a TLR8 agonist conjugated to a HER2-directed monoclonal antibody and is designedmultiple independent opportunities for subcutaneous delivery with tumor-localized activation of myeloid cells.

Background and Our Approach in Addressing Limitations with Current Immuno-oncology Therapies

Checkpoint inhibitors (CPIs) such as a programmed death receptor-1 (PD-1) and CTLA-4 blockers have emerged as important foundational immuno-oncology therapies because of their ability to generate durable responses in some patients, in previously intractable cancers and to improve the overall survival. Despite the significant benefit for patients with durable responses to CPIs, most patients unfortunately do not respond or have limited benefit. One of the important reasons whyfurther growth, IQVIA claims data indicates that many diagnosed, identifiable eligible patients do not respond to CPIs is the absence of a sufficient number of T cells within the tumor. To achieve an anti-tumor response with a CPI, a baseline level of T cells must already be present in the tumor. Scientists and clinicians have termed tumors that lack the requisite T cell levels as “immune cell deserts” or “cold tumors,” but more accurately these are “T cell deserts.”

Solid tumors, including those resistant to T cell targeted immunotherapy, such as PD-1 and CTLA-4 blockers, are permeated with myeloid cells, which can comprise between 5% and 10%receive prescriptions for intra-muscular injectables. Outside of the tumor—at least twicefive million patients who were recently prescribed an epinephrine injectable device, there are approximately 11 million patients who are under the numbercare of T cells inphysicians per IQVIA claims data, but have not been prescribed an epinephrine intra-muscular injectable device, as well as another approximately 9 million patients not currently under the TME. Myeloid cells are a classcare of innate immune cells comprised of both immunosuppressive and pro-inflammatory subpopulations. Activation of myeloid cells, either by reprogramming immunosuppressive myeloid cells towards a more pro-inflammatory phenotype or stimulating other myeloid cells that have been silenced (e.g., dendritic cells), results in direct tumor killing and recruitment of immune cells. Further, activated myeloid cells can prime and amplify T cell and NK cell responses, bridging the innate and adaptive immunity to elicit broad, durable anti-tumor responses. Successful activation of myeloid cells can lead to anti-tumor immunity, even in tumors that are refractory to immune checkpoint blockade, which we believe may bring substantial benefit to a larger fraction of patients.physicians.

We designed SBT6050 to potently activate the myeloid cell compartment in the TME. We performed a thorough assessment of innate immune receptors with the goal of identifying a payload target that was well expressed in human myeloid cells. Ex-US Market Opportunity

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Commercial Strategy

We believe TLR8that the epinephrine market is unique in its breadth of expression across human myeloid cell subpopulations and its restricted expressiona highly consumer driven market. We expect this to the myeloid cell lineage. In consideration of internally generated data and emerging external research on human myeloid cell biology, we selected TLR8 as the best payload targetbe especially true for activation of myeloid cells resulting in direct tumor killing and recruitment and activation of additional immune cells, such as T cells and NK cells, to further effect the anti-tumor response.

Activating the Myeloid Cell Compartment Through TLR8 Agonism

Myeloid cells develop from common monocyte-dendritic cell progenitor cells and are critical mediators of innate immune responses. These cells are plastic in nature and their function and phenotype are heavily influenced by environmental cues. In the TME and tumor draining lymph nodes, macrophages, conventional dendritic cells, myeloid derived suppressor cells, and monocytes are highly prevalent, but also skewed towards inactive or immunosuppressive states. We believe TLR8 is the optimal target for activating these myeloid cell types due to its restricted expression and function within these cells. As shown in the figure below, TLR8 activation of human myeloid cells elicits an anti-tumor response through a multi-pronged mechanism of action, including direct tumor cell killing, recruitment of immune cells, and the secondary activation of NK cells, T cells and B cells, thus driving both an innate and adaptive immune response against the tumor.

TLR8 is Highly Expressed in Human Myeloid Cell Types That Drive Anti-Tumor Responses When Activated

As a resultneffy, given that 100% of the broad immune activation triggeredphysicians surveyed in our quantitative market research studies indicated that they would prescribe neffy if asked by a TLR8 agonist, systemically administered but untargeted TLR8 small molecule therapeutic candidates from other companies have resulted in an adverse event profile that we believe has limited achieving a dose level sufficient to produce the desired therapeutic benefit. An exemplary TLR8 small molecule agonist is motolimod, originally developed by Array Biopharmapatient and licensed to VentiRx. Motolimod was the first TLR8 specific, but untargeted, agonist tested in the clinic for the treatmentapproximately 70% of solid tumors. Early trials of subcutaneously administered motolimod yielded adverse events we believe to be consistent with broad myeloid cell activation in the periphery, including injection site reactions and symptoms associated with systemic cytokine release, which limited dose-escalation.physicians would recommend neffy. As a result, we believe that sufficient drug exposuredriving consumer awareness, so that patients and parents ask their healthcare provider for neffy, while minimizing both access and educational barriers to acceptance is essential.

Our plan to execute on our go-to-market strategy for neffy includes the following:

We plan to create healthcare professional and consumer awareness and anticipation prior to launch. We are refining our go-to-market strategy and creating awareness about our company and our technology. We expect to expand medical affairs capabilities prior to commercial launch to establish additional relationships with key opinion leaders and gain insight into current practice patterns and burdens. The medical affairs team will also collaborate with the commercial team to help payers fully understand neffy’s value proposition and the limitations associated with needle injectors. We also plan to begin to raise awareness and support meaningful education through partnership with patient advocacy groups and medical societies as well as a disease education campaign including through social media and digital.

Based on the unmet needs that we identified, our pre-launch activities may be focused on delivering disease awareness and education surrounding the appropriate epinephrine use to prevent anaphylaxis to allergists and pediatricians as well as parents and patients in partnership with allergy and professional advocacy groups. These disease education efforts will more specifically reinforce the TME was not reachedimportance of early administration of epinephrine at the first sign of a severe Type I allergic reaction, help stakeholders understand the factors that are associated with hesitation to elicit meaningful anti-tumor activity. Similarly, Gilead Sciences is developingfill and use epinephrine earlier in a reaction, and the importance of alternative epinephrine delivery options to support those affected by severe allergic reactions. In our market research, 42% of patients who had used an orally administered untargeted TLR8 agonist for the treatmentepinephrine injectable device during a recent episode reported that they delayed use by an average of cHBV. This therapeutic has resulted in adverse events consistent approximately 9 minutes. If neffy were available, these patients reported that they would reduce their average wait time to use by 45%. Additionally, 47% of patients reported they were more likely to fill prescriptions and 86% of patients reported they would carry neffy with myeloid cell activation in the gastrointestinal tract, including diarrhea and nausea.them. We believe these two casesa broad understanding of this evidence will help to establish and increase the urgency to treat patients with neffy and support our hypothesis that tissue directed, localized activation is criticalrapid launch uptake following FDA approval, if achieved.

We plan to maximizing the therapeutic potential of a TLR8 agonist.

TLR8 was selected as a target for an agonist after bioinformatic and functional assessments of several innate immune receptor targets. Important criteria of these targets we considered during our payload selection was intracellular localization and robust expression in myeloid cell compartments, with limited expression in non-immune FcR positive cells. Our selection of TLR8 as the optimal target to activate myeloid cells without activating other cell types outside of the hematopoietic lineage was supported by both external research results and internal data.

As shown in figure A below, unlike other intracellular innate immune receptors, TLR8 is highly expressed in human myeloid cell types, including conventional dendritic cells and macrophages. Conversely, as shown in figure B below, TLR8 is not expressed in fibroblasts and endothelial cells and we believe this restricted expression will reduce the risk of toxicities due to on-target, off-cell activation.

TLR8’s Expression is Restricted to Human Myeloid Cells

Following the identification of TLR8 as the optimal receptor to activate myeloid cells in the TME, we designed and created a library of TLR8 agonists. Our proprietary TLR8 agonists were evaluated in the format of HER2 antibody conjugates for their ability to activate myeloid cells ex vivo. Within this library, we identified a HER2 antibody-TLR8 conjugate that activated myeloid cells in moderate and high HER2 settings as is found in HER2-expressing tumors.

Tissue Directed and Localized Activation Through HER2 Expression

Many solid tumors, including those expressing HER2, are refractory to immunotherapy due to minimal T cell infiltrates. As shown in the figures below, HER2-expressing tumors (stained in blue, left panel) frequently contain abundant populations of tumor-associated myeloid cells which express TLR8 (stained in yellow, right panel).

HER2-Expressing Tumors and TLR8-Expressing Myeloid Cells are Adjacent in the Human TME

HER2 is an optimal marker to direct therapies like TLR8 agonist conjugates due to its differential expression between tumors and healthy tissue. Furthermore, HER2 expression is prevalent in meaningfully large patient sub-populations in a wide variety of tumor types including breast (estimated 83,000), gastric (estimated 6,400), non-small cell lung (estimated 31,500), colorectal (estimated 9,000), bladder (estimated 7,500), uterine (estimated 11,000), pancreatic (estimated 4,000), head and neck (estimated 2,000), ovarian (estimated 1,100), esophageal (estimated 2,500), and biliary (estimated 3,000) cancers, providing the potential to address a large HER2-expressing tumor agnostic market estimated to be more than 160,000 newly-diagnosed patients annuallyinitially commercialize neffy in the United States with acombination of direct promotion, virtual sales consultants, and non-personal promotion intended to reach, at a minimum, the healthcare professionals that account for 45% of the current epinephrine prescriptions. Our promotion willfocus the launch on the highest potential practicing allergists, pediatricians, and primary care physicians. In our market research, approximately 80% of patients see their treating physicians at least every six months, and 98% at least once a year. We plan to optimize our field representatives based in part on estimated prevalence rates. The 2020 American Cancer Society annual reportplanned research on cancer statistics was usedcurrent market dynamics, geo-targeting and assessment of current professional-industry interaction preferences initially to determinereach these professionals. We expect significant reach to be achieved based on expanded use of non-personal promotional tactics and virtual sales representatives to reach healthcare professionals and focus on the estimated incidencesequential activation of patient demand through direct-to-consumer tactics that will help also drive physician awareness due to overlapping exposure.

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We intend to partner with patient advocacy organizations as well as influencers and leverage an omnichannel strategy including direct-to-patient and parent tactics, social and traditional media, digital presence, and additional public relations to drive awareness, for each cancer type. HER2 overexpression and amplification prevalence rates documented in the literature were appliedpatients to the incidence rateask for each cancer type to approximate the HER2-overexpressing sub-populations in each cancer type; 30.0%, 16.4%neffy, and 23.2% HER2 overexpression rates were usedcommunicate our value proposition. The pent-up patient demand that we believe is ready to be activated by neffy is reflected in our market research where 87% of patients indicated a high likelihood to proactively visit their physician in-person and ask about getting a new prescription for breast cancer, gastric cancer,neffy (43% of patients indicating a 10 out of 10 likelihood, and non-small cell lung cancer (NSCLC), respectively.

As shown in44% of patients indicating a 7-9 out of 10 likelihood). Our research also showed that physicians would recommend neffy to approximately 70% of their patients. In addition, the figure below, the SBT6050 potential mechanism of action is outlined sequentially as follows:

Potential Mechanism of Action: SBT6050 is Designed to Localize TLR8 Activation of Myeloid Cells in Tumors via a HER2-Directed Antibody

Preclinical Development of SBT6050

Our preclinical studies have shown the potential for SBT6050 to activate innate and adaptive anti-tumor responses in the TME and demonstrate anti-tumor activity as a single agentsevere Type I allergy market has historically been highly promotionally sensitive, and in combination with standard of care agents such as anti-PD-1 and trastuzumab-based therapiesrecent years, there has been limited investment in HER2-expressing solid tumors. Highlights of our preclinical work using SBT6050 in vitro and SBT6050-S (our mouse surrogate) in vivo via subcutaneous delivery demonstrated:

Collectively, these data supported our decision to clinically evaluate the anti-tumor activity of SBT6050 as a single agent and in combination with anti-PD-1 and trastuzumab-based therapeutics in relevant HER2-expressing tumor types.

SBT6050 In Vitro Preclinical Data

In our in vitro studies, SBT6050 potently activated human myeloid cell types, including macrophages, dendritic cells, and monocytes. This activation resulted in the induction of multiple myeloid cell effector functions, including the production of cytokines and chemokines that are critical to the generation of anti-tumor immune responses. In addition, SBT6050 activation of myeloid cells in vitro resulted in the subsequent, indirect activation of NK cells and T cells. In our in vitro studies, SBT6050 also mediated antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. Further, TLR8 agonism drove the downmodulation of SIRPa, highlighting the potential to block the CD47-SIRPa pathway, which, in turn, can potentially enable phagocytosis of tumor and red blood cells.

In our in vitro studies, human peripheral blood mononuclear cells (PBMC) were co-cultured with HER2^poseducation or HER2^neg tumor cell lines in the presence of SBT6050. As shown in the figures below, SBT6050 potently induced multiple anti-tumor immune activities, including general activation of myeloid cells as measured by pro-inflammatory cytokine and chemokine production (TNFa), direct activation of dendritic cells (IL-12p40), and inflammasome activation (IL-18) in the presence of HER2^pos tumor cells. No activation was seen when SBT6050 was co-cultured with HER2^neg cells.

SBT6050 Activated Myeloid Cells in the Presence of HER2^pos Tumors

Similar in vitro studies using PBMCs were conducted to compare SBT6050 with conjugates that contain a TLR7 agonist, resiquimod or a resiquimod variant payload that were designed to mimic competitor molecules. Of note, the EC₅₀ of the free, unconjugated TLR7 small molecule agonist was 9 nM on a TLR7 reporter line and no activity was observed on a TLR8 reporter line. The EC₅₀ of unconjugated resiquimod on TLR7 was ~700 nM and >3 µM on TLR8, demonstrating that resiquimod is a weak TLR8 agonist. The resiquimod variant was of slightly better potency compared to resiquimod. As shown in the figures below, in these internal head-to-head studies SBT6050 demonstrated a

superior ability to induce TNFa, IL-12p40, and IL-18 in the presence of HER2^pos tumor cells. This highlights the potential for favorable activity of SBT6050,promotion, which we believe is dueprovides an opportunity for significant promotional lift from our planned marketing efforts.

We intend to efficient engagement of TLR8 in conjugate form. SBT6050’s functional profile was not replicated with conjugates comprised of TLR7-specific or resiquimod-derived agonists.

SBT6050 Was Superior at Activating Human Myeloid Cells Compared to HER2 Antibody Conjugates that Use Either a Selective TLR7 Agonist or Resiquimod

Robust activation ofestablish neffy as the myeloid cell compartment is also known to trigger an adaptive immune cell response. In an additional in vitro study using a similar PBMC assay, SBT6050 induced indirect activation of mediators associated with NK celldominant and T cell responses (IFNg and granzyme B), as shownmost recognized brand in the figures below. Incategory. We believe neffy’s potential brand recognition and user-friendly profile can be an important driver of growth and source of competitive differentiation, especially as the first “no needle, no injection” solution for severe Type I allergic reactions. We have designed neffy to offer healthcare professionals, patients and caregivers a separate in vitro study,simple, injection-free, portable, highly reliable and user-friendly alternative that facilitates early administration of epinephrine to provide rapid symptom relief and to stop the inductionallergic reaction from progressing to more serious events. We believe the attractiveness and meaningful differentiation of IFNgneffy across both physicians and granzyme Bpayers will stimulate a high patient and parent desire to switch to or return to managing their condition with neffy.

We intend to secure affordable market access for all consumers by SBT6050 was shownoptimizing contracting, co-pay support and distribution of neffy. To ensure access and affordability for neffy, we plan to be secondaryengage with payors to myeloid cell activation as blockadeconvey the clinical rationale and value proposition of IL-12 and/or IL-18 abrogatedneffy. To date, we have conducted extensive market research with approximately 50 decision-makers at payors to help forecast the IFNg and granzyme B response.

SBT6050 Indirectly Activated Mechanisms Associated with CTL/NK Cell Responsespotential commercial opportunity for neffy in the PresenceUnited States. Health insurers surveyed have indicated that neffy is perceived as differentiated brand from epinephrine auto-injector products, with its needle-free route of HER2^pos Tumors

HER2 expression in tumor cells variesadministration and increased likelihood of being carried as the most important product attributes. Based on these analyses and our planned contracting strategy, we believe payers can be measured by protein expression using immunohistochemistry (IHC) to understand the amount of HER2 in tumor cells. It is also common to determine the gene copy number using fluorescence in situ hybridization (FISH) or other methodologies as another way to understand if the HER2 gene is amplified. Gene amplification typically results in overexpression of the protein usually at the IHC3+ level, but some HER2-amplified tumors express protein at the IHC2+ level. It has become standard practice among pathologists to characterize protein expression using IHC1+, IHC2+ or IHC3+support favorable and also to measure gene copy number because certain FDA-approved therapies, such as Herceptin, are approvedbroad market access for neffy. Further, we will offer comprehensive patient support programs in the settingform of high HER2 expression levels. High HER2 expression tumors are categorized by either IHC3+ or IHC2+/FISH positive. Low HER2 expression inco-pay buydowns to help ensure access and affordability for all patients.

We intend to expand the industry is categorized as IHC2+/FISH negative and IHC1+. In our preclinical, studies we characterized IHC1+ HER2 tumor cells as expressing less than 25,000 HER2 receptors per cell. SBT6050 has been tuned to work in settings of IHC2+/FISH negative (moderate expression) as well as IHC3+ (high expression) but not IHC1+ (low expression). Targeting tumors with moderate HER2 expression allows us to address a patient population where most current HER2 targeted therapies are not effective.market beyond the 3.3 million patients currently filling epinephrine injection device prescriptions. We believe that avoiding some normal tissuesthe severe Type I allergy market is currently significantly underpenetrated due to the lack of, and limitations in, current treatment options. We believe the availability of neffy could drive increased device uptake among the existing 3.3 million patients currently filling epinephrine injection device prescriptions, adoption by the approximately 2.5 million patient that express low levels of HER2 provides the opportunity for an improved safety and tolerability profile.

As shown in the figures below, our in vitro studies demonstrated that SBT6050 stimulated myeloid cells in the presence of IHC 2+ and 3+,receive, but not in the presence of IHC 1+/- tumor cell lines.

SBT6050 Activated Myeloid Cells Only in the Presence of IHC 2+ and 3+ Tumor Cell Lines

SBT6050 In Vivo Preclinical Data

Background Regarding SBT6050-S

Because mice do not fill their prescription, and the 11 million patients diagnosed and managed by physicians who do not currently have an epinephrine auto-injector, especially those incorrectly using antihistamines as a functional homologuesubstitute. Other launches of human TLR8, we designed SBT6050-S to enable preclinical mouse studies withintranasal products for emergency use into previously injection-only markets such as NARCAN (marketed by Emergent BioSolutions), VALTOCO (marketed by Neurelis), NAYZILAM (marketed by UCB) and BAQSIMI (marketed by Eli Lilly) have rapidly captured a moleculesignificant percentage of the existing market, and also expanded their respective markets. Both products use the same device that in mice matches the myeloid cell activation profile of SBT6050. TLR7 expression in mouse myeloid cells mirrors that of TLR8 in human myeloid cells. RNA sequencing data published by third parties, as shown in the figures below, highlight the differential expression of TLR8 and TLR7 across mouse and human myeloid cell sub populations. Activation of TLR7 in mouse myeloid cells results in a similar downstream functional profile as TLR8 activation does in human myeloid cells.

TLR7 Is Highly Expressed in Mouse Myeloid Cells and TLR8 Is Highly Expressed in Human Myeloid Cells, Whereas TLR7 Is Expressed at Low Levels in Human Myeloid Cells

SBT6050-S is a proprietary conjugate that contains a selective TLR7 linker-payload and a mouse IgG2a Fc domain to promote uptake in mouse myeloid cells. Our preclinical data, as shown in the figure below, demonstrated similar in vitro potency of SBT6050 on human myeloid cells and SBT6050-S on mouse myeloid cells. In addition, the in vitro activity of SBT6050-S is HER2-dependent as is the case for SBT6050 as described earlier.

Functional Results with TLR7 Conjugate, SBT6050-S, on Mouse Myeloid Cells Matched Those of SBT6050 on Human Myeloid Cells In Vitro

Our SBT6050-S Monotherapy In Vivo Data

Using SBT6050-S in preclinical studies, we have demonstrated that a systemically administered, HER2-directed myeloid cell agonist activated a broad spectrum of anti-tumor mechanisms and led to curative single agent activity in both a human tumor xenograft model lacking T cells and B cells and with defective NK cells as well as a T cell-excluded syngeneic mouse tumor model. In these models, the term “curative effects” describe the complete clearance of tumors (tumor size of 0 mm³).

As shown in the figures below, SBT6050-S (at 10 mg/kg) demonstrated curative effects as a monotherapy in a human tumor xenograft (NCI-N87) mouse model that has an absence of T cells along with defective NK cells. This study was poweredchosen for statistical significance using survival as a readout which is defined as tumor size remaining below 1,000 mm³. Treatment with SBT6050-S resulted in a statistically significant increase in survival as compared to the isotype and HER2 mAb control groups (p value<0.0001)neffy. We believe that the activity of SBT6050-SNARCAN’s widespread use clearly demonstrates market uptake in this model is indicative of the potential of myeloid cells to drive tumor eradication. These data indicate that SBT6050 may have activity in tumors with low or no T cell infiltrate, which we believe has important implications regarding the substantial potential benefit of SBT6050 for patients who do not respond to T cell-directed immunotherapy.

SBT6050-S Drove Robust, Curative Single Agent Activity in T Cell, NK Cell-Deficient Mouse Strains

In addition, in our preclinical studies, administration of SBT6050-S as a monotherapy resulted in durable curative effects in a HER2-expressing, T cell excluded EMT6 syngeneic mouse tumor model. EMT6 is a mouse tumor that we engineered to express human HER2. Expression of human HER2 in this model is moderate, heterogenous, and may be lost over time, which is representative of certain HER2^pos tumor types such as gastric cancer. While conducted in immunocompetent mice, the EMT6 model is also known to be resistant to anti-PD-1 treatment because T cells are excluded from tumor entry. The left panel in the figure below illustrates tumor cells that were demarcated by H&E staining. The central panel in the figure below illustrates that in the HER2-EMT6 model, CD8 T cells were sequestered on the periphery of the tumor. In contrast, the right panel below illustrates the presence of macrophage infiltrate within this T cell-excluded mouse tumor model.

IHC Staining in EMT6 Tumor Models, Depicting CD8 T Cells and Macrophages (F4/80)

As shown in the figures below, SBT6050-S (at 10 mg/kg) as a monotherapy resulted in a complete response (CR) rate, the percentage of animals with tumors < 30 mm³ at the end of study, of between 40% and 80% in the HER2-EMT6 model, depending on the study. This study was powered for statistical significance using survival as a readout which is defined as tumor size remaining below 1,000 mm³. Treatment with SBT6050-S resulted in a statistically significant increase in overall survival when compared to the isotype and HER2 mAb control groups (p value=0.002). Approximately 30-50% of EMT6 tumor cells express human HER2 at the time of dosing initiation. Given the lack of stability of HER2 expression in this model, we believe HER2 expression was lost in the tumors of the mice that did not respond to SBT6050-S in this study.

Treatment with SBT6050-S Monotherapy Resulted in CR Rate of 40-80% in HER2-EMT6 Model

As shown in the figure on the left below, HER2-EMT6 tumor-bearing mice that were cured by SBT6050-S treatment, meaning that no tumor was detectable, were fully protected from an EMT6 tumor re-challenge, indicative of the generation of immunological memory. As shown in the figure on the right below, mice that were re-challenged with EMT6 tumors that did not express HER2 were also shown to have complete protection, indicating SBT6050 engendered activationadvantages of an anti-tumor T cell responseintranasal product via proven device over injection, considering in particular that was not restrictedNARCAN is used in life threatening rescue situations where reliable administration is required for confident administration, similar to HER2. This is consistent with the expansion of T cells reactive to tumor neoantigens observed in the tumors of mice after treatment with SBT6050-S.

SBT6050-S Conferred HER2-Independent Protection in Preclinical Tumor Re-Challenge Studies

Preclinical Data Supporting the Potential for Combination of SBT6050 with Other Therapies

In our preclinical studies, SBT6050-S drove robust anti-tumor activity as a single agent and in combination with standard of care agents.

As shown in the figures below, our preclinical data demonstrated that the single agent activity of SBT6050-S in the immune-competent, checkpoint resistant HER2-EMT6 tumor model was further enhanced when combined with an anti-PD-1.

The Combination of SBT6050-S and Anti-PD-1 Drove Robust, Durable Anti-Tumor Activity

In a HER2^pos human xenograft mouse model, a combination of low dose SBT6050-S with trastuzumab greatly enhanced the anti-tumor activity observed with either agent alone. As shown in the figures below, our preclinical data demonstrated the potential for enhanced clinical activity with SBT6050 in combination with trastuzumab. In this study, a lower dose of SBT6050-S (1 mg/kg) was used to allow for the combinatorial benefit to be observed. A lower dose of SBT6050-S (1 mg/kg) was used as a monotherapy control. We believe that the potential to combine with trastuzumab-based therapies unlocks the possibility of accessing earlier lines of therapy in breast and gastric cancer, where trastuzumab is a part of the standard of care.

The Combination of SBT6050-S and Trastuzumab Drove Robust, Durable Anti-Tumor Activity

SBT6050 Was Well Tolerated in Non-Human Primates by the Subcutaneous Route of Administration

SBT6050 demonstrated a wide therapeutic window in safety and tolerability studies following repeat subcutaneous administration including in the GLP toxicology study in non-human primates (NHP) that determined our first-in-human (FIH) dose. Forty-one NHPs have been administered repeat SC doses of SBT6050 in three NHP toxicity studies. In two non-GLP studies, 15 NHPs were treated at SC dose levels of 0.1 to 12 mg/kg, with the majority (8 of 15) administered 6 or 12 mg/kg every 2 or 3 weeks (Q2W or Q3W) for 4 doses. In the GLP toxicity study, 26 NHPs received doses of 2, 6 or 12 mg/kg Q2W for 4 doses, with a 4-week recovery period for the higher two dose levels. Across the studies, there was no evidence of injection site reactions or cytokine release syndrome (CRS) in any animal. There were transient, dose-related hematological, clinical chemistry, and cytokine and chemokine changes reflective of the potential mechanism of action of SBT6050. Because of the broad therapeutic

window demonstrated in these studies, our FIH starting dose level of 0.3 mg/kg was selected because of its equivalency to the minimum pharmacologically active dose level in NHP and the projection that this dose level may be pharmacologically active in patients. The FIH dose levels of immune activators, particularly those that are viewed as having a significant risk of CRS, are typically below the projected pharmacologically active dose of the agent, resulting in lengthy dose-escalations to an active dose level. Notably, that is not the case with SBT6050. Based on the totality of our preclinical data,severe Type I allergic reactions. Beyond just reliability, we believe that we have potential to reach the recommended phase 2 dose (RP2D)an intranasal product has unique advantages for SBT6050 between the second and fourth dose levels.

Repeat administration of fully human or humanized proteins, such as that included in SBT6050, to preclinical species, liketreating a NHP, has been extensively evaluated by many organizations over the years and has been found to frequently lead to the generation of anti-drug antibodies (ADA), reflecting the development of immunogenic responses with repetitive challenge of NHP with non-self or foreign proteins. Importantly, the generation of ADA against human or humanized proteins in NHP, even when accompanied by ADA-mediated toxicities such as anaphylaxis, has not been predictive of immunogenicity in humans. ADA developed against SBT6050 in our NHP toxicology studies. The formation of ADA against SBT6050 in NHP was expected given the inherent immunogenicity of humanized proteins in NHP and the potential mechanism of action of SBT6050, which includes the promotion of presentation of foreign antigens by dendritic cells, a mechanism critical to the formation of immune responses to tumor neoantigens. The development of ADA in NHP resulted in decreased exposure following repeat dosing. As has been seen with other immune agonists administered in the presence of ADA in preclinical species, repeat intravenous dosing with SBT6050 resulted in anaphylaxis but anaphylaxis was not seen in NPH studies using subcutaneous dosing of SBT6050. While no animal treated with SBT6050 subcutaneously showed signs of acute anaphylaxis, one animal in the highest dose group was euthanizedsevere Type I allergic reaction due to what is believed to be ADA-related immune complex deposits in certain organs. Given the precedent data in the field, we do not believe that neutralizing ADA formation that affected SBT6050 exposure in NHP will translate into the clinic. Nevertheless, a reduction in exposure following repeat dosing of SBT6050 in the Phase 1/1b clinical trial could present a risk for clinical development. Of note, in our ongoing Phase 1/1b clinical trial, we have repeat dose pharmacokinetics (PK) after four doses of 0.3 mg/kg for one patient and reductions in SBT6050 exposure were not observed. Variable ADA titers have been observed across patients ranging from undetectable to low without impact on pharmacodynamic activity.

SBT6050 Clinical Development Planparent fear and Strategy

SBT6050 demonstrated a wide therapeutic window in our GLP toxicology study in NHP, enabling a FIH starting doseavoidance of 0.3 mg/kg, which was projected to be pharmacologically activeinjection and within 2-3 cohorts of where we could potentially achieve anti-tumor activity. In NHP, 0.5 mg/kg was defined as the minimum pharmacologically active dose as determined by blood-based biomarkers, 6 mg/kg was determined to be the No Adverse Event Level and the highest dose level evaluated was 12 mg/kg. Our FIH starting dose of 0.3 mg/kgbecause time is the human equivalent of the minimum pharmacologically active dose level in NHPessence. This perspective is distinct from other diseases with chronic use of injection products, administration by a trained professional is required, or where the injection is more manageable and projected to be pharmacologically active in patients. Based on the totality oftolerated. In our preclinical data,market research, respondents have described neffy as “game-changing” and we believe that the RP2D will be reached between the secondneffy, if approved, can make a significant difference in patient lives and fourth dose levels in our Phase 1 dose-escalation, particularly if 0.3 mg/kg demonstrates pharmacological activity as projected from our preclinical modeling. Additional dose levels may be explored in our Phase 1/1b clinical trialoutcomes.

If approved, we plan to further characterize the tolerability profile. At the RP2D, we believe there is potential to demonstrate single agent anti-tumor activity in dose expansion cohorts.

Our IND for SBT6050 was cleared in June 2020 withestablish a starting dose of 0.3 mg/kg. In July 2020, we initiated a Phase 1/1b FIH, open-label, multicenter, dose-escalation and expansion clinical trial in patients with HER2-expressing solid tumors that have progressed following standard therapies. The trial is designed to evaluate the safety, tolerability, PK, pharmacodynamics (PD), immunogenicity, and

anti-tumor activity of SBT6050 as a single agent and in combination with pembrolizumab, a PD-1 inhibitor.

In our Phase 1/1b clinical trial, we are monitoring key PD biomarkers in both the blood and the tumor which have been associated with tumor regression in our preclinical mouse studies and was observed in our preclinical NHP studies. Key biomarkers in the blood include elevations in MCP-1, IP-10, and C-reactive protein and induction of additional PD markers indicative of on target mechanism of action such as IFNg. We will be obtaining tumor biopsies at baseline and on treatment to measure biomarkers that correlate with the activation of myeloid cells, T cells and NK cells in cohorts 2 and later.

The trial consists of four parts: monotherapy dose-escalation and expansion (Part 1), monotherapy dose expansion in tumor-specific cohorts (Part 2), pembrolizumab combination dose-escalation (Part 3), and a pembrolizumab combination dose expansion cohort (Part 4).

Part 1: SBT6050 Single Agent Dose-Escalation and Expansion

In Part 1, a standard 3 + 3 dose-escalation of SBT6050 is planned to study safety, tolerability, and PK of SBT6050, and to determine the maximum tolerated dose (MTD) and the RP2D. The MTD is defined as the dose just below the dose level where 2 or more out of 6 patients (³33%) experience dose-limiting toxicities (DLTs). The starting dose of the SBT6050 regimen is 0.3 mg/kg administered via subcutaneous injection once every 14 days. One or two dose levels may be expanded to 12 patients to obtain additional information to select the RP2D. Eligible patients must have HER2-expressing (HER2 IHC 2/3+) or HER2-amplified cancer refractory to or relapsed after standard therapies. We anticipate enrolling approximately 30 participants in Part 1.

Part 2: SBT6050 Single Agent Dose Expansion in Tumor-Specific Cohorts

Patients will be enrolled into parallel expansion cohorts based on tumor type and HER2 expression level. Patients enrolled in the expansion cohorts will receive SBT6050 at the recommended dose and schedule established in Part 1. The purpose of Part 2 is to further characterize the tolerability profile of the RP2D and evaluate the anti-tumor activity and PD effects of SBT6050 as a single agent. Enrollment will follow a Simon 2-stage design. Planned expansion cohorts, which may also be informed by experience in the dose-escalation phase, include the following tumor types:

Part 3: SBT6050 Plus Pembrolizumab Dose-Escalation Cohort

In Part 3, a standard 3 + 3 dose-escalation of SBT6050 plus the anti-PD-1 CPI, pembrolizumab is planned to determine the MTD and RP2D of SBT6050 when given in combination with pembrolizumab. The MTD is defined as above. SBT6050 will be administered via subcutaneous injection on Days 1, 15, and 29 of 42-day cycles in combination with 400 mg pembrolizumab administered via intravenous injection on Day 1 of each cycle. Eligible patients will have HER2-expressing or HER2-amplified solid tumors. Part 3 of the study will open when changes in PD markers exceeds the pre-defined criteria for pharmacological activity with demonstration of acceptable safety and tolerability in a cohort treated with

single agent SBT6050. The pre-defined threshold is based on changes in peripheral PD markers in preclinical studies, and includes C-reactive protein elevation to ³ 150 mg/L and 3-5x changes from baseline in certain cytokines and chemokines such as IP-10 and/or MCP-1 and induction of additional pharmacodynamic markers indicative of on-target mechanism of action, such as IFNg. We anticipate enrolling approximately 15 participants in Part 3.

Part 4: SBT6050 Plus Pembrolizumab Dose Expansion Cohort

The combination treatment expansion part of the trial will be initiated once the RP2D has been defined by the safety monitoring committee from Part 3. The purpose of Part 4 is to further characterize the tolerability profile of the RP2D and evaluate the anti-tumor activity and PD effects of SBT6050 in combination with pembrolizumab. Approximately 30 patients with HER2-expressing or HER2-amplified tumors of multiple histologies will be enrolled.

Update on SBT6050 Phase 1/1b Clinical Trial

As of November 25, 2020, six patients had been enrolled at 0.3 mg/kg in Part 1 of the study (SBT6050 monotherapy dose-escalation). This first cohort of patients included two patients who had radiological reassessments, one patient with stable disease at her 8 and 16 week reassessments, one patient with a greater than 30% reduction in the diameter of her target lesion at 8 weeks per the investigator’s assessment, and two additional patients that had completed the DLT period and remained on study. The most common adverse events included flu-like symptoms (fever, chills, nausea, vomiting, fatigue) and redness and swelling at the injection site. Changes in pharmacodynamic markers consistent with the potential mechanism of action were observed in treated patients. This included increases in plasma levels of CRP (C-reactive protein), a marker of inflammation, increases in MCP-1, IP-10 and IL-6, which are indicative of myeloid cell activation, increases in IFNg, which is a marker for T and NK cell activation, and transient decreases in hemoglobin, which we believe to be due to macrophage phagocytosis.

We anticipate providing an update on interim data from the Phase 1 single agent dose-escalation cohorts in the second half of 2021. Enrollment and treatment has been initiated in Part 3 of the study (SBT6050 plus pembrolizumab dose-escalation). We anticipate providing an update on interim data from the Phase 1 SBT6050 plus pembrolizumab combination in the first half of 2022. We anticipate providing a further update on interim data from the Phase 1 monotherapy and combination dose-escalation, as well as a first update of the Phase 1b monotherapy in tumor-specific expansion cohorts and the Phase 1b combination cohort, in the second half of 2022.

SBT6050 Addressable Market

As shown in the figure below, HER2 IHC 2+ and 3+ overexpression and amplification are documented in at least 11 different tumor types including breast (estimated 83,000), gastric (estimated 6,400), non-small cell lung (estimated 31,500), colorectal (estimated 9,000), bladder (estimated 7,500), uterine (estimated 11,000), pancreatic (estimated 4,000), head and neck (estimated 2,000), ovarian (estimated 1,100), esophageal (estimated 3,000), and biliary (estimated 3,000) cancers, providing the potential to address a large HER2-expressing tumor agnostic market estimated to be more than 160,000 newly-diagnosed patients annuallydistribution channel in the United States basedfor the commercialization of neffy. We expect to sell neffy to wholesalers, who, in part on estimated prevalence rates. HER2 IHC2+turn, will sell our neffy to retailors and 3+ overexpression in breast cancer, gastric cancer,other customers. We expect to use a third-party logistics provider for key services related to logistics, warehousing and NSCLC are 30.0%, 16.4%,inventory management, distribution, contract administration, order management and 23.2%, respectively. Most HER2 targeted therapies require the tumor cellschargeback processing and accounts receivable management. We also plan to be dependent on HER2 signaling, often called an oncogenic driver. HER2 oncogenic-driven tumors are limited to subsets of breast and gastric cancer and hence the FDA-approved therapies that require HER2 signaling are limited to these indications as noted in the figure. SBT6050 does not require the tumor cells to be dependent on HER2 signaling for its anti-tumor activity and instead utilizes

the HER2 protein to deliver the conjugate to adjacent myeloid cells. We believe that this expands the market opportunity beyond HER2-driven breast and gastric cancer in which targeted HER2 agents have been approved and are established as standard of care. Because of the rationale to combine SBT6050 with CPI’s, which is supported by our preclinical data, we have noted in the figure below those tumor types with an approved CPI.

Large Potential Market Opportunity for SBT6050 in Tumors that Express HER2 and in Combination with HER2 Targeted Agents and CPIs

HER2 expression rates are well-understood in tumor types for which there is an FDA-approved HER2 targeted therapy available. Breast and gastric cancer cases are routinely screened for HER2 expression as a part of the standard of care. HER2 overexpression has been reported in other tumor types, but because of the lack of effective therapies targeting cancersTo target markets outside of breast and gastric, screening is not readily performed. In calculating our potential addressable market for these tumor types, the figure above shows a range of HER2 expression cited in the literature and the lower end of the range was utilized for market considerations. In the United States, we believe that, based in part on estimated prevalence rates as described in the figure above, more than 48,000 patients annuallyhave entered into strategic partnerships with solid tumors that are refractoryseveral pharmaceutical companies to standard of care treatments may benefit from SBT6050 as a single agent or combination therapy, if successfully developedobtain regulatory approval and approved. In the future, if SBT6050 advancesmarket neffy. These include Alfresa Pharma for Japan and Pediatrix Therapeutics for China. We intend to earlier lines of treatment, based in part on estimated prevalence rates as described in the figure above, more than 160,000 patients annually may benefit.

In considering the market for combination treatment, SBT6050 was specifically designed to bind to the HER2 sub-domain II, the pertuzumab epitope, to enable combinations with trastuzumab-based therapies that bind to HER2 sub-domain IV such as Herceptin (trastuzumab), Kadcyla (trastuzumab-DM1), and Enhertu (DS-8201), all of which are FDA-approved HER2 agents. Our preclinical data has demonstrated the potential to use SBT6050 in combination with trastuzumab and CPI’s. We believe that SBT6050 may also have the potential to be combined with tyrosine kinase inhibitors such as Tukysa (tucatinib), which is approved for combination with trastuzumab and Xeloda (capecitabine)pursue strategic partnerships for the treatmentcommercialization of HER2^pos metastatic breast cancer. When considering the market potential for combination therapy, only combinations with trastuzumab and CPI’s was utilized neffy in our calculations.

SBT6050 is also active in HER2 IHC 2+ / FISH negative tumors, expanding the market beyond the scopeadditional regions outside of current approved HER2 targeted therapies indicated for IHC 3+ and IHC 2+ / FISH positive tumors as shown in the figure below. We considered this potential market extension in breast cancer and gastric cancer in calculating the potential addressable market.

SBT6050 Potential Addressable Market in Indications with an FDA-Approved HER2 Targeted Therapy

SBT6290: TLR8 Agonist Conjugated to a Nectin4 Antibody

Our second product candidate, SBT6290, is comprised of the same TLR8 linker-payload used in SBT6050 conjugated to a Nectin4-directed monoclonal antibody. Nectin4 has been prioritized as our second target based on differential expression of extracellular proteins on tumor cells in comparison to healthy tissue, as well as the degree of myeloid cell infiltrate in the TME. Nectin4 is overexpressed in cancers including bladder, triple negative breast, head and neck, and NSCLC, among others.

Nectin4 is a target that has been clinically validated by Seagen (formerly Seattle Genetics) through the approval of the Nectin4-directed antibody-drug conjugate Padcev. In 2019, Padcev was approved under the FDA’s accelerated approval program indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 inhibitor, and a platinum-containing chemotherapy.

Targeting Nectin4 to deliver a TLR8 agonist to adjacent myeloid cells presents a significant therapeutic opportunity across different cancers. As shown in the figure below, the estimated incidence of newly diagnosed patients with bladder, triple negative breast, head and neck cancers, and NSCLC that express Nectin4 represents over 181,000 patients annually in the early line setting. The estimated yearly deaths of patients with bladder, triple negative breast, head and neck cancer, and NSCLC that express Nectin4 represents over 73,000 patients with relapsed or refractory cancer annually in the United States.

Nectin4 Overexpression Across Select Tumor Types

Bioinformatic analysis of data from The Cancer Genome Atlas (TCGA) database indicates that myeloid cells are present in Nectin4-expressing tumor types, as shown in the figure below. As reported

in TCGA, myeloid cells can comprise, on average, between 7% to 14% of the tumor which is higher than the average number of T cells in the same tumor types.

Nectin4-Expressing Tumor Types Are Infiltrated By Myeloid Cells

In our in vitro studies, human PBMCs were co-cultured with Nectin4^pos or Nectin4^neg tumor cell lines in the presence of SBT6290. As shown in the figures below, SBT6290 potently activated myeloid cells with an EC₅₀ of ~200 pM, in the presence of Nectin4-expressing tumor cells. TNFa production was measured as a marker of myeloid cell activation. The levels of TNFa induced by SBT6290 matched those observed with SBT6050 when tested in a similar in vitro assay. Not only did these data highlight the Nectin4-dependent activity of SBT6290, but also demonstrated that the TLR8 linker-payload used in SBT6050 was transferable to antibodies directed to diverse antigens.

SBT6290 Potently Activated Human Myeloid Cells

Nectin4 was recently described to be a ligand for T cell immunoglobulin and ITIM domain (TIGIT). TIGIT has emerged as an inhibitor of anti-tumor immune responses and several agents inhibiting this pathway are being tested in clinical trials. In addition to SBT6290’s primary mechanism of action through TLR8 activation, the figure below demonstrated that the binding of TIGIT to Nectin4-expressing tumor cells was blocked by the binding domain of SBT6290.

SBT6290 Binding Domain Blocked TIGIT Binding to Nectin4-Expressing Tumor Cells

We engineered a mouse surrogate of SBT6290 (SBT6290-S) using a TLR7 agonist conjugated to a Nectin4 monoclonal antibody to account for species differences in our in vivo studies, as was described for SBT6050. As shown in the figure below, SBT6290-S improved overall survival in a Nectin4-expressing EMT6 mouse model. This study was powered for statistical significance using survival as a readout which is defined as tumor size remaining below 1,000 mm³. SBT6290-S demonstrated a statistically significant improvement in survival as compared to the two control groups as noted in the figure below.

Administration of SBT6290-S as Monotherapy Resulted in Improved Overall Survival in a Nectin4-Expressing EMT6 Preclinical Model

As shown in the figure below, subcutaneous administration of SBT6290-S to mice bearing Nectin4-expressing EMT6 tumors induced the production of cytokines and chemokines in the tumors of treated mice. MCP-1 and IP-10 upregulation are indicative of myeloid cell activation and IFNg and IL-2 production are indicative of T cell activation in the treated mice.

Administration of SBT6290-S as Monotherapy Induced the Production of Cytokines and Chemokines in Nectin4-Expressing EMT6Tumors

In a single and repeat dose exploratory safety study, Nectin4-TLR8 conjugate was administered subcutaneously to NHP at a dose level >10-fold of the anticipated, minimum pharmacologically active dose level, a dose that was also evaluated with SBT6050. The overall safety, tolerability, PK and PD findings of the Nectin4-TLR8 conjugate were very similar to those observed with SBT6050 at this dose. A non-GLP toxicology study for SBT6290 has been completed, and we believe the results are supportive of a wide therapeutic window similar to that observed with SBT6050. GLP NHP toxicity studies are expected to commence in first half of 2021. In parallel, we are in the process of creating a master cell bank for GMP production of SBT6290. In our pre-IND interactions with the FDA that took place in February 2021, alignment on SBT6290 preclinical, Chemistry, Manufacturing, and Controls (CMC), and clinical plans was achieved. We anticipate submitting the SBT6290 IND in the fourth quarter of 2021 and initiating a Phase 1 clinical trial in the first quarter of 2022.

SBT8230: TLR8 Agonist Conjugated to an ASGR1 Antibody

As our lead virology program, we have engineered SBT8230 to treat cHBV using our ImmunoTAC platform. SBT8230 is comprised of an ASGR1 monoclonal antibody conjugated to the same TLR8 linker-payload as SBT6050 and SBT6290 and is designed to elicit an anti-viral immune response by targeting TLR8 activation to the liver.

cHBV infection remains a worldwide problem affecting approximately 257 million people and contributing to an estimated 887,000 deaths in 2015. In the United States, alone, approximately 860,000 people suffer from cHBV. cHBV is estimatedsubject to FDA approval of neffy.We anticipate that in certain markets additional clinical trials of neffy may be the cause of 60-80% of the world’s primary liver cancers. There is a significant unmet need for therapies that can elicit a functional cure for the disease, which is defined as sustained loss of hepatitis B surface antigen (HBsAg) in the blood. Many of the approved therapies for cHBV have low functional cure rates required to obtain regulatory approval and/or lack durability over time.ensure market access.

Clinical and preclinical evidence by third parties have demonstrated that IFNg-mediated immune responses, including the activation of IFNg+ T cell and IgG B cell anti-viral responses, can lead to a functional cure in cHBV patients and animal models of HBV. In HBV transgenic mice, HBV-specific CD4 and CD8 T cells have exhibited the ability to inhibit hepatocellular replication by a noncytopathic process that is mediated primarily by IFNg. In acutely infected chimpanzees, viral replication was almost completely abolished soon after CD3 and IFNg mRNA increased in the liver. Evidence by third parties has demonstrated that HBV-specific IFNg producing CD4 T cells were associated with viral clearance in patients with cHBV infection. Additionally, these studies have demonstrated that TLR8 agonists were particularly effective in activation of myeloid cells and the induction of IFNg. The figure below shows IFNg production after human blood or liver-derived mononuclear cells were stimulated with the indicated TLR agonist. TLR8 was unique in its ability to induce IFNg.

TLR8 Drove IFNg Production from Liver Mononuclear Cells in Third Party Preclinical Studies22

Competition

In addition, the figures below show concentrations of individual cytokines quantified in the supernatant of purified PBMC or isolated mononuclear cells from the liver after stimulation with either a TLR8 or TLR7 agonist. TLR8 agonism, but not TLR7 agonism, induced IFNg production, along with the production of other cytokines important in the generation of anti-viral immunity such as TNFa, IL-1ß, and IL-6, from both liver and blood immune cells. We believe these data from third parties demonstrate that TLR8 is the agonist of choice for improving the outcome for patients with cHBV.

TLR8 Agonism Drove Cytokine Production

Figure source: Jo et al, PLOS Pathogens, 2014.

In a preclinical woodchuck model of cHBV conducted by a third party, oral administration of a TLR8 agonist small molecule, GS-9688 (selgantolimod), was shown to drive seroconversion and reduce woodchuck hepatitis virus S antigen and woodchuck hepatitis B viral levels. Selgantolimod’s effectiveness in cHBV patients has been limited, however. We believe (i) this is due to not achieving necessary exposures because of DLTs associated with activation of myeloid cells outside of the liver and (ii) that systemically delivered but liver localized TLR8 agonism could improve the potential for effective therapy and lead to functional cures in cHBV.

SBT8230 is a Liver-Localized TLR8 Agonist Designed to Achieve Functional Cure in cHBV

As shown in the figure below, we designed SBT8230 to be comprised of an ASGR1 monoclonal antibody conjugated to a TLR8 linker-payload with the goal of activating the myeloid cell compartment in liver tissue only. The conjugate is designed to be internalized in myeloid cells in an FcR-mediated manner when ASGR1 is present on adjacent liver cells.

Potential Mechanism of Action: SBT8230 is Designed to Localize TLR8 Activation of Myeloid Cells in the Liver Via a Directed ASGR1 Antibody

As shown in the figures below, in our preclinical studies utilizing human PBMCs ex vivo, ASGR1-TLR8 induced IFNg-promoting activity through its activation of myeloid cells.

ASGR1-TLR8 Potently Activated Human Myeloid Cells, Resulting in a Robust IFNg Response

Activation of human myeloid cells by TLR8 was mirrored in mouse myeloid cells by TLR7 as was demonstrated previously in the SBT6050 and SBT6290 programs. Therefore, to evaluate the ability of

a liver-targeted myeloid cell agonist conjugate to drive seroconversion in a mouse model of cHBV, we engineered a surrogate for SBT8230 comprised of an ASGR1 monoclonal antibody conjugated to a TLR7 agonist (ASGR1-S). The antibody contained an IgG2a Fc domain to facilitate uptake into mouse myeloid cells.

Seroconversion, together with reductions in HBsAg levels and expansion of IFNg-producing anti-viral T cells, is associated with achievement of functional cures in cHBV. The AAV-HBV (adenovirus-hepatis B virus) mouse model is a commonly used preclinical model for cHBV. Paralleling their inability to drive seroconversion in cHBV patients, cHBV standard of care therapies and other agents that target the HBV life cycle such as capsid inhibitors, have not resulted in seroconversion in this or similar models. In contrast, statistically significant increases in seroconversion and reductions in HBsAg was demonstrated with ASGR-S as compared to the vehicle and unconjugated antibody control groups in the AAV-HBV model, as shown in the figures below.

ASGR1-S Reduced HBsAg and Drove Seroconversion in Mouse AAV-HBV Model

In addition, ASGR1-S treatment generated potent anti-viral T cell and B cell immune responses and significantly increased anti-HBV core and S antigen IFNg+ T cells and anti-HBsAg+ B cells, as shown in the figures below.

ASGR1-S Increased IFNg+ Anti-Viral T Cells

ASGR1-S Increased B Cells Producing Anti-HBs Antigen Antibodies

Importantly, as shown in the figures below, no changes in serum ALT or body weight were noted after treatment with ASGR1-S as compared to controls. In addition, there were no findings in the liver by histopathology after treatment with ASGR1-S. Together, these data indicated that ASGR1-S was well tolerated in the mouse AAV-HBV model.

ASGR1-S Was Well Tolerated in Mice

Initial exploratory NHP toxicology studies demonstrated a wide therapeutic window. Preclinical studies in mice and NHP for our ASGR1-TLR8 ImmunoTAC candidate are ongoing. We selected a development candidate for this program in the fourth quarter of 2020, and we anticipate initiating IND enabling toxicity studies in the first quarter of 2022 and submitting the IND in the second half of 2022.

Other Programs

Additional Immuno-Oncology Programs

In addition to HER2 and Nectin4, we have selected two undisclosed targets that may enable us to address a broader range of solid tumor indications. In these programs, the antibodies have been created and conjugated to the same TLR8 linker-payload utilized in SBT6050 and SBT6290. In addition, our undisclosed product candidates display an in vitro activity profile on human immune cells similar to that of SBT6050 and SBT6290. Further, one of these conjugates was evaluated in an exploratory NHP toxicology study with repeat subcutaneous dosing. The dose level evaluated in this

study was previously used in NHP toxicology studies with SBT6050 and SBT6290 to demonstrate a therapeutic window. At this dose level, the undisclosed product candidate was found to have a similar tolerability profile to SBT6050 and SBT6290, indicating that it may have a similar therapeutic window.

Fibrosis Program: TGFßR1 Antagonist Conjugated to an ASGR1 Antibody

We designed our ASGR1-TGFßR1 antagonist conjugate to achieve liver-localized inhibition of TGFß-signaling to treat fibrosis.

Fibrosis is the overgrowth, hardening and scarring of tissue due to accumulation of extracellular matrix molecules, such as collagen, that is produced by fibroblasts. Chronic fibrotic diseases often result in widespread distortion of normal tissue architecture and account for up to 45% of deaths in the United States. Fibrosis can occur in most major tissues, however idiopathic pulmonary fibrosis and hepatic cirrhosis are among the more common fibrotic diseases.

Hepatic cirrhosis and hepatocellular carcinoma (HCC) are leading causes of morbidity and mortality worldwide. Patients with liver cirrhosis are at high risk of deadly hepatic failure and approximately 80%-90% of HCC develop on a cirrhotic background. HCC ranks as the sixth most common cancer and, with over 600,000 deaths per annum, it constitutes a major global health problem. The most common causes of hepatic cirrhosis in the United States are hepatitis C, alcoholic liver disease, and nonalcoholic liver disease.

TGFß Pathway and its Role in Fibrosis

Progress has been made to treat the underlying etiologies initiating liver fibrosis, yet significant needs remain for therapies that slow, halt, or reverse fibrosis and thereby prevent late-stage liver failure and HCC. TGFß signaling is a key mediator of liver fibrosis initiation and progression through multiple mechanisms, including hepatocyte apoptosis, hepatic stellate cell transdifferentiation to myofibroblasts, and pro-fibrotic macrophage activation.

TGFß is secreted by many cell types and is implicated in a wide range of cell functions, critically regulating tissue homeostasis and repair, immune and inflammatory responses, extracellular matrix deposition, and cell differentiation and growth. In healthy tissues, TGFß is expressed at a low level to enable homeostatic mechanisms and is also transiently upregulated in response to tissue injury, which initiates a cascade that results in collagen production and, ultimately, healing of the tissue. In fibrotic tissue, TGFß production and signaling is dysregulated and perpetuated, leading to excess collagen deposition in the absence of acute tissue injury.

While inhibiting the TGFß receptor kinase domains is the most direct way to down-regulate TGFß signaling, systemic availability of TGFß receptor 1 (TGFßR1) antagonists is associated with DLTs due to the homeostatic functions of TGFß in multiple organ systems. Preventing TGFß activity with antibody blockade of ligands or their activation machinery is challenging due to the presence of multiple ligands and activation mechanisms, and TGFß’s sequestration in extracellular matrix. We believe a systemically delivered TGFßR1 antagonist with liver-localized activity has the potential to ameliorate liver fibrosis while avoiding the toxicities associated with non-targeted TGFß receptor inhibition.

Using a similar strategy of liver localization that was employed in our cHBV program, as shown in the figure below, we engineered an ASGR1-TGFßR1 antagonist ImmunoTAC intended to inhibit the TGFß pathway to treat liver fibrosis. ASGR1 is a scavenger receptor that is highly expressed exclusively on hepatocytes and internalizes and recycles rapidly upon engagement. Thus, the ASGR1-TGFßR1 antagonist conjugate is designed for systemic administration with liver-localized inhibition of the TGFß receptor.

ASGR1-TGFßR1 ImmunoTAC Therapeutic is Designed for Liver-Localized TGFß Signaling Inhibition for Anti-Fibrotic Effects

As shown in the figure below, our initial preclinical studies with ASGR1-TGFßR1 antagonist conjugates demonstrated potent inhibition of TGFß signaling in vitro. This activity was dependent on ASGR1 binding as no activity was observed on cells with low or no ASGR1 expression.

ASGR1-TGFßR1 ImmunoTAC Therapeutic: Potent and Complete Inhibition of TGFß Signaling in pSMAD Reporter Assay

ASGR1^pos pSMAD Reporter Assay

Preclinical studies in mouse disease models are ongoing for this program.

Competition

The pharmaceuticalOur industry is highly competitive and dynamic, owingsubject to rapidly advancing technologies. We facerapid technological changes. Our potential competition from many different sources, including majorcompetitors include large pharmaceutical and biotechnology companies, specialty pharmaceutical and biotechnologygeneric drug companies, academic institutions, government agencies and public and private research institutions. AnyMany of our potential competitors have substantially greater financial, technical, commercial and human resources than we do and significantly more experience in the discovery, development and regulatory approval of product candidates and the commercialization of those products. We believe that the key competitive factors that will affect the development and commercial success of neffy and the other product candidates that we successfullymay develop are their efficacy, safety and commercialize will compete with existing treatmentstolerability profile, convenience in dosing, product labeling, value and new treatments that may become availableprice, in the future.

We compete with other companies workingaddition to develop immunotherapies and targeted therapies for the treatment of cancer including divisions of large pharmaceutical and biotechnology companies of various sizes. These companies are developing therapies of many different modalities including small molecules, monoclonal antibodies, antibody-drug conjugates, bi-specific antibodies, cell therapies, oncolytic viruses and vaccines.

Specifically,whether there are many companies pursuing a varietyalternative therapies approved for other indications and prescribed for off-label use and the availability of approaches to TLR-directed therapies, including Apros Therapeutics, Ascendis, BioNTech, Bolt Biotherapeutics, Bristol Myers Squibb, Checkmate Pharmaceuticals, CureVac, Exicure, Galaderma, Gilead, Idera, Mologen, Nektar, Novartis, Primmune Therapeutics, Roche, Seven&Eight, Shanghai De Novo, Sumitomo Dainippon, TriSalus,reimbursement from the government and UroGen. Other companies using antibody-drug conjugates to target innate immune receptors include Actym Therapeutics, Mersana, and Takeda Pharmaceuticals. Immunotherapy and validated pathway approaches are further being pursued by many smaller biotechnology companies as well as larger pharmaceutical companies. We also face competition from validated pathway therapy treatments offered by companies such as AstraZeneca, Byondis, Daiichi Sankyo, Genentech, MacroGenics, Pieris, Puma, Seagen (formerly Seattle Genetics), Spectrum Pharmaceuticals, and Zymeworks. We also face competition from companies that continue to invest in innovation in the antibody-drug conjugate field, including but not limited to AbbVie, ADC Therapeutics, Astellas, BioAtla, Celldex, CytomX, Eli Lilly and Company, GlaxoSmithKline, Genmab, ImmunoGen, Immunomedics, Millennium Pharmaceuticals, MorphoSys AG, Novartis, Pfizer, Sanofi, Seagen (formerly Seattle Genetics), Sutro Biopharma, and VelosBio.

Many of our competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, preclinical testing, clinical trials, manufacturing, and marketing than we do. Future collaborations and mergers and acquisitions may result in further resource concentration among a smaller number of competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors will also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and subject registration for clinical trials, as well as in acquiring technologies complementary to, or that may be necessary for, our programs.

other third parties. Our commercial potentialopportunity could be reduced or eliminated if our competitors develophave products which are better in one or more of these categories.

We expect that, if approved, neffy would compete with a number of existing products and commercializeother product candidates that target Type I allergic reactions, including certain products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than products that we may develop. Our competitors also may obtain FDA or other regulatory approvalbecome generic products. Additionally, the development of new treatment methods for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position beforethe diseases we are able to entertargeting could render our current or future product candidates non-competitive or obsolete.

We anticipate that, if approved, neffy will compete primarily against epinephrine intra-muscular injectable products, for the market or make ouremergency treatment of Type I allergic reactions including EpiPen and its generics, which are marketed by Viatris, Inc. and Teva Pharmaceuticals, Inc., respectively; Adrenaclick, which is marketed by Amneal Pharmaceuticals, Inc.; Auvi-Q, which is marketed by Kaleo, Inc.; and Symjepi, which is marketed by Sandoz, Inc., a Novartis division.

We are not aware of any other company that has a “no needle, no injection” epinephrine product candidate in clinical development more complicated. The key competitive factors affectingin the successUnited States that has demonstrated PKs bracketed by the approved injection products for all pharmacokinetic parameters requested by the FDA. We are also not aware of allany “no needle, no injection” epinephrine product candidate for the pediatric population that is in clinical development.

We are aware of our programs are likelyseveral companies developing higher dose intranasal candidates including Bryn Pharma, Hikma Pharmaceuticals, Inc. (previously INSYS Therapeutics, Inc.), Nasus Pharma and Orexo AB. Amphastar Pharmaceuticals, Inc. is reported to be efficacy, safetydeveloping an intranasal candidate, but has not disclosed its dose. Aquestive Therapeutics is developing a sublingual candidate based on a prodrug of epinephrine.

Manufacturing and convenience.Supply

Manufacturing

Our antibody-drug conjugate is produced by chemical conjugation of a non-cytotoxic linker-payload to a monoclonal antibody. We have significant internal expertise in engineering and humanization of antibodies and designing linker-payloads to customize the drug conjugate for a desired target profile. The small molecule linker-payload is chemically synthesized, and the antibody is produced by conventional biological process technology. The manufacturing process involves production of the linker-payload and antibody process intermediates, the conjugation of the intermediates to produce bulk therapeutic substance, and fill/finish of the therapeutic product.

We do not own or operate and currentlymanufacturing facilities for the production of neffy, nor do we have no plans to establish, any manufacturing facilities subject to compliance with current good manufacturing practices (cGMP). We operate on an outsourced model and rely on contracts with third-party development and manufacturing organizations designed to comply with cGMPs to produce and test the intermediates, therapeutic substance and therapeutic product to support clinical development, and commercialization, if any of our product candidates obtain marketing approval. We are working with these manufacturers to scale up our manufacturing capabilities to support our clinical plans. We also rely on third parties to package, label, store and distribute our product candidates, as well as for our commercial products if marketing approval is obtained. We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for us to invest ondevelop our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resourcesoperations for clinical materials or commercial products in the foreseeable future. We currently depend on the design and developmentthird-party contract manufacturing organizations (“CMOs”) for all of our required raw materials, drug substance and drug product candidates.for our preclinical research and clinical trials.

Commercialization Plan

We intend to retain significant developmentcurrently rely on suppliers for raw materials including drug substance and commercial rights tomultiple manufacturers for our product candidates and expect to rely on third-party suppliers and manufacturers for the commercial supply of any approved products. We currently employ internal resources and third-party consultants as needed to manage our CMOs. These CMOs offer a comprehensive range of contract manufacturing and packaging services and have successfully handled the scale up of neffy in preparation for commercialization.

neffy is presented as a nasal spray in aqueous solution with epinephrine as the active pharmaceutical ingredient (“API”) filled into glass vials and closed with a rubber stopper and assembled into the unit dose sprayer device. Over time, epinephrine is oxidized and loses potency resulting in a finite shelf-life, and the neffy solution inside the unit dose sprayer changes to an amber to brown color.

Epinephrine is the API used in neffy. We intend to use Cambrex Profarmco (“Cambrex”) as one of our commercial sources for epinephrine API. Cambrex holds a U.S. drug master file for epinephrine produced at its facility in Italy, and its manufacturing process is fully validated. We have entered into a commercial supply agreement with Cambrex, and while we believe that Cambrex has sufficient capacity to satisfy our long-term requirements, there are several sources of API available, and we intend to launch with a second source of API and are in the process of qualifying this second API source.

Dodecyl maltoside or Intravail is purchased through our license agreement with Aegis Therapeutics, Inc. from two manufacturers, Dr. Reddy Laboratories and Inalco, which are based in India and Italy, respectively.

The unit dose sprayer device used to delivery drug product in neffy is produced by Aptar Pharma (“Aptar”). Aptar produces devices in France and we believe Aptar has sufficient capacity to satisfy our long-term requirements. The patent for the Aptar unit dose nasal spray device expired in early 2020, and we believe there will be generic supplies available soon after launch.

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Manufacturing drug product for neffy is conducted by Renaissance Pharmaceuticals, Inc. (“Renaissance Pharma”), which has been actively involved in supporting the manufacture of neffy devices in our clinical development. We intend to use its facility in Lakewood, New Jersey as our primary source for drug product manufacturing and final packaging. We have entered into a commercial supply agreement with Renaissance Pharma, and believe they have sufficient capacity to satisfy our long-term requirements, although we are evaluating alternating sourcing options.

Ongoing stability studies demonstrate that neffy is stable at room temperature for at least 18 months, based on stability data from the 2.0 mg dose of neffy for 12 months and the 1.0 mg dose of neffy for 24 months, and we plan to continue to conduct ongoing registration stability studies that we anticipate will enable us to indicate on our label, if marketing approvalapproved, that neffy is obtained,stable at room temperature for 18 months at 25oC. We have also conducted studies indicating that neffy is also stable at temperature excursions including 40oC for up to commercializesix months, and at 50oC for up to three months.

Intellectual Property

We strive to protect our intranasal epinephrine product candidates onby seeking, maintaining, and defending our own, or potentially with a partner,patent rights in the United States and other regions. We currently have no sales, marketinginternationally. Our policy is to pursue, maintain and defend patent rights in strategic areas, whether developed internally or commercial product distribution capabilitieslicensed from third parties, and have no experience as a company commercializing products. We intend to build the necessary infrastructure and capabilities over time for the United States, and potentially other regions, following further advancement of our product candidates. Clinical data, the size of the addressable patient population, the size of the commercial infrastructure and manufacturing needs may all influence or alter our commercialization plans.

License Agreement

Cell Line License Agreement with WuXi Biologics (Hong Kong) Limited

In October 2019, we entered into a cell line license agreement with WuXi Biologics (Hong Kong) Limited (WuXi Bio), pursuant to which we received a non-exclusive, worldwide, sublicensable license under certain of WuXi Bio’s intellectual property rights, know-how and biological materials (WuXi Bio Licensed Technology), to make, use, sell, offer for sale and import a product developed through the use of the WuXi Bio Licensed Technology (WuXi Bio Licensed Product). The WuXi Bio Licensed Technology is used to manufacture a component of our lead product, SBT6050.

In January 2020, we paid a license fee of $100,000 to WuXi Bio. In December 2020, we incurred an additional license fee of $50,000 to WuXi Bio. Additionally, if we do not engage WuXi Bio to manufacture the WuXi Bio Licensed Products for our clinical and commercial supplies, we are required to make milestone payments to WuXi Bio upon the achievement of certain sales milestones. Under such scenarios, upon achieving certain thresholds for the aggregate annual net sales of a WuXi Bio Licensed Product, we would owe WuXi Bio aggregate milestone payments of up to $10.8 million.

The WuXi Bio Agreement will continue indefinitely unless terminated in accordance with the agreement. The WuXi Bio Agreement may be terminated (i) by us upon six months’ written notice provided we pay all amounts due to WuXi Bio through the effective date of termination, (ii) by either party for the other party’s material breach that remains uncured for 30 days after written notice, and (iii) by WuXi Bio after 45 days’ written notice if we fail to make a payment within 30 days after receiving notice of such failure.

Master Services Agreements

Master Services Agreement with CE3, Inc.

In January 2020, we entered into a master services agreement (MSA) with CE3, Inc. (CE3) pursuant to which CE3 will perform certain clinical research and administrative services in connection with our lead product SBT6050, including trial management, site selection, site management, project management, data collection and analysis, and other related services, in support of certain clinical research and trials. In addition to the fees for these services, we are obligated to pay the fees and expenses incurred in connection with the services provided by CE3.

The CE3 MSA will expire in January 2025, unless earlier terminated in accordance with the MSA. The MSA can be terminated (i) by either party at any time upon 30 days’ written notice provided any ongoing work order will continue until the termination date set forth in such work order; (ii) by either party for the other party’s material breach that remains uncured for 60 days after written notice; (iii) by either party if the other party becomes insolvent or bankrupt; or (iv) by us if either party is unable to obtain required ongoing review and/or approvals from regulatory agencies in connection with services to be performed under the MSA.

Master Laboratory Services Agreement with Q Squared Solutions LLC

In May 2020, we entered into a Master Laboratory Services Agreement (MLSA) with Q Squared Solutions LLC (Q Squared) pursuant to which Q Squared will perform certain project planning, laboratory design consultation, laboratory analysis, data management and other laboratory services in connection with our lead product SBT6050. In addition to the fees for these services, we are obligated to pay the fees, expenses and pass-through costs incurred in connection with the services provided by Q Squared.

The Q Squared MLSA will continue until May 2025, at which time it will automatically renew annually unless either party elects not to renew by providing 30 days’ written notice prior to the date of

an automatic renewal. Additionally, the MLSA can be terminated (i) by either party at any time upon 90 days’ written notice; (ii) by either party for the other party’s material breach that remains uncured for 30 days after written notice; (iii) by either party if the other party becomes insolvent or files for bankruptcy; or (iv) by Q Squared if its continued performance of services would constitute a potential or actual violation of regulatory or scientific standards of integrity.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to our business, including seeking, maintaining and defending patent rights, whether developed internally or licensed from third parties. We own the issued patents and patent applications relating to our lead product candidate SBT6050. Our policy includes seeking to protect our proprietary position by, among other methods, filing patent applications, in the United States and in jurisdictions outside of the United States, directed to our proprietary technology, inventions, improvements, and product candidates that are important to the development and implementation of our business. We also rely on trade secrets that may be important to the development of our business.

We co-own or exclusively license the patents and know-howpatent applications relating to our intranasal epinephrine product candidates. As of December 31, 2022, our patent portfolio consisted of issued patents and pending patent applications that we co-own or exclusively license from Aegis Therapeutics LLC in the United States and other countries throughout the world. In total, as of that date, our patent portfolio consisted of four issued U.S. patents, one granted Australian patent, one granted Japanese patent, one granted Chinese patent, one granted patent in South Korea, one granted European patent, three granted United Kingdom patents, three pending U.S. non-provisional patent applications, and over fifteen pending foreign patent applications directed to intranasal epinephrine formulations and methods of their use. These issued patents and pending patent applications are expected to expire as early as 2038, absent any patent term adjustments or patent term extensions for regulatory delay.

In addition to patent protection, we also rely on trademark registration, trade secrets, know how, and other proprietary technology and product candidates, continued innovation, and in-licensing opportunitiesinformation to develop strengthen and maintain our proprietary positioncompetitive position. We seek trademark protection in the field of immunotherapy.United States and in certain other jurisdictions where available and when we deem appropriate. We also plan to rely on data exclusivity, market exclusivity,currently have registrations for our “neffy” mark in the United States as well as in foreign jurisdictions, including the United Kingdom, European Union, and patent term extensions when available. Japan.

Our commercial success will depend in part on our ability to obtainobtaining and maintainmaintaining patent protection and other proprietarytrade secret protection for our technology, inventions, and improvements; to preserve the confidentiality of our trade secretscurrent and know-how;future product candidates and the methods used to obtaindevelop and maintain licenses to use intellectual property owned by third parties; to defend and enforce our proprietary rights, including any patents that we may own in the future; and to operate without infringing on the valid and enforceable patents and other proprietary rights of third parties.

As of February 28, 2021, our licensed and owned patent portfolio included four owned U.S. patents, 23 owned U.S. provisional and non-provisional patent applications, 13 owned patent applications filed under the Patent Cooperation Treaty (PCT), 50 owned foreign patent applications filed in 16 different countries or regions, including in Australia, Brazil, Canada, China, European region, Hong Kong, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia, Singapore, Taiwan, and South Africa, directed to TLR8 agonists and conjugates, including SBT6050, TGFßR1 antagonists and conjugates, TGFßR2 antagonists and conjugates, TLR7 agonists and conjugates, and various applications of our proprietary antibody conjugates and antibodies, including antibodies specific for Nectin4 and ASGR,manufacture them, as well as certain of our other proprietary antibodies, compounds, conjugates, formulations, technology, inventions, improvements, and other product candidates. Anysuccessfully defending these patents that issue from these pending patent applications will expire between March 2038 and October 2041, absent any patent term adjustments or extensions. We also possess and/or in-license substantial know-how and trade secrets relating to the development and commercialization of our product candidates, including related manufacturing processes and technology.

Specifically, our patent portfolio includes the following families and/or groups of families:

With respect to our product candidates and processes, we intend to develop and commercialize in the normal course of business, and we intend to pursue patent protection directed to, when possible, compositions, methods of use, methods of making, dosing, and formulations. We may also pursue patent protection with respect to manufacturing, therapeutic development processes and technologies, and therapeutic delivery technologies.

Issued patents can provide protection for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance, and the legal term of patents in the countries in which they are obtained. In general, patents issued for applications filed in the United States can provide exclusionary rights for 20 years from the earliest effective filing date. In addition, in certain instances, the term of an issued U.S. patent that is directed to or claims an FDA approved product can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period, which is called patent term extension. The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval. The term of patents outside of the United States varies in accordance with the laws of the foreign jurisdiction, but typically is also 20 years from the earliest effective filing date. However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its claims, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, and the validity and enforceability of the patent.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. No consistent policy regarding the scope of claims allowable in patents in the field of immunotherapy has emerged in the United States. The relevant patent laws and their interpretation outside of the United States is also uncertain. Changes in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our technology or product candidates and enforce the patent rights that we license, and could affect the value of such intellectual property. In particular, ouragainst third-party challenges. Our ability to stop third parties from making, using, selling, offering to sell or importing our products that infringe our intellectual property will depend in partdepends on our success in obtainingthe extent to which we have rights under valid and enforcing patent claimsenforceable patents or trade secrets that cover our technology, inventions, and improvements. With respect to both licensed and company-owned intellectual property, wethese activities. We cannot guaranteebe sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may filefiled by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our product candidates and processes. For this and more comprehensive risks related to our intellectual property, please see “Risk Factors—Risks Related to Our Intellectual Property.”

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application. In the United States, the patent term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process. The Drug Price Competition and Patent Term Restoration Act of 1984 (the “Hatch-Waxman Act”) permits a patent term extension of up to five years beyond the expiration of the patent. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our products the methods of use or manufacture ofreceive FDA approval, we expect to apply for patent term extensions on patents covering those products. Moreover, even theWe plan to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

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We also seek to protect our intellectual property in part by entering into confidentiality agreements with companies with whom we share proprietary and confidential information in the course of business discussions, and by having confidentiality terms in our agreements with our employees, consultants, scientific advisors, clinical investigators, and other collaborators and contractors and also by requiring our employees, commercial contractors, and certain consultants and investigators, to enter into invention assignment agreements that grant us ownership of any discoveries or inventions made by them while in our employ. However, such confidentiality agreements and invention assignment agreements can be breached, and we may not have adequate remedies for any such breach. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

The patent positions of specialty pharmaceutical companies like ours are generally uncertain and involve complex legal, scientific and factual questions. Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, or our drugs or processes, obtain licenses or cease certain activities. Our breach of any license doagreements or our failure to obtain a license to proprietary rights required to develop or commercialize our future products may have a material adverse impact on us. If third parties prepare and file patent applications in the United States that also claim technology to which we have rights, we may have to participate in interference or derivation proceedings in the U.S. Patent and Trademark Office (the “USPTO”) to determine priority of invention. For more information, see “Risk Factors—Risks Related to Our Intellectual Property.”

Our Collaboration and Licensing Agreements

License Agreement with Aegis

In June 2018, we entered into a license agreement with Aegis Therapeutics, LLC (“Aegis”), which was amended in July 2020 and January 2021. Pursuant to the agreement, Aegis granted us an exclusive, worldwide, sublicensable license under patents and know-how relating to the INTRAVAIL drug delivery technology to research, develop, make (subject to Aegis supplying the INTRAVAIL drug delivery technology to us under a supply agreement), use, sell, offer for sale, import, and otherwise commercialize products incorporating epinephrine compounds (“Aegis Licensed Compounds”), including the neffy nasal spray. During the term of the agreement, we are required to use commercially reasonable efforts to obtain regulatory approval for products containing one or more Aegis Licensed Compounds and using the excipient (including INTRAVAIL) (“Aegis Licensed Products”) and to thereafter maximize sales of the Aegis Licensed Products, and Aegis may not guarantee usdirectly or indirectly exploit an Aegis Licensed Product or Aegis Licensed Compound or derivatives thereof without our consent.

Under the agreement, Aegis received an upfront license fee of $50,000 and is entitled to receive development milestone payments of up to $3.95 million in aggregate and commercialization milestone payments up to $16.0 million in the aggregate for each Aegis Licensed Product. We made a $0.5 million milestone payment to Aegis upon the achievement of a regulatory milestone during 2019, and a $1.0 million payment to Aegis upon the FDA’s acceptance of our US NDA filing, which occurred in the third quarter of 2022. We will be required to pay Aegis a milestone payment of $2.5 million contingent upon the FDA approval of the first Aegis Licensed Product and a milestone payment of $5.0 million contingent upon first commercial sale of the first Aegis Licensed Product. Additionally, Aegis is entitled to receive a low- to mid-single-digit percentage royalty, subject to reductions under certain conditions including due to generic competition or below threshold levels of profitability in specific countries around the world, on net sales of all Aegis Licensed Products during the applicable royalty term, which commences on the first commercial sale of a Aegis Licensed Product in a country and ends upon the later of the expiration of all licensed patents covering such Aegis Licensed Product in such country or 15 years after the date of the first commercial sale of the Aegis Licensed Product in such country (“Aegis Royalty Term”).

The agreement will continue until the expiration of the last-to-expire Aegis Royalty Term, unless sooner terminated. We have the right to practiceterminate the agreement at any time after a specified notice period to Aegis. Either party may terminate the agreement for uncured material breach of the other party, or upon notice for insolvency-related events of the other party that are not discharged within a defined time period.

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Collaboration and License Agreement with Alfresa

In April 2020, we entered into a collaboration and license agreement with Alfresa Pharma Corporation (“Alfresa”). Pursuant to the agreement, we granted Alfresa (i) an exclusive, sublicensable license under our patents relating to neffy to develop, use and import epinephrine compositions (“Alfresa Licensed Compositions”) and related products (“Alfresa Licensed Products”) in Japan (the “Alfresa Territory”) and to promote, distribute, offer for sale and sell Alfresa Licensed Products in the Alfresa Territory, and (ii) a non-exclusive, sublicensable license to manufacture and commercialize Alfresa Licensed Products under the license described in clause (i), under our technology to make and have made Alfresa Licensed Compositions and Alfresa Licensed Products in relation toand outside the commercializationAlfresa Territory solely for the purpose of our products. Patent and other intellectual property rightsexercising the license described in clause (i) in the pharmaceuticalAlfresa Territory. We expressly reserved all rights to practice and biotechnology space are evolving and involve many risks and uncertainties. For example, third parties may have blocking patents that could be used to prevent us from commercializinggrant licenses under our product candidates and practicing our proprietary technology and the issued patents that we in-license and those that may issue in the future may be challenged, invalidated, or circumvented, which could limit our ability to stop competitors from marketing related products or could limit the term of patent protection that otherwise may exist for our product candidates. In addition, the scope of the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology.

Furthermore, our competitors may independently develop similar technologies that are outside the scope of the rightslicenses granted under any issued patents that we own or exclusively in-license. For these reasons, we may face competition with respect to our product candidates. Moreover, becauseAlfresa, including the right to manufacture Alfresa Licensed Compositions and Alfresa Licensed Products in the Alfresa Territory. During the term of the extensive timeagreement, (1) we and Alfresa are obligated to use commercially reasonable efforts to develop a Alfresa Licensed Product throughout the Alfresa Territory, and (2) Alfresa is obligated to use commercially reasonable efforts to (A) seek pricing and reimbursement approval, (B) seek and maintain regulatory approval for the Alfresa Licensed Products through the Alfresa Territory, and (C) market, promote and otherwise commercialize Alfresa Licensed Products in the field throughout the Alfresa Territory.

Under the agreement, we received a one-time upfront payment of $2.0 million and earned $5 million upon the achievement of a clinical milestone during 2021. We are eligible to receive regulatory milestones of up to $8.0 million in the aggregate. Further, we are eligible to receive a negotiable transfer price expected to be in the low double-digit percentage on net sales subject to the regulatory approval to commercialize neffy in Japan. We share the cost of any additional clinical studies required for development, testingapproval of neffy in Japan. Additionally, Alfresa is obligated to either (i) enter into a commercial supply agreement with us pursuant to which we will supply drug product for commercial sale at an agreed upon transfer price, or (ii) if Alfresa elects to manufacture its own supply of drug product, pay us a royalty payment on the net sales of drug product in the Alfresa Territory in an amount equal to monetary value we would receive by supplying drug product to Alfresa at the transfer price.

The agreement will continue until the later of (i) expiration of the last-to-expire valid claim of our patents or joint patent with Alfresa covering the composition, method of manufacture or method of use in the field of any Alfresa Licensed Product in the Alfresa Territory, and (ii) 10 years after the first commercial sale of any Alfresa Licensed Product in the Alfresa Territory. Alfresa has the right to terminate the agreement (1) at any time after a specified notice period to us, or (2) upon notice to us if a binding decision is rendered invalidating any of our patents. Either party may terminate the agreement for uncured material breach of the other party, or upon notice for insolvency-related events of the other party that are not discharged within a defined time period.

Collaboration and Distribution Agreement with Pediatrix

In March 2021, we entered into a collaboration and distribution agreement with Pediatrix Therapeutics (“Pediatrix”). Pursuant to the agreement, we granted Pediatrix (i) an exclusive, royalty-bearing, sublicensable license under our patents relating to neffy to develop, use, register and import epinephrine compositions (“Pediatrix Licensed Compositions”) and related products (“Pediatrix Licensed Products”) in China, Macau, Hong Kong and Taiwan (the “Pediatrix Territory”) and to promote, offer for sale and sell Pediatrix Licensed Products in the Pediatrix Territory; and (ii) an exclusive, royalty-bearing, sublicensable license to manufacture Pediatrix Licensed Compositions and Pediatrix Licensed Products solely for the purpose of exercising the license described in clause (i) in the Pediatrix Territory. We expressly reserved all rights to practice and grant licenses under our technology outside the scope of the licenses granted to Pediatrix. During the term of the agreement, Pediatrix is obligated to use commercially reasonable efforts to (1) develop the Pediatrix Licensed Products throughout the Pediatrix Territory, (2) prepare, obtain, maintain and renew all necessary regulatory reviewapprovals for the Pediatrix Licensed Products in the Pediatrix Territory, and (3) market, promote and otherwise commercialize the Pediatrix Licensed Products throughout the Pediatrix Territory.

Under the agreement, we received a one-time upfront payment of $3.0 million and are eligible to receive a regulatory milestone payment of $4.0 million and net sales milestone payments of up to $80.0 million in the aggregate. We will receive a per unit supply price for any sale of commercial supply to Pediatrix. Additionally, we are eligible to receive a tiered royalty on the net sales of all Pediatrix Licensed Products during the applicable royalty term, which is less than one percent below a minimum annual sales threshold, and increasing to low-to-mid double-digit percentages above the minimum annual sales threshold, subject to reductions under certain conditions including due to generic competition. Pediatrix’s obligation to pay us royalties continues on a Pediatrix Licensed Product-by- Pediatrix Licensed Product and region-by-region basis in the Pediatrix Territory, until the latest of (i) expiration of the last-to-expire valid claim of our patents covering such Licensed Product in such region; (ii) the expiration of all regulatory exclusivities that cover such Licensed Product in such region; or (iii) ten years after the first commercial sale of such Pediatrix Licensed Product in such region (the “Pediatrix Royalty Term”).

The agreement will continue until the expiration of the last-to-expire Pediatrix Royalty Term. Pediatrix has the right to terminate the agreement at any time after a specified notice period to us. Either party may terminate the agreement for uncured material breach of the other party, or upon notice for insolvency-related events of the other party that are not discharged within a defined time period.

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Manufacturing Agreement with Renaissance

In September 2020, we entered into a manufacturing agreement with Renaissance Lakewood, LLC (“Renaissance”). Pursuant to the agreement, Renaissance agreed to manufacture for, and provide to us, neffy nasal unit dose sprays (“Renaissance Products”). We are obligated to provide Renaissance with certain supplies to manufacture the Renaissance Products and to purchase from Renaissance a mid double-digit percentage of our annual aggregate Renaissance Product requirements in the EU, and a high double-digit percentage of our annual aggregate Renaissance Product requirements in the U.S. The agreement contains conventional commercial pharmaceutical manufacturing provisions including certain minimum purchase amounts to be determined in the future based on forecast needs and minimum batch size projections. We may also request Renaissance perform certain services related to the Renaissance Product, for which we will pay reasonable compensation to Renaissance.

The initial term of the agreement commenced on the date it was entered into and continues (a) for Renaissance Product designated for commercial sale in the U.S. until the earlier of the fifth anniversary of the (i) target U.S. launch date and (ii) the initial U.S. launch date (“U.S. Initial Term”), and (b) for Renaissance Product designated for commercial sale in the EU and other countries, the earlier of the fifth anniversary of (i) the target EU launch date and (ii) the initial EU launch date (“EU Initial Term”), in each case unless earlier terminated by one of the parties. The U.S. Initial Term and EU Initial Term automatically renew for successive two-year terms (“Renewal Term”). Either party may elect not to renew the U.S. Renewal Term and/or the EU Renewal Term by providing the requisite prior notice to the other party. Either party may terminate the agreement (1) for uncured material breach of the other party, (2) upon notice for insolvency-related events of the other party that are not discharged within a defined time period, (3) on a product-by-product basis if the manufacture, distribution or sale would materially contravene any applicable law, (4) by providing the requisite notice if (a) we have not submitted a regulatory filing for any Renaissance Product in the U.S. on or before June 30, 2022, (b) the authorization and approval to distribute or sell Renaissance Product in the U.S. is not granted on or before the target U.S. launch date, (c) the authorization and approval representing more than a targeted number of units of Renaissance Product sold in the U.S. during the last calendar year is withdrawn by the FDA, or (d) we decided in our sole discretion to cease commercializing the Renaissance Product in the U.S., (5) in the case of a potential product, it is possibleforce majeure event that before any particular product candidate can be commercialized, any patent protectioncontinues for such product may expiresix months or remainmore, or (6) a violation by the other party of trade control or anti-corruption laws.

Government Regulation and Product Approval

As a pharmaceutical company that operates in force for only a short period following commercialization, thereby reducing the commercial advantage the patent provides.

Government Regulation

United States, we are subject to extensive regulation. Government authorities in the United States at(at the federal, state and local levellevel) and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture,manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products such as our investigational medicines and any future investigational medicines. Generally, before a new drug or biologic can be marketed, considerable data demonstrating its quality, safety and efficacythose we are developing. Product candidates that we develop must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

Regulatory ApprovalFDA, before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries. Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences. Additionally, some significant aspects of regulation in Europe are addressed in a centralized way, but country-specific regulation remains essential in many respects.

Regulation of Combination Products in the United States

neffy is comprised of drug and delivery device components that would normally be subject to different regulatory frameworks by the FDA and frequently regulated by different centers at the FDA. These products are known as combination products. Under the Federal Food, Drug and Cosmetic Act (“FDCA”), the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product. The determination of which center will be the lead center is based on the “primary mode of action” of the combination product. Thus, if the primary mode of action of a drug-device combination product is attributable to the drug product, the FDA center responsible for premarket review of the drug product would have primary jurisdiction for the combination product.

A combination product with a primary mode of action attributable to the drug component, such as neffy, generally would be reviewed and approved pursuant to the drug approval processes set forth in the FDCA. In reviewing the NDA for such a product, however, FDA reviewers would consult with their counterparts in the device center to ensure that the device component of the combination product – the sprayer - met applicable requirements regarding safety, effectiveness, durability and performance. In addition, under FDA regulations, combination products such as neffy are subject to cGMP requirements applicable to both drugs and devices, including the Quality System Regulations applicable to medical devices.

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U.S. Drug Development Process

In the United States, pharmaceutical productsthe FDA regulates drugs under the FDCA, and implementing regulations. A new drug must be approved by the FDA through the NDA process before it may be legally marketed in the United States. Drugs are also subject to extensive regulation by the FDA. The FDCA, and other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations govern, among other things,require the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotionexpenditure of substantial time and marketing, distribution, post- approval monitoring and reporting, sampling, and import and export of pharmaceutical products. Biological products used for the prevention, treatment or cure of a disease or condition of a human being are subject to regulation under the FDCA, except the section of the FDCA that governs the approval of new drug applications, NDAs. Biological products, such as our ImmunoTAC product candidates, are approved for marketing under provisions of the Public Health Service Act (PHSA), via a BLA. However, the application process and requirements for approval of BLAs are very similar to those for NDAs, and biologics are associated with similar approval risks and costs as drugs.financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject a companyan applicant to a variety of administrative or judicial sanctions. FDA sanctions such as clinical hold, FDAcould include, among other actions, refusal to approve pending NDAs or BLAs,applications, withdrawal of an approval, a clinical hold, warning or untitled letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil penalties andor criminal prosecution.

Our investigational medicines and any future investigational medicines must be approvedpenalties. Any agency or judicial enforcement action could have a material adverse effect on us. The process required by the FDA pursuant tobefore a BLA before theydrug may be legally marketed in the United States. The processStates generally involves the following:

The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, or at all.

Preclinical Studies

Before testing any biological product candidatescompounds with potential therapeutic value in humans, the product candidate must undergo rigorousenters the preclinical testing.testing stage. Preclinical studiestests include laboratory evaluationevaluations of product candidateschemistry, toxicity and formulations,formulation, as well asin vitro and animal studies, to assess the potential for adverse eventssafety and in some cases to establish a rationale for therapeutic use.activity of the product candidate. The conduct of the preclinical studies is subject totests must comply with federal regulations and requirements including GLP regulations for safety/toxicology studies. An INDrequirements. The sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans fora proposed clinical studies, among other things,protocol, to the FDA as part of anthe IND. An IND is a request for authorization from the FDA to administer an investigational drug product to humanshumans. The central focus of an IND submission is on the general investigational plan and must become effective beforethe protocol(s) for human clinical trials may begin.trials. Some long-term preclinical testing may continue even after the IND is submitted. AnThe IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or moreregarding the proposed clinical trials and places the trialIND on clinical hold.hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. AsThe FDA may also impose clinical holds on a result, submission of an IND may not result in the FDA allowingproduct candidate at any time before or during clinical trials due to commence.safety concerns or non-compliance.