10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year endedDecember 31, 2023

Commission File Number 001-39661

ATEA PHARMACEUTICALS, INC.

(Exact name of registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (857) 284-8891

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

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common Stock, $0.001 par value per share AVIR The Nasdaq Global Select Market

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 ☐No☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. YES ☐No☒

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

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

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

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 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 registrant is a shell company (as defined in Rule 12b-2 of the Act). YES ☐ NO ☒

As of June 30, 2023, the aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant, based on the last reported sales price for the registrant’s common stock, par value $0.001 per share, on the Nasdaq Global Select Market on such date, was approximately $283.7 million.

The number of shares of Registrant’s Common Stock outstanding as of February 25, 2024 was 84,164,545.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s definitive proxy statement for its 2024 Annual Meeting of Stockholders, which the registrant intends to file with the Securities and Exchange Commission within 120 days after the end of the registrant’s fiscal year ended December 31, 2023, are incorporated by reference into Part III of this Annual Report on Form 10-K.

Table of Contents

Page

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS ii

SUMMARY RISK FACTORS iv

PART I

Item 1. Business 1

Item 1A. Risk Factors 50

Item 1B. Unresolved Staff Comments 122

Item 1C. Cybersecurity 122

Item 2. Properties 123

Item 3. Legal Proceedings 123

Item 4. Mine Safety Disclosures 123

PART II

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 138

Item 8. Financial Statements and Supplementary Data 138

Item 9A. Controls and Procedures 138

Item 9B. Other Information 139

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 139

PART III

Item 10. Directors, Executive Officers and Corporate Governance 140

Item 11. Executive Compensation 140

Item 14. Principal Accountant Fees and Services 140

PART IV

Item 15. Exhibits, Financial Statement Schedules 141

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical development timelines and results and other future conditions. The words “aim,” “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” "objective," "on track," “plan,” “possible,” “potential,” “predict,” “project,” “seek,” “should,” “target,” “will,” “would” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

These forward-looking statements include, among other things, statements about:

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our expectations relating to clinical trials for our product candidates, including projected costs, study designs and the timing for initiation, recruitment, completion, and reporting interim, top-line and final data;

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the potential therapeutic benefits of our product candidates and the potential indications and market opportunities therefor;

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the potential of bemnifosbuvir to retain antiviral activity against circulating COVID-19 variants of concern and to treat Coronavirus disease 2019 ("COVID-19");

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the safety profile and related adverse events of our product candidates;

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our plans to research, develop and commercialize our current and future product candidates;

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the potential benefits of any future collaboration we may enter into;

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the timing of and our ability to obtain and maintain regulatory approvals for our product candidates;

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the rate and degree of market acceptance and clinical utility of any products for which we may receive marketing approval;

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our manufacturing and commercialization capabilities and strategy;

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our estimates regarding future revenue, expenses and results of operations;

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the progress of, timing of and amount of expenses associated with our research, development and commercialization activities;

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our future financial position, capital requirements, cash runway, needs for additional financing and the availability of such financing;

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our business strategy;

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developments relating to our industry and our competitors, including competing treatments and vaccines for diseases we are treating;

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our expectations regarding federal, state and foreign laws and regulations;

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our ability to attract, motivate, and retain key personnel; and

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the impact on our business as COVID-19 continues to evolve.

These forward-looking statements are based on management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important 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 the forward-looking statements. Factors that may cause actual results to differ materially from current expectations include the initiation, execution

and completion of clinical trials, uncertainties surrounding the timing of availability of data from our clinical trials, ongoing discussions with and actions by regulatory authorities, our development activities and those other factors we discuss in Part I, Item 1A. “Risk Factors.” You should read these risk factors and the other cautionary statements made in this report as being applicable to all related forward-looking statements wherever they appear in this report. The risk factors are not exhaustive and other sections of this report may include additional factors which could adversely impact our business and financial performance.

Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Preliminary and interim results from any trial and results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. Moreover, we operate in a very competitive and rapidly changing environment. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors nor can we assess the impact 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, or implied by, any forward-looking statements.

Given these uncertainties, you should not rely on these forward-looking statements as predictions of future events. Except as required by law, we assume no obligation to update or revise these forward-looking statements for any reason, even if new information becomes available in the future.

As used in this Annual Report on Form 10-K, unless otherwise specified or the context otherwise requires, the terms “we,” “our,” “us,” and the “Company” refer to Atea Pharmaceuticals, Inc. and its subsidiary. All brand names or trademarks appearing in this Annual Report on Form 10-K are the property of their respective owners.

iii

SUMMARY RISK FACTORS

Our business is subject to numerous risks and uncertainties, including those described in Part I, Item 1A. “Risk Factors” in this Annual Report on Form 10-K. The principal risks and uncertainties affecting our business include the following:

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There is significant uncertainty around our development of bemnifosbuvir as a potential treatment for COVID-19.

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We are expending significant resources to develop bemnifosbuvir for the treatment of COVID-19 and to develop the combination of bemnifosbuvir and ruzasvir for the treatment of Hepatitis C virus ("HCV") and in anticipation of potential commercialization of these product candidates. We may not be able to recover these resources if these product candidates are not approved for the treatment of the respective indication for which they are being developed, we are not successful at commercializing these product candidates or in the case of the development of bemnifosbuvir for the treatment of COVID-19, bemnifosbuvir is rendered inferior or obsolete due to rapid changes in COVID-19 epidemiology as a result of the emergence of new SARS-CoV-2 variants or subvariants.

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If approved, each of our product candidates will face significant competition from other treatments, including direct acting antivirals, that are currently marketed and in the case of COVID-19, are in development.

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Our business, operations and financial results may be materially and adversely affected by the continuing evolution of COVID-19.

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We have a limited operating history and no history of successfully developing or commercializing any approved antiviral products, which may make it difficult to evaluate the success of our business to date and to assess the prospects for our future viability.

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We have incurred significant operating expenses since inception. We expect our expenditures will increase for the foreseeable future. We have no products that have generated any commercial revenue and we may not again achieve or maintain profitability.

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We will require substantial additional financing, which may not be available on acceptable terms, or at all. A failure to obtain this necessary capital when needed could force us to delay, limit, reduce or terminate our product development or commercialization efforts.

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Our ability to use our net operating loss carryforwards and other tax attributes to offset taxable income may be subject to certain limitations.

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Our business is highly dependent on the success of our most advanced product candidates. If we fail to successfully develop bemnifosbuvir for the treatment of COVID-19 or the combination of bemnifosbuvir and ruzasvir for the treatment of HCV or we are unable to obtain regulatory approval or successfully commercialize any of our product candidates, or are significantly delayed in doing so, our business will be harmed.

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The regulatory approval processes of the U.S. Food and Drug Administration (“FDA”) and comparable foreign regulatory authorities are lengthy, expensive, time-consuming and inherently unpredictable.

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Clinical development, including enrollment of patients in clinical trials, is an expensive, lengthy and uncertain process. We may encounter substantial delays and costs in our clinical trials, or may not be able to conduct or complete our clinical trials on the timelines we expect, if at all.

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We intend to develop certain of our product candidates in combination with other product candidates that we discover or acquire, which exposes us to additional risks.

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Our product candidates may be associated with serious adverse events, undesirable side effects or have other properties that could halt their clinical development, prevent their

regulatory approval, limit their commercial potential or result in significant negative consequences.

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We currently conduct and may in the future conduct clinical trials of our product candidates in sites outside the United States ("US"). The FDA may not accept data from trials conducted in foreign locations.

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Interim, topline and preliminary data from our clinical trials that we announce or publish from time to time may change as more data become available and are subject to audit and verification procedures that could result in material changes in the final data.

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We may not be successful in our efforts to identify and successfully develop additional product candidates.

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Risks related to healthcare laws and other legal compliance matters may materially and adversely affect our business and financial results.

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Risks related to commercialization may materially and adversely affect our business and financial results.

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Risks related to manufacturing and our dependence on third parties may materially and adversely affect our business and financial results.

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Risks related to intellectual property may materially and adversely affect our business and financial results.

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We are highly dependent on our management, directors and other key personnel.

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We have only a limited number of employees, which may be inadequate to manage and operate our business.

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We may need to expand our organization, and we may experience difficulties in managing this growth, which could disrupt our operations.

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Our business and operations may suffer in the event of system failures, security breaches, deficiencies or intrusions which could materially affect our results.

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We may engage in acquisitions or strategic collaborations that could disrupt our business, cause dilution to our stockholders, reduce our financial resources, cause us to incur debt or assume contingent liabilities, and subject us to other risks.

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We or the third parties whom we depend upon may be adversely affected by natural disasters or other unforeseen events resulting in business interruptions and our business continuity and disaster recovery plans may not adequately protect us from such business interruptions.

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Increased attention to, and evolving expectations for, environmental, social, and governance (“ESG”) initiatives could increase our costs, harm our reputation, or otherwise adversely impact our business.

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Litigation against us could be costly and time-consuming to defend and could result in additional liabilities.

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

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Risks related to our common stock may materially and adversely affect our stock price.

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If we fail to maintain effective internal control over financial reporting and effective disclosure controls and procedures, we may not be able to accurately report our financial results in a timely manner or prevent fraud, which may adversely affect investor confidence in our company.

PART I

Item 1. Business.

Overview

We are a clinical-stage biopharmaceutical company leveraging our deep understanding of antiviral drug development, medicinal chemistry, biology, biochemistry and virology to discover and develop novel orally administered product candidates to treat serious viral diseases. Currently, we are developing our lead product candidate, bemnifosbuvir, in a global Phase 3 clinical trial as a monotherapy for the treatment of COVID-19, and in a global Phase 2 clinical trial as part of a combination therapy with ruzasvir, an NS5A inhibitor, for the treatment of HCV infection.

Bemnifosbuvir

Derived from our internal discovery program, bemnifosbuvir (AT-527), is an investigational, novel, orally administered guanosine nucleotide analog polymerase inhibitor that combines a unique nucleotide scaffold with novel double prodrugs for the intended purpose of inhibiting the enzymes central to viral replication. We believe that utilizing this double prodrug moiety approach allows us to maximize formation of the active metabolite potentially resulting in an oral antiviral product candidate that is selective for and highly effective at preventing replication and transcription of SARS-CoV-2, the causative agent of COVID-19, HCV and other single stranded RNA (“ssRNA”) viruses while avoiding toxicity to host cells.

COVID-19 – Our Strategy and Objective

More than four years after emerging as a global pandemic and public health crisis, COVID-19 remains a persistent and serious health threat because of continued variant fueled surges of infection. The SARS-CoV-2 virus is accumulating mutations with amino acid substitutions faster than any other endemic ssRNA virus and the constant evolution of new variants has resulted in continued waves of infections globally.

Our COVID-19 strategy is focused on the development of bemnifosbuvir for the treatment of COVID-19. We believe that oral antivirals protecting against the development of severe infection and transmission remain urgently needed particularly for high-risk patients who currently have few or no treatment options due to limitations of currently available vaccines and therapeutics. High-risk patients include those who are unvaccinated, patients who fail to respond to available vaccines, vaccinated patients with waning efficacy, which can occur between three to six months after immunization, and patients for whom current treatments are contraindicated. Without suitable treatments, high-risk patients remain vulnerable to severe COVID-19 and associated hospitalization and death.

As COVID-19 continues to persist as a global endemic disease, we believe that the global COVID-19 therapeutic market, and in particular the US market, will remain a multi-billion-dollar commercial opportunity for many years to come. Further, as the commercialization of COVID-19 therapeutics enters more fully into traditional distribution and reimbursement channels in 2024 and after, we anticipate that a major consideration for third-party payers will be a cost/value analysis that is driven in part by the economic burden of hospitalization, especially for high-risk populations.

The objective of our COVID-19 development program is to address the current unmet medical needs of high-risk patients who remain vulnerable to hospitalization and death from COVID-19 by developing bemnifosbuvir, as a safe, effective, convenient, oral antiviral without the key limitations of current treatment options, including drug-drug interactions, tolerability and other safety concerns. The FDA has granted Fast Track designation for the investigation of bemnifosbuvir to treat COVID-19. Currently, we are evaluating bemnifosbuvir in SUNRISE-3, a global Phase 3 clinical trial that is enrolling high-risk patients with mild to moderate COVID-19.

For COVID-19, bemnifosbuvir targets the SARS-CoV-2 RNA polymerase (Nsp12), a highly conserved enzyme that is unlikely to change as the virus mutates and new variants continue to emerge. The RNA polymerase complex is responsible for both replication and transcription of SARS-CoV-2. Bemnifosbuvir

has a unique dual mechanism of action at both the RNA-dependent RNA polymerase ("RdRp") and nidovirus RdRp associated nucleotidyltransferase ("NiRAN") active sites on the highly conserved SARS-CoV-2 RNA polymerase, which has the potential to create a high barrier to resistance. In vitro data have shown that bemnifosbuvir was active with similar activity against all SARS-CoV-2 variants of concern ("VOC") and variants of interest ("VOI") that have been tested to date, including Omicron subvariants BA.4, BA.5 and XBB and EG.5.1.

HCV – Our Strategy and Objective

Despite the availability of direct acting antiviral oral combination treatment regimens, HCV continues to be a serious viral disease in the US and globally. Approximately 58 million people globally are living with chronic HCV infection. The World Health Organization ("WHO") estimates a global incidence of 1.5 million new infections and 290,000 deaths per year.

In the US, HCV is recognized as a health crisis with approximately 2.4 million individuals estimated to be infected. Prevalence of HCV in the US is expected to remain constant over the coming years as rising HCV incidence is largely attributable to the opioid crisis, IV drug use, and HCV reinfection, especially among younger adults, offsets the number of new patients treated.

Our HCV strategy focuses on the development of bemnifosbuvir in combination with ruzasvir, an HCV NS5A inhibitor, a product candidate which we have exclusively licensed from MSD International GmbH, an affiliate of Merck & Co, Inc. ("Merck"). Combination therapy utilizing two or more direct acting antivirals with different mechanisms of action is a scientifically and clinically well-established approach that is utilized by currently available human immunodeficiency virus, hepatitis B virus and HCV treatment regimens.

The objective of our HCV development program is to improve upon the current standard of care ("SOC") by offering, if successfully developed, the combination of bemnifosbuvir and ruzasvir, as a potentially differentiated eight-week duration, pan-genotypic protease inhibitor-free regimen for HCV-infected patients with or without cirrhosis. Currently, we are conducting a Phase 2 clinical trial of bemnifosbuvir in combination with ruzasvir in treatment naïve HCV infected patients, either without cirrhosis or with compensated cirrhosis.

For HCV, the combination of bemnifosbuvir and ruzasvir targets the HCV non-structural protein 5B (“NS5B”) and the HCV non-structural protein 5A (“NS5A”), respectively, and is designed to inhibit these enzymes which are essential for HCV replication. Both bemnifosbuvir and ruzasvir have individually demonstrated potent, pan-genotypic, antiviral activity against HCV and the combination of bemnifosbuvir and ruzasvir has exhibited synergistic activity against HCV in vitro.

Key Clinical Trials

COVID-19 – SUNRISE-3: Global Phase 3 Clinical Trial of Bemnifosbuvir

SUNRISE-3, is a currently ongoing global, multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial that is evaluating bemnifosbuvir (550 mg twice-daily ("BID") for five days) in high-risk non-hospitalized patients with mild or moderate COVID-19. SUNRISE-3 is designed to evaluate bemnifosbuvir as monotherapy (primary analysis) but it is also exploring the effect of combination therapy in a smaller sub-set of patients who receive a compatible antiviral drug along with bemnifosbuvir (secondary analysis).

The trial consists of two study populations derived from the type of SOC received: 1) a “supportive care population” (those patients who do not qualify for another antiviral treatment or where other antivirals are not locally available) which is assessing bemnifosbuvir given as monotherapy (primary analysis) and 2) a “combination antiviral population” which is assessing combination therapy if the SOC includes treatment with other compatible antiviral drugs against COVID-19 (secondary analysis). Patients are being randomized 1:1 to receive either bemnifosbuvir 550 mg BID plus locally available SOC or placebo BID plus locally available SOC for five days.

The primary endpoint of the SUNRISE-3 study is all-cause hospitalization or death through Day 29 in approximately 2,200 patients in the supportive care monotherapy population. Secondary endpoints in each of the supportive care monotherapy patient population and the combination antiviral population

include COVID-19 related hospitalization or death, COVID-19 complications, medically attended visits, symptom rebound/relapse and viral load rebound.

The trial is enrolling patients who are ≥70 years old (regardless of other risk factors), patients ≥55 years old with one or more risk factors, patients ≥50 years old with two or more risk factors and patients ≥18 years old with certain risk factors including immunocompromised conditions, all regardless of COVID-19 vaccination status. We believe that this population encompasses those patients who currently remain at high-risk for progression of COVID-19 to severe disease and associated hospitalization and death.

In January and February 2024, we announced the enrollment of more than 650 patients and more than 1,350 patients, respectively, in the supportive care monotherapy cohort. Each of these patient enrollment milestones triggers an interim analysis by an independent data safety monitoring board (“DSMB”) principally for safety and futility after the respective patient group has completed Day 29 post treatment. As a result, we currently anticipate that the first interim analysis by the DSMB will occur in March of 2024 and the second interim analysis by the DSMB will occur in the second quarter of 2024. Patient enrollment in the SUNRISE-3 trial, which has currently surpassed 1,400 patients in the supportive care monotherapy population, continues and topline data from the trial are anticipated in the second half of 2024.

HCV – Global Phase 2 Clinical Trial of the Combination of Bemnifosbuvir and Ruzasvir

Currently, we are conducting a global Phase 2 clinical trial of bemnifosbuvir in combination with ruzasvir in treatment-naïve, HCV-infected patients either without cirrhosis or with compensated cirrhosis. This study is designed to evaluate the safety and efficacy of eight weeks of treatment with the combination consisting of once daily bemnifosbuvir 550 mg and ruzasvir 180 mg. Up to approximately 280 HCV-infected, treatment-naïve patients across HCV genotypes (“GT”), including a lead-in cohort of 60 patients without cirrhosis, are expected to be enrolled in this Phase 2 clinical trial. The primary endpoints of the study are safety and sustained virologic response ("SVR") at Week 12 post-treatment (“SVR12”). Other virologic endpoints include virologic failure, SVR at Week 24 post-treatment (“SVR24”) and resistance.

In February 2024, we announced final results from the full lead-in cohort in which a 98% SVR at Week 4 post-treatment ("SVR4") rate was observed [58 of 59 subjects achieved SVR4 with one patient who did not return for post-treatment follow-up]. The one patient who did not achieve SVR4 had poor adherence, and was infected with HCV GT-2. These results are consistent with the initial results announced in January 2024. The SVR4 rate exceeded the protocol-defined efficacy criterion of ≥90% SVR4 for continuing the study. As a result, in January 2024 we commenced enrolling up to an additional 220 patients in the study, including patients with cirrhosis. In the lead-in cohort, very rapid kinetics were observed with viral load for each patient near or below the lower limit of quantification ("LLOQ") at four weeks of treatment, which we believe is supportive of an eight-week treatment regimen for the combination of bemnifosbuvir and ruzasvir. All 60 patients in the lead-in cohort achieved viral load below the LLOQ by the end of the eight-week treatment regimen.

The combination of bemnifosbuvir and ruzasvir in the lead-in cohort was generally safe and well tolerated and there were no drug related serious adverse events ("SAEs"), no treatment discontinuations and adverse events ("AEs") were mostly mild. Final SVR12 results from all 280 patients enrolled in the global Phase 2 study are anticipated in the second half of 2024.

Our Corporate Strategy

Our corporate goal is to become a global leader in the discovery, development, and commercialization of novel oral antiviral therapies for serious viral infections. We intend to achieve this goal by pursuing the following strategies:

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Deploy our expertise and experience, particularly our depth of knowledge with respect to nucleos(t)ide analogs, to discover, in-license and develop novel or differentiated direct acting antivirals that have the potential to meet unmet medical needs or improve the current SOC.

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Develop and commercialize bemnifosbuvir for the treatment of high-risk patients who face the greatest threat of progression to severe COVID-19 as a result of the limitations of current therapies.

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Explore combination therapy for specific COVID-19 patient populations.

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Improve the existing SOC for the treatment of HCV with a pan-genotypic eight-week, protease inhibitor-free regimen combining bemnifosbuvir and ruzasvir.

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Maximize the value of our product candidates by selectively seeking advantageous collaborations to strengthen our commercialization capabilities in the US and enhance our global commercialization reach.

Our Development Pipeline

The following table summarizes our orally administered antiviral product candidate pipeline. We have full global rights to commercialize all our product candidates in all indications.

Antiviral Therapy

Viral Polymerase as an Antiviral Target

The viral polymerase, which is the single protein present in all RNA viruses, is a key enzyme in the replication of viruses making it an attractive target for antiviral therapeutics. Among other things, the core structural features of viral polymerase are highly conserved, making drugs targeted to the polymerase less susceptible to the effects of viral mutation and resistance. Among RNA viruses, there are two types of viral polymerase:

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RdRp: All ssRNA viruses, including SARS-CoV-2 and HCV, depend on the RdRp, encoded in the viral genome, for replication and transcription. Since these enzymes are not present in the host cell, this facilitates the design of selective inhibitors of viral replication, which target viral but not host cell polymerases.

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RNA-dependent DNA polymerase (“RdDp" or "reverse transcriptase”): Reverse transcriptase is used by certain DNA or RNA viruses, such as HBV and HIV-1, to replicate their genomes.

Advances in technology have enabled intensive structural and functional studies of viral RNA polymerase including the identification, in the case of SARS-CoV-2, of NiRAN and have opened avenues for the development of new and more effective antiviral therapies.

Viral Resistance and Variants – Challenges to the Development of Antiviral Therapeutics

A major challenge to the development of direct acting antivirals is the emergence of viral resistance. Resistance is a function of a virus’ ability to genetically mutate which can make them less susceptible to certain antiviral therapies over time. In the case of RNA viruses, which generally lack proofreading abilities, the rate of mutation is substantially higher than DNA viruses and can occur at six orders of magnitude greater than the rate of mutation of host cells.

Another anticipated and naturally recurring consequence of viral mutations is the emergence of new variants. Variants are new strains of the original virus with genetic codes that are unique from the original virus. As a result of the unique genetic code, variants may have more or less transmissibility or virulence and may result in more severe disease than the original virus. Additionally, because of the changes in the genetic code of the variant, the effectiveness of vaccines and therapeutics may be reduced to the point of obsolescence.

Our Lead Antiviral Candidate - Bemnifosbuvir

Bemnifosbuvir is an investigational, novel, proprietary, orally administered double prodrug of a guanosine nucleotide analog which has been derived from our internal discovery program. More specifically, bemnifosbuvir is the hemisulfate salt of a phosphoramidate protide, AT-511, that is metabolized after multistep activation to the active 5’-triphosphate metabolite, AT-9010, which is an inhibitor of SARS-CoV-2 and HCV replication.

Our medicinal chemists designed bemnifosbuvir with the following critical elements to achieve the objectives noted below:

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specific modifications at the 6-position of the purine base, acting as a prodrug, were designed to prevent the toxic effects of other such modifications and enhance cell membrane permeability, resulting in an intermediate metabolite that maximizes formation of the triphosphate active metabolite in cells;

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the stereospecific phosphoramidate, acting as a prodrug, was designed to bypass the first rate-limiting phosphorylation enzyme in the intracellular activation pathway;

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specific modifications in the sugar moiety of the purine nucleotide scaffold, to produce potent antiviral activity with a high degree of selectivity; and

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highly specific salt form to enhance solubility and drug bioavailability.

We believe that these modifications together with the double prodrug approach impart the following potentially advantageous characteristics and features to bemnifosbuvir:

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enhanced antiviral activity and selectivity, as well as well-established pharmacology and animal models to predict clinical activity;

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favorable safety profile;

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convenience of oral administration; and

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efficient, predictable, scalable, and reproducible manufacturing, as well as long shelf life for potential stockpiling.

Our Development Programs

Bemnifosbuvir for the Treatment of COVID-19

COVID-19 – Disease Overview and Limitation of Current Standard of Care

COVID-19, the disease caused by infection with SARS-CoV-2 and its variants, gave rise to a global pandemic that swept rapidly throughout the world beginning in 2020. In 2023, public health emergencies

declared by each of the WHO and Centers for Disease Control and Prevention ("CDC") ended, however, SARS-CoV-2 continues to cause vast rates of infection and in many cases serious COVID-19 disease due to waning immunity and continued emergence of SARS-CoV-2 variants. The COVID-19 surge in the US and globally during the winter of 2023 / 2024 demonstrates that newly emerged variants such as JN.1 continue to thrive and become dominant despite the availability of treatments and updated vaccines.

In the US, COVID-19 remains a major cause of respiratory virus-associated hospitalizations and is a continuing threat, particularly for those most vulnerable to severe disease. Older adults and individuals who have risk factors or who are immunocompromised are at a higher risk for developing more serious complications from COVID-19, leading to hospitalization and death.

At the outset of the pandemic, unprecedented progress was made with both COVID-19 vaccines and treatment options. Despite this progress, substantial limitations remain to currently available vaccines and therapies, including waning immunity to both naturally acquired and vaccine generated immunity, failure of certain populations to mount an adequate immune response to vaccines and lack of efficacy of currently available monoclonal antibodies to currently circulating SARS-CoV-2 subvariants.

Limitations of current oral antivirals include drug-drug interactions with many commonly prescribed medications including anti-seizure medications, anti-psychotics, anti-coagulants and other safety concerns. As a result, many high-risk patients currently do not have suitable outpatient therapies and as a result, are also more likely to be hospitalized because of severe disease.

With the ongoing evolution of the SARS-CoV-2 virus and the continuing emergence of new variants, there remains an urgent need to develop new oral therapies that are safe, efficacious, convenient and with low risk of drug-drug interactions for the treatment of COVID-19 that can be utilized as monotherapy and potentially as part of a combination therapy. We believe that oral therapies protecting against the development of severe infection and transmission remain urgently needed particularly for vulnerable patients who currently have limited or no treatment options. This includes patients who are unvaccinated, patients who fail to respond to available vaccines, vaccinated patients with waning efficacy, which can occur between three to six months after immunization, and patients for whom vaccines and existing treatments are contraindicated. As COVID-19 remains endemic with continued variant fueled pandemic surges, we believe that this need will continue for years.

Vaccines for Prevention

Several vaccines are either approved or authorized under an emergency use authorization ("EUA") and additional vaccines are in development to prevent COVID-19 infection.

The ability of vaccines to produce durable immunity protection against disease and transmission is currently limited due to multiple factors, including:

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limited efficacy against certain viral variants;

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limited durability of response impacting the ability to achieve long term immunity;

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failure of certain patient populations to mount immune response to vaccines;

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delayed onset of protection; and

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vaccine hesitancy.

Monoclonal Antibodies ("mAbs") for the treatment and prevention of COVID-19

Starting in November 2020 and into 2022, the FDA granted EUAs to several mAbs for the prophylaxis and/or treatment of COVID-19. The use of mAbs for the treatment of COVID-19 was subsequently limited and is currently not authorized in the US for the following reasons:

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limited or no efficacy against currently circulating variants has led to the recission of all previously granted EUAs; and

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inconvenience of intravenous administration such as the need to administer in specialized facilities that were properly equipped to accommodate IV infusions in actively infected patients.

Even if future mAbs are developed, the continued emergence of new SARS-CoV-2 variants may make even these new mAbs ineffective for the treatment of COVID-19.

Project NextGen

In 2023, the US federal government announced the Project NextGen initiative with the purpose to accelerate and streamline the rapid development of the next generation of vaccines and treatments through public-private collaborations. Based at the Department of Health and Human Services (“HHS”) and seeded with an initial investment of $5 billion, Project NextGen is coordinating across the US federal government and the private sector to fund and advance a pipeline of new, innovative vaccines and mAbs into clinical trials and potential review by the FDA. Project NextGen is focusing on:

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mucosal vaccines;

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vaccines that provide broader protection against variants of concern and a longer duration of protection;

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pan-coronavirus vaccines;

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new and more durable monoclonal antibodies that are resilient against new variants as they arise; and

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advancing new technologies that will improve access and enable faster, cheaper, rapid and more flexible production of vaccines and therapeutics.

Antivirals for the treatment of COVID-19

Antiviral therapies, which are complementary to vaccines, have been approved or authorized for the treatment of COVID-19. In the US, Veklury® (remdesivir), an RdRp inhibitor, is approved for the treatment of COVID-19 in adults and certain pediatric patients who are hospitalized or outpatients at high-risk of progression to severe COVID-19. LagevrioTM (molnupiravir), an orally administered direct-acting antiviral for the treatment of adults with mild to moderate COVID-19 in the outpatient setting is authorized for use under an EUA in the US. PaxlovidTM is approved in the US for adults with mild to moderate COVID-19 in the outpatient setting and is available under EUA for pediatric patients 12 years and older weighing at least 40 kg. All three antiviral therapies are approved or authorized for use in many additional countries globally. Other oral antiviral therapies are approved in other countries including Xocova® (enstirelvir), a protease inhibitor which is approved in Japan.

Limitations of currently authorized or approved antiviral therapies include:

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Drug-Drug interactions.Due to the potentially serious drug-drug interactions associated with Paxlovid (ritonavir-boosted nirmatrelvir) and many commonly prescribed medications, including strong CYP3A4 inducers and certain other anti-coagulant, anti-convulsant, anti-arrhythmic, chemotherapeutic, and neuropsychiatric medications, the Paxlovid prescribing information includes a boxed warning and many patients with COVID-19 may be ineligible for treatment with Paxlovid or if eligible, require careful management including close monitoring of the patient by the prescriber.

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Safety.Lagevrio (molnupiravir) is a mutagenic ribonucleoside agent that is recommended by the NIH COVID-19 Treatment Guidelines Panel (“NIH Panel”) for use only when Paxlovid is not available, not feasible to use or clinically inappropriate. Additionally, the NIH Panel recommends against the use of Lagevrio in pregnant patients unless there are no other options and COVID-19 therapy is clearly indicated.

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IV infusion. Veklury is administered via intravenous infusion which minimizes the convenience of administration.

Our Development of COVID-19 Product Candidates

We are developing bemnifosbuvir, an investigational, orally administered, novel antiviral product candidate, for the treatment of COVID-19. We believe bemnifosbuvir as a monotherapy has the potential

to address the key limitations of current therapies and the continued unmet medical need particularly for high-risk patients with limited treatment options. SUNRISE-3 is a global Phase 3 randomized, double-blind, placebo-controlled clinical trial that is currently evaluating bemnifosbuvir (550 mg BID for 5 days) in high-risk non-hospitalized patients with mild or moderate COVID-19.

While SUNRISE-3 is principally designed to evaluate bemnifosbuvir as monotherapy (primary analysis) in approximately 2,200 patients, it is also designed to explore the effect of combination therapy in a smaller sub-set of patients who receive a compatible antiviral drug along with bemnifosbuvir (secondary analysis). We intend to use data from the smaller subset of patients who receive combination therapy to inform our development plans to evaluate bemnifosbuvir as combination therapy for the treatment of COVID-19.

In parallel with conducting SUNRISE-3, we are engaging in efforts to identify and advance a protease inhibitor product candidate for the treatment of COVID-19. We are seeking a protease inhibitor that is highly potent, well tolerated with limited drug-drug interactions and does not require a pharmacokinetic ("PK") booster (e.g., ritonavir). The optimization of lead compounds is ongoing.

Targeting SARS-COV-2 NiRAN/RdRp to treat COVID-19

The RNA polymerase complex of SARS-CoV and SARS-CoV-2 supports the transcription and replication of their approximately 30,000-nucleotide viral RNA genomes. It is the largest and most complex RNA synthesis machinery among RNA viruses. As shown in the illustration below, the multi-subunit SARS-CoV polymerase complex is composed of a number of non-structural proteins ("Nsp") including viral RdRp ("Nsp12"), processivity factors ("Nsp7", "Nsp8"), a proofreading exonuclease, a N7-methyl transferase ("Nsp14"), and a helicase ("Nsp13"). The Nsp12 protein contains two domains, an RdRp core, which is the catalytic subunit incorporating ribonucleotides into RNA templates, and an N-terminal NiRAN domain, the function of which was previously unknown.

We have investigated the mechanism by which SARS-CoV initiates viral RNA synthesis and have discovered that there are two distinct pathways: one protein-primed and mediated by the NiRAN through the UMPylation of Nsp8, and the other through de novo synthesis of dinucleotide primers in a NiRAN-independent manner. Importantly, both functions can be inhibited by AT-9010, the active triphosphate metabolite of bemnifosbuvir. Furthermore, we have obtained a 2.98 Å cryo-EM quaternary structure of Nsp12/7/8/RNA/AT-9100, which confirms that AT-9010 not only bound to the NiRAN active site but also was incorporated by the RdRp and functions as a chain terminator. We believe this unique dual mechanism of bemnifosbuvir creates a potentially higher barrier to resistance compared to other direct acting antiviral inhibitors.

SARS-CoV-2 Variants

SARS-CoV-2 has proven to be able to mutate quickly with more than seven million variants identified since fall 2020 and more than one million identified in 2023 alone. A number of these variants have been designated by the WHO and CDC as VOI because there is evidence of increased transmissibility, more

severe disease, reduced effectiveness of vaccines or antibodies, or diagnostic detection failures. The WHO and CDC have also identified several VOCs which express similar attributes to VOIs but are more likely to be responsible for greater disease severity across the globe. Previously identified VOCs included Alpha, Beta, Gamma, and Delta while the currently circulating VOC is Omicron, which includes BA.1, BA.2, BA.3 BA.4, BA.5, XBB, EG.5.1, JN.1 and descendent lineages.

In the US, as of February 17, 2024, JN.1 is estimated to account for over 90% of all currently circulating SARS-CoV-2 variants.

Given the mutagenic nature of SARS-CoV-2, we expect that the evolution of the virus will continue with more variants emerging and presenting new and varied health challenges. The continued emergence of dominant SARS-CoV-2 variants is a key contributor to COVID-19 remaining as an endemic threat where the virus will still be circulating, with surges from time to time.

Potent in vitro inhibition of SARS-CoV-2 replication across variants

Since bemnifosbuvir targets viral RNA polymerase, a highly conserved enzyme critical to viral replication and transcription, we expect it will maintain its antiviral activity even against the recently emerged variants with mutations in the spike (S) protein responsible for the receptor recognition and host cell membrane fusion process.

We have assessed the in vitro potency of AT-511 (free base of bemnifosbuvir) against SARS-CoV-2 VOC and VOI. The data from these studies are summarized in the table below showing that AT-511 maintained its potency against all major VOC and VOI tested. These data support the key mechanistic advantage of the compound, which targets the highly conserved viral RNA polymerase.

Non-mutagenic

Results from non-clinical studies indicated that bemnifosbuvir was non-mutagenic and non-teratogenic and it has shown no reproductive toxicity.

More specifically, analysis of SARS-CoV-2 infected Huh7.5 cells treated with AT-511 (the free base of bemnifosbuvir) by next generation sequencing ("NGS") showed that bemnifosbuvir was not a mutagen (which is consistent with the lack of genotoxicity observed in the preclinical in vitro and in vivo studies) and did not introduce mutations in the viral genome.

In addition to the standard battery of preclinical safety, pharmacology and repeat dose toxicity studies, which showed no adverse effects of bemnifosbuvir treatment in rats and non-human primates at respective doses up to 650 and 1000 mg/kg/day for 13 weeks, completed preclinical studies have demonstrated that bemnifosbuvir did not affect male or female fertility in treated rats, did not affect early embryo-fetal development in treated pregnant rats or rabbits, and did not affect the pre- or post-natal development, reproductive capability, or behavioral assessments of the offspring of rats treated prior to and during mating (males) and prior to mating through pregnancy and lactation (females).

Clinical Development

Summary

At the outset of the COVID-19 pandemic, we initiated our COVID-19 program with a global Phase 2 clinical trial of bemnifosbuvir in hospitalized patients. This was followed by the initiation, together with our former collaborator, F. Hoffmann-LaRoche Ltd. and Genentech, Inc. (together, “Roche”), of MOONSONG, a Phase 2 outpatient clinical trial, MORNINGSKY, a Phase 3 outpatient clinical trial and MEADOWSPRING, a Phase 3 six-month follow-up study for patients who had been enrolled in MORNINGSKY.

Together with Roche, we completed the Phase 2 outpatient MOONSONG clinical trial in October 2021 and, due to the complexities and time required to effect the transfer of study sponsorship from Roche to us following the termination of the collaboration, the very dynamic COVID-19 landscape in which SARS-CoV-2 was rapidly evolving and the introduction of the original vaccines and antivirals, after careful consideration, each of the Phase 3 MORNINGSKY and MEADOWSPRING clinical trials were discontinued after careful consideration prior to completion in December 2021 and March 2022, respectively. We leveraged the key clinical data obtained from these patient studies, including clinical efficacy data from MORNINGSKY, with additional supporting Phase 1 and clinical pharmacology studies conducted in healthy subjects, to support the design of SUNRISE-3, the currently ongoing Phase 3 clinical trial of bemnifosbuvir for the treatment of COVID-19.

SUNRISE-3 – Global Phase 3 clinical trial

In 2023, the FDA granted Fast Track designation for the investigation of bemnifosbuvir for the treatment of COVID-19. In SUNRISE-3, we are targeting the patient population whom we believe are at the greatest risk for disease progression to severe COVID-19 or mortality, and for whom there are currently the fewest treatment options.

In January and February 2024, we announced the enrollment of more than 650 patients and more than 1,350 patients, respectively, in the supportive care monotherapy cohort of the trial. As a result, we currently anticipate that the first interim analysis by the DSMB will occur in March of 2024 and the second interim analysis by the DSMB will occur in the second quarter of 2024. At each interim analysis, we anticipate the DSMB will evaluate the data principally for safety and futility. Patient enrollment in the SUNRISE-3 trial, which has currently surpassed 1,400 patients in the supportive care monotherapy population, continues and topline data from the trial are anticipated in the second half of 2024.

MORNINGSKY - Global Phase 3 clinical trial

The Phase 3 MORNINGSKY study was a global, randomized, placebo-controlled study across 50 centers globally in non-hospitalized adult and adolescent patients with mild or moderate COVID-19 who were at high-risk or standard risk for disease progression regardless of vaccination. Due to the complexities and time required to effect the transfer of study sponsorship from Roche to us following the termination of the collaboration, and the very dynamic COVID-19 landscape including the rapid evolution of SARS-CoV-2 and the introduction and availability of the original vaccines and antivirals, after careful consideration, MORNINGSKY was discontinued prior to completion in December 2021.

Patients were randomized (2:1; active:placebo) to receive bemnifosbuvir 550 mg BID or placebo for five days. The primary endpoint was time to alleviation/improvement of COVID-19 symptoms. Secondary endpoints included the proportion of patients requiring hospitalization, all-cause mortality, and change in viral load. At the time of discontinuation, 216 patients had been randomized, with 207 patients included in efficacy analyses. The study enrolled a broad outpatient population, including 47% with high-risk factors, 28% who received ≥1 doses of vaccine against COVID-19, and 56% who were seropositive for SARS-CoV-2 at baseline. Because the study was prematurely discontinued, no formal statistical comparisons were made.

While the primary endpoint of the MORNINGSKY study, time to symptom alleviation, was not achieved, the results from MORNINGSKY showed that non-hospitalized adult and adolescent patients who received bemnifosbuvir (n=137) experienced a 71% relative reduction in risk of hospitalization (2.9% versus 10%) (p=0.047, unadjusted, exploratory; secondary endpoint) versus placebo (n=70), regardless of vaccination status. In an exploratory analysis, an 82% reduction in risk of hospitalization was seen in a subset of patients greater than 40 years of age in the bemnifosbuvir arm. In another ad hoc analysis, the proportion

of patients who were considered standard risk experienced a similar relative reduction in risk of hospitalization as those who were considered high-risk (75% versus 69%).

Error bars denote the 97.5% Confidence Interval

No deaths were observed during the study. No clear differences in any of the virology end points between the bemnifosbuvir and placebo arms were observed. Overall, bemnifosbuvir was well tolerated. There were no drug-related SAEs reported, and proportions of patients with AEs leading to study drug discontinuation were low (2.8% in the bemnifosbuvir arm vs 7.0% in the placebo arm).

The MEADOWSPRING trial, originally designed as a six-month follow-up study of patients previously enrolled in MORNINGSKY, was closed out in March 2022 after enrolling only 72 patients. As a result, firm conclusions about the long-term symptoms of COVID-19 could not be drawn from this study.

Hospitalized Patients - Global Phase 2 clinical trial

This Phase 2 study was a randomized, double-blind, placebo-controlled, study that evaluated bemnifosbuvir in hospitalized/confined patients with moderate COVID-19 versus placebo. The study was initially designed to assess the treatment effect of bemnifosbuvir (550 mg BID; Part A) on a primary endpoint of proportion of subjects with Progressive Respiratory Insufficiency ("PRI"). However, low background rates of disease progression precluded completion of the study as initially planned. The protocol was amended to explore higher doses of bemnifosbuvir (1100 mg BID; Part B), however the study was prematurely discontinued in January 2022. Only two subjects (both receiving placebo) had been enrolled in Part B.

Rates for reduction of PRI were low in 550 mg BID patients and no difference was seen between treatment groups (Intent To Treat [ITT] population: 3/41 7.3% bemnifosbuvir patients and 4/40 10.0% placebo patients). The all-cause mortality for the Part A 550 mg BID subjects was 0/41 in the bemnifosbuvir group and 5.0% (2/40) in the placebo group. In addition, one placebo patient in the Part B 1100 mg BID group died.

Virology results indicated that treatment with bemnifosbuvir rapidly reduced the SARS-CoV-2 viral load from baseline, as measured by PCR of nasopharyngeal swabs. Compared with placebo, participants on bemnifosbuvir had a 0.61 log10 (95% CI: -1.38–0.16) greater mean reduction from baseline viral load on Day 2, and this trend was sustained through Day 8.

Bemnifosbuvir’s SARS-CoV-2 antiviral activity was also observed in patients with baseline viral loads above the median of 5.36 log10 as compared to placebo. In this subset, those in the bemnifosbuvir arm achieved SARS-CoV-2 clearance as early as Day 2 (in 6% of patients), Day 8 (in 13% of patients) Day 10 (in 33% of patients), and Day 12 (in 31% of patients) compared to 0% of patients in the placebo arm at the same timepoints. By Day 14 (last viral sampling study day), 50% of patients in the bemnifosbuvir arm and 23% in the placebo arm had no detectable RNA virus.

After dosing with 550 mg BID for five days, bemnifosbuvir was generally well tolerated and there were no drug-related SAEs. AEs were equally distributed across treatment arms. Most were mild-to-moderate in severity and assessed as not related to bemnifosbuvir.

MOONSONG - Global Phase 2 clinical trial

This Phase 2 study was a randomized, double-blind, multi-center, placebo-controlled trial, that evaluated the antiviral activity, safety, efficacy and PK of bemnifosbuvir in adult outpatients with mild or moderate COVID-19. Patients were randomized 1:1 to bemnifosbuvir 550 mg or placebo (Cohort A) and 3:1 to bemnifosbuvir 1,100 mg or placebo (Cohort B); all doses were given BID for 5 days. The modified intent-to-treat infected population comprised 100 patients (bemnifosbuvir 550 mg, n = 30; bemnifosbuvir 1,100 mg, n = 30; cohort A placebo, n = 30; cohort B placebo, n = 10). Treatment with bemnifosbuvir in this study did not meet the primary endpoint of showing a reduction in SARS-CoV-2 viral load in the overall population of patients compared to placebo, of whom approximately two thirds were low-risk with mild symptoms.

However, in high-risk patients with underlying health conditions, a reduction of viral load of approximately 0.5 log10 at Day 7 was observed with administration of 550 mg BID as compared to placebo (prespecified subgroup analysis Cohort A n=7; placebo n=10) and with administration of 1,100 mg BID as compared to placebo (exploratory subgroup analysis Cohort B; n=14; placebo n=7).

Bemnifosbuvir was generally well tolerated in this study. The proportion of patients experiencing any AE was 28% in the placebo group, 20% in the bemnifosbuvir 550 mg BID group and 33% in the bemnifosbuvir 1100 mg BID group. There were three non-drug related SAEs in each of the treatment groups and all other AEs were grade 1 or 2. Gastrointestinal ("GI")-related AEs were the most commonly reported AEs: 8% in the placebo group; 7% in the bemnifosbuvir 550 mg BID group; 20% in the bemnifosbuvir 1100 mg BID group, with mild to moderate nausea/vomiting resulting in premature study drug discontinuation of 3% in the placebo group, 0% in the bemnifosbuvir 550 mg BID group and 17% in the bemnifosbuvir 1100 mg BID group. No clinically significant differences in laboratory abnormalities were observed in the treatment arms as compared to placebo.

Other Studies

Supporting Phase 1 and clinical pharmacology studies, including a bronchoalveolar lavage ("BAL") study, multiple drug-drug interaction studies and a mass balance study, have been conducted and completed since we initiated our COVID-19 program. In these studies, the safety and PK of bemnifosbuvir has been evaluated at doses up to 1100 mg BID for five days in healthy subjects.

Results from the BAL study in healthy subjects demonstrated that bemnifosbuvir was efficiently delivered to the lungs (epithelial lining fluid), the primary site of SARS-CoV-2 infection. Five clinical drug-drug interaction studies were completed with results demonstrating an overall low drug-drug interaction potential associated with bemnifosbuvir.

Phase 1 – Drug-Drug Interaction Studies

A series of Phase 1 studies demonstrated an overall low drug-drug interaction potential associated with bemnifosbuvir, including no dosage adjustment needed for co-administration of bemnifosbuvir with drugs that are CYP3A substrates or for drugs that are sensitive substrates of efflux and hepatic uptake transporters. CYP3A is an enzyme that metabolizes many classes of medicines and supplements, and the sensitive substrates of efflux and hepatic uptake transporters regulate cellular trafficking of drugs that are commonly prescribed among high-risk COVID-19 patients.

In these studies, bemnifosbuvir was administered with index drugs for CYP3A4 (midazolam), P-glycoprotein (digoxin, cyclosporine, carbamazepine), breast cancer resistance protein and organic anion transporter polypeptide 1B1 (rosuvastatin). Based on low potential for drug interaction, we believe bemnifosbuvir has the potential to be co-administered with commonly prescribed therapeutics that are often taken for other conditions, especially in vulnerable patient populations who are at high-risk for disease progression to severe COVID-19.

Bemnifosbuvir has been generally well tolerated in healthy subjects. Consistent with the results from the MOONSONG Phase 2 outpatient clinical trial, an increased incidence of mild to moderate GI-related adverse events, specifically nausea and vomiting, were observed at doses greater than 550 mg BID in healthy subjects. As 550 mg BID has been well tolerated for up to ten days, the 550 mg BID dose for five days was selected for the Phase 3 SUNRISE-3 study.

In addition, other completed clinical pharmacology studies supporting a potentially favorable PK and safety profile for bemnifosbuvir include a study in healthy Japanese subjects as well as a study assessing the effects of bemnifosbuvir on cardiac repolarization in healthy adult subjects. Other supporting clinical pharmacology studies in special populations (e.g., subjects with hepatic and renal impairment) are ongoing.

Bemnifosbuvir and Ruzasvir for the Treatment of HCV

HCV – Disease Overview and Current Standard of Care

HCV is a blood-borne, positive sense, ssRNA virus, primarily infecting cells of the liver. HCV is a leading cause of chronic liver disease and liver transplants and spreads via blood transfusion, hemodialysis, and needle sticks. In the US, injection drug use accounts for approximately 60% of all new cases of HCV. Diagnosis of HCV is made through blood tests, including molecular tests that allow for the detection, quantification and analysis of viral genomes and the classification of an infection into specific viral GTs. Hepatitis C becomes chronic Hepatitis C in 55% to 85% of acute cases, with an incubation period lasting from two to 26 weeks.

HCV is classified into seven GTs (GT-1 through GT-7) and 67 subtypes, with HCV GT-1 being responsible for more than 70% of HCV cases in the US. Patients with HCV are also classified by liver function status: compensated cirrhosis (liver scarring) denotes those patients that do not yet have impaired liver function, while decompensated cirrhosis describes patients with moderate to severe liver function impairment.

According to the WHO, an estimated 58 million people globally have chronic HCV infection, with about 1.5 million new infections occurring per year. The most recently published CDC HCV surveillance report showed a continuing increase in HCV infections in the US. The WHO estimated that approximately 290,000 people died in 2019 from HCV related liver diseases, with the majority of deaths related to cirrhosis and hepatocellular carcinoma.

The CDC HCV surveillance report also showed a continuing increase in HCV infections in the US and new and reinfection rates exceeding cures on a yearly basis with the number of reported cases of acute HCV in the US more than doubling between 2014 and 2021 (129% increase). However, there is a wide gap between the number of reported cases versus estimated cases. Most individuals who become infected with HCV remain unaware that they are infected because HCV can go undetected until the condition progresses to symptomatic disease or until specific clinical tests are performed to confirm diagnosis. Consequently, cases are unreported, skewing actual disease prevalence rates. The burden of underreporting is realized when high medical expenditures (comorbid treatment costs, liver transplants) and mortality rates from advanced chronic liver disease do not proportionally align with reported prevalence rates.

Increasing Incidence of HCV in the US

Source: CDC. 2021 Viral Hepatitis Published September 2022.

Despite significant advances in treatment beginning in 2013, there remains a large, underserved, HCV patient population in the US. The US HCV prevalence is expected to continue to remain steady over the coming years as rising HCV incidence offsets the number of new patients treated.It is estimated that a substantial global market for HCV therapeutics will exist for the foreseeable future. The HCV commercial market is expected to remain large. Reported global net sales exceeded $3.0 billion in 2023, with the US contributing about 50% of these sales.

The US HCV prevalence is expected to continue to remain steady over the coming years as rising HCV incidence offsets the number of new patients treated.It is estimated that a substantial global market for HCV therapeutics will exist to 2050 and beyond. The HCV commercial market is large and expected to remain large. Reported global net sales exceeded $3.0 billion in 2023, with about 50% attributable to the US.

Antivirals for the treatment of HCV

No vaccine exists for the prevention of HCV but beginning in 2013 several sequentially introduced and improved oral antiviral therapeutics have boosted SVR rates to over 95% in a majority of patients, with treatment durations of eight to 12 weeks depending upon the regimen and patient population. The leading HCV products are combination therapies comprised of agents with differing mechanisms of action and therapeutic targets: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B nucleos(t)ide polymerase inhibitors. A patient’s GT, cirrhotic status, and prior treatment failures determine the appropriate antiviral therapeutic used in treatment. In the US, currently the two leading therapeutics for treatment of chronic HCV are:

Epclusa® (sofosbuvir and velpatasvir): an orally administered, fixed dose combination regimen consisting of an HCV nucleotide analog NS5B polymerase inhibitor and an HCV NS5A inhibitor, was first approved by the FDA in 2016. It is indicated for the treatment of adults and pediatric patients ≥3 years with chronic HCV GT-1, -2, -3, -4, -5 or -6 infection, either without cirrhosis or with compensated cirrhosis. For patients with decompensated cirrhosis, Epclusa is approved for use in combination with ribavirin. Patients on Epclusa require 12 weeks of treatment.

Mavyret® (glecaprevir and pibrentasvir): an orally administered, fixed dose combination regimen consisting of an HCV NS3/4A protease inhibitor and an HCV NS5A inhibitor was first approved by the FDA in 2017. It is indicated for the treatment of adults and pediatric patients ≥3 years with

chronic HCV GT-1, -2, -3, -4, -5 or -6 infection, without cirrhosis or with compensated cirrhosis. Mavyret is also approved for HCV patients with GT-1 infection who have been previously treated with a regimen either containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (but not both). Mavyret was the first eight-week treatment approved for HCV GT-1, -2, -3, -4, -5 or -6 in adult patients without cirrhosis and with compensated cirrhosis who have not been previously treated. Longer treatment durations (up to 16 weeks) are indicated for some treatment-experienced populations. Mavyret is not approved for use in patients with decompensated cirrhosis.

Even with the presence and availability of these currently approved direct acting antivirals, only 6% of the prescribers of HCV therapeutic products who participated in quantitative market research we recently conducted indicated that there are no unmet medical needs with current treatments. The key unmet medical needs identified in this market research included the need for treatments with fewer contradictions than exist with current options, including in particular fewer drug-drug interactions, and the need for treatments with shorter treatment durations given that respondents estimated approximately 17% of patients fail to complete current regimens. This research was conducted by an independent market research consulting firm who surveyed 157 US healthcare providers including hepatologists, infectious disease specialists, gastroenterologists and primary care physicians each of whom, within the 12 months prior to the participation in the project, had treated at least 25 HCV patients, initiated more than 15 patients on direct acting antivirals and prescribed Epclusa or Mavyret to at least 50% of their eligible patients.

Our Development of HCV Product Candidates

We are developing bemnifosbuvir in combination with ruzasvir for the treatment of HCV. Bemnifosbuvir is an investigational oral, potent inhibitor of HCV NS5B RdRp. Ruzasvir is an investigational oral, potent, pan‐genotypic NS5A inhibitor that we licensed from Merck in December 2021. Based on our preclinical and clinical data to date, we believe that this combination, if approved, could offer the following potential benefits:

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convenient and short duration (eight weeks) protease inhibitor-free treatment in HCV‐infected patients with or without cirrhosis;

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equivalent antiviral potency across all GTs, regardless of cirrhosis status, including the difficult to treat HCV GT-3 population;

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obviate the need for extensive pretreatment assessments, including genotyping, procedures to assess cirrhosis, and liver function assessment; and

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well tolerated regimen, with low potential for drug-drug interactions.

Rationale supporting the combination of bemnifosbuvir and ruzasvir for HCV

With the antiviral potency observed with bemnifosbuvir, especially in more difficult to treat GT-3 infected patients, we believe that the combination of bemnifosbuvir and ruzasvir has the potential to improve on the SVR12 rates observed in the prior studies conducted by Merck.

To further support our clinical development of the combination of bemnifosbuvir and ruzasvir, we have conducted in vitro synergy experiments in HCV GT-1b replicon assays. As shown in the figure below, these experiments demonstrated that the combination resulted in substantially greater inhibition of HCV replication than with either agent alone, suggesting a synergistic antiviral effect between the two inhibitors.

In vitro Synergy: Assay performed in HCV GT1b replicon

Viral resistance has emerged as an important consideration since it may impact the effectiveness of antiviral treatments for HCV infection. We profiled the antiviral activity of AT-511, the free base of bemnifosbuvir, and ruzasvir against major HCV NS5A and NS5B Resistance-Associated Variants ("RAVs") selected in vitro or identified in HCV patients with hard-to-treat sub-genotypes who have failed treatment with currently available direct acting antivirals.

In these in vitro studies, AT-511 was approximately 10-fold more active than sofosbuvir against a panel of laboratory strains and clinical isolates of HCV GTs tested (GT-1, -2, -3, -4, -5)) and bemnifosbuvir was not resistant to known sofosbuvir RAVs such as S282T and L159F/S282T. AT-511 also retained antiviral activity against all HCV GT-1a and HCV GT-3a NS5A RAVs tested. In GT-1a, ruzasvir was 10 times more active than velpatasvir, a direct acting antiviral, and retained single-digit picomolar potency against a panel of RAVs selected by previous NS5A inhibitors and was 10 times more potent than velpatasvir against selected double mutants. In HCV GT-3a, one of the most difficult to treat HCV GTs, ruzasvir was six times more active than velpatasvir and retained sub-nanomolar potency against select NS5A RAVs which were treatment-emergent in HCV GT-3 patients failing direct acting antivirals.

Ruzasvir and a panel of other NS5A inhibitors were profiled for antiviral activity against seven difficult-to-treat HCV sub-genotypes using the HCV GT-1b replicon backbone. Both ruzasvir and velpatasvir maintained picomolar potency over the majority of these difficult-to-treat sub-genotypes such as HCV GT-1l, -4r, and -6v. All tested NS5A inhibitors exhibited 100- to 1000-fold EC50 shifts for HCV GT-3b and GT-3g.

In a 13-week combination toxicity study in rats, bemnifosbuvir and ruzasvir were well tolerated when administered orally at 500 mg/kg/day alone or in combination. No test article-related adverse effects were noted for any of the three dose groups. Systemic exposures of bemnifosbuvir, its metabolites, and ruzasvir were similar when dosed alone or in combination, suggesting no significant drug-drug interactions between the two drugs.

Clinical Development

Summary

To date, we have completed two clinical trials of bemnifosbuvir in HCV infected patients to support the treatment of chronic HCV infection and have one on-going, global Phase 2 clinical study.

Open Label Study – Ongoing Global Phase 2 clinical trial

In June 2023, we initiated enrollment of a Phase 2 clinical trial of bemnifosbuvir in combination with ruzasvir in treatment-naïve, HCV-infected patients either without cirrhosis or with compensated cirrhosis. This study is designed to evaluate the safety and efficacy of eight weeks of treatment with the pan-genotypic combination consisting of once daily bemnifosbuvir 550 mg and ruzasvir 180 mg. Up to 280 HCV-infected, treatment-naive patients across all GTs, including a lead-in cohort of approximately 60 patients are expected to be enrolled in this Phase 2 clinical trial. The primary endpoints of the study are safety and SVR12. Other virologic endpoints include virologic failure, SVR24 and resistance.

Phase 2 Open Label Study of Bemnifosbuvir + Ruzasvir in HCV Patients

In February 2024, we announced final results from the full lead-in cohort in which a 98% SVR4 rate was observed [58 of 59 subjects achieved SVR4 with one patient who did not return for post-treatment follow-up]. The one patient who did not achieve SVR4 had poor adherence, and was infected with HCV GT-2. These results are consistent with the initial results announced in January 2024. The SVR4 rate exceeded the protocol-defined efficacy criterion of ≥90% SVR4 for continuing the study. As a result, in January 2024 we commenced enrolling up to an additional 220 patients in the study, including patients with cirrhosis.

Proportion of Patients with HCV RNA <LLOQ by Study Visit with Eight Weeks of Treatment with the Combination of Bemnifosbuvir and Ruzasvir

In the lead-in cohort, very rapid kinetics were observed with viral load for each patient near or below the LLOQ at four weeks of treatment, which we believe is supportive of an eight-week treatment regimen for the combination of bemnifosbuvir and ruzasvir. All 60 patients in the lead-in cohort achieved viral load below the LLOQ by the end of the eight-week treatment regimen.

On-Treatment Viral Kinetics – Individual HCV RNA Levels in Patients Receiving Combination of Bemnifosbuvir and Ruzasvir for Eight Weeks

In the lead in cohort, the combination treatment was generally safe and well tolerated. There were no drug related SAEs, no treatment discontinuations and AEs were mostly mild.

If the Phase 2 study is successfully completed, subject to discussion and alignment with regulatory authorities, we anticipate initiating a Phase 3 clinical development program in the second half of 2024. Currently, we expect these initial Phase 3 studies will target a population ofHCV-infected patients either without cirrhosis or with compensated cirrhosis that is similar to the patients being enrolled in the Phase 2 clinical trial.

Bemnifosbuvir in combination with daclatasvir - Phase 2 clinical trial

We conducted a Phase 2, open-label clinical trial to evaluate bemnifosbuvir in combination with daclatasvir, an approved commercially available HCV NS5A inhibitor, in HCV-infected subjects. Ten treatment-naïve, non-cirrhotic HCV GT-1 infected subjects received 553 mg free base bemnifosbuvir and 60 mg daclatasvir once daily for a period of eight or 12 weeks. The primary efficacy endpoint of the study was SVR12 (a sustained viral response, defined as HCV RNA < LLOQ at 12 weeks after end of treatment (“EOT”)). Secondary efficacy endpoints included HCV RNA< LLOQ, and Target Not Detected (“TND”) (an assessment of virologic response that is more rigorous than LLOQ), by study visit, virologic failure, and appearance of RAVs to either of the study drugs.

Despite the use of a less potent first-generation HCV NS5A inhibitor, daclatasvir, all subjects achieved HCV RNA < LLOQ and TND at the EOT and nine of the ten subjects achieved SVR12. One subject who was TND by week two received eight weeks of treatment, achieved SVR4, and then experienced likely virologic relapse at post-treatment week 12. The single subject who relapsed with GT 1b virus had the following multiple RAVs/variants both at baseline and at the SVR12 timepoint: NS5A: R30Q; NS5B: L159F/A218S/C316N. Phenotypic analysis demonstrated that bemnifosbuvir retained the same potency against clinical isolates obtained from this relapsed subject at baseline and SVR12 (only a 1.1 and 0.8-fold shift, respectively, in EC50 compared to reference). Compared to sofosbuvir, the EC50 and EC90m values for bemnifosbuvir were ~10-fold lower. Thus, the significance of the RAVs in this case is unclear. No other subjects had pre-existing NS5A RAVs at baseline.

As shown in the graph below, viral load decreased rapidly after initiation of study drugs, with 70% of subjects achieving plasma HCV RNA < LLOQ by week two (and 50% achieving TND by week 2).

Proportion (%) of subjects achieving HCV RNA <LLOQ and TND by study visit with bemnifosbuvir in combination with daclatasvir

We believe that the rapid early clearance of HCV RNA observed in the Phase 2 clinical trial evaluating bemnifosbuvir in combination with daclatasvir supported continued evaluation of bemnifosbuvir in shortened treatment regimens, ideally with a more potent, next-generation HCV NS5A inhibitor. This has led us to conduct the currently ongoing Phase 2 clinical trial evaluating bemnifosbuvir in combination with ruzasvir.

Bemnifosbuvir in combination with ruzasvir – Phase 1 clinical trial

A Phase 1 clinical study in healthy subjects was conducted in first quarter of 2023 to evaluate the potential drug-drug interaction between bemnifosbuvir and ruzasvir and the effect of food on the PK of the agents. The study drugs were well-tolerated and plasma PK profiles were not substantially affected by food nor concomitant dosing, the latter indicating lack of drug-drug interaction between bemnifosbuvir and ruzasvir. These data supported the evaluation of the combination in HCV-infected patients.

Bemnifosbuvir as a single agent – Phase 1 clinical trial

We conducted a Phase 1 trial to evaluate single and multiple doses of bemnifosbuvir as a single agent in healthy and HCV-infected subjects for up to seven days. All HCV-infected subjects were treatment-naïve with HCV RNA ≥5 log10 IU/mL. The objectives of the trial were to assess safety, tolerability, PK and antiviral activity.

The trial evaluated single oral doses of bemnifosbuvir up to 400 mg salt form (369 mg free base) in healthy subjects (Part A), single doses up to 600 mg salt form (553 mg free base) in non-cirrhotic HCV-infected subjects (Part B), and multiple doses up to 600 mg salt form (553 mg free base) once daily for seven days in non-cirrhotic HCV GT-1b infected subjects (Part C). Additional cohorts evaluated 600 mg salt form (553 mg free base) once daily for seven days in non-cirrhotic GT-3, (Part D) and Child-Pugh A cirrhotic GT -1, -2, -3, HCV-infected subjects (Part E). The tables below show the dosage and mean maximum HCV RNA reductions for each treatment cohort.

A total of 88 subjects were dosed across all parts of the trial, with 72 subjects who received active drug and 16 subjects who received placebo. In this trial, bemnifosbuvir showed equivalent pan-genotypic antiviral activity in both cirrhotic and non-cirrhotic HCV infected patients. The mean maximum HCV reduction after a single dose (Part B) was 2.3 log10IU/mL, and the mean maximum HCV RNA reduction after seven days of dosing with bemnifosbuvir at 553 mg free base was 4.6 log10IU/mL. Data also showed a mean maximum HCV RNA reduction of 4.4 log10IU/mL after seven days of dosing of bemnifosbuvir at 553 mg free base in non-cirrhotic GT-1b HCV-infected subjects, and a mean reduction of 4.5 log10IU/mL after seven days of dosing in non-cirrhotic GT-3 HCV-infected subjects. The PK data in cirrhotic subjects was similar to non-cirrhotic subjects. Emax modeling predicted that a dose of 553 mg free base of bemnifosbuvir once daily would result in maximum viral load reduction.

Maximum HCV RNA change in Part B (single dose in non-cirrhotic, HCV GT-1 infected subjects)

Maximum HCV RNA change in Part C (multiple dose in non-cirrhotic, HCV GT-1 infected subjects)

Maximum HCV RNA change in Part D (multiple dose in non-cirrhotic, HCV GT-3 infected subjects) and Part E (multiple dose in cirrhotic HCV-infected subjects)

Maximum Reduction(log10 IU/mL) Part D – GT-3 Part E – Cirrhotic

* SD = standard deviation

** QD = once daily

Bemnifosbuvir HCV safety

No SAEs, dose-limiting toxicities or AEs leading to trial discontinuation were observed in the HCV Phase 1 or Phase 2 clinical trials of bemnifosbuvir that we have completed to date. The most common side effects observed were headache and small increases in blood lipid levels, with no consistent patterns in other reported effects. Most side effects were not severe and were not thought to be related to bemnifosbuvir.

Ruzasvir

Ruzasvir is an investigational oral, pan-genotypic NS5A inhibitor that we licensed from Merck in December 2021. In studies conducted by Merck, ruzasvir demonstrated in vitro potent antiviral activity with an EC50 in the sub- to low picomolar range against all GTs (<10 pM against GTs 1-7). The antiviral activity of ruzasvir was evaluated in a proof-of-concept ("POC") study in HCV-infected patients, where viral load reductions >3 log10 were observed in HCV GT-1, GT-2 and GT-3 infected patients after treatment with monotherapy. This clinical antiviral activity is on par with what was achieved, as single

agents, with pibrentasvir and velpatasvir, the NS5A inhibitor components of Mavyret and Epclusa, respectively. These POC data supported evaluation of ruzasvir in larger phase 2 multiple drug combination studies (including two and three drug regimens) previously conducted by Merck. These studies included treatment-naïve and interferon-experienced patients with or without compensated cirrhosis. In general, high SVR12 rates (>90%) were observed in two-drug combination studies (ruzasvir plus uprifosbuvir, a pyrimidine nucleotide prodrug, for 12 weeks) conducted by Merck in GT-1, -2, -4 and -6-infected patients (C-Breeze 1 and 2). A lower SVR12 rate was observed in GT-3 subjects with compensated cirrhosis (40% SVR12; C-Breeze 1). We believe this lower rate is attributed to the reduced antiviral activity associated with the nucleotide uprifosbuvir in GT-3 cirrhotic subjects as an increase in ruzasvir dose to 180 mg substantially increased the SVR12 rate in this population (68% SVR12; C-Breeze 2), highlighting the observed dose-related clinical antiviral activity of ruzasvir in GT-3 subjects with cirrhosis.

In studies conducted by Merck, over 1,200 HCV-infected participants received ruzasvir at daily doses up to 180 mg for durations up to 12 weeks as part of 2-drug and 3-drug regimens with or without ribavirin. The overall safety data indicates that ruzasvir was generally well-tolerated with no consistent treatment-related changes in laboratory, vital signs, or electrocardiogram parameter values. SAEs and discontinuations due to AEs were rare in all studies conducted by Merck.

Dengue

In February 2023, after advancing AT-752 into a Phase 2 clinical trial, we decided not to pursue further clinical development of AT-752 for the treatment and prophylaxis of dengue. This action was taken due to the long timelines anticipated for patient enrollment, expected clinical operational challenges, including the challenge of successfully administering an antiviral very shortly after infection which is not feasible with the current diagnostic tests, and the estimated resource burdens, including substantial costs, associated with the further clinical development of an antiviral for each of the treatment and prophylaxis of dengue.

Roche License Agreement

In October 2020, we entered into a license agreement (“Roche License Agreement”) with Roche in connection with the global development, manufacture and commercialization of bemnifosbuvir, products containing bemnifosbuvir or AT-511, the free base of bemnifosbuvir, and related companion diagnostics.

As partial consideration for the rights we granted to Roche under the Roche License Agreement, Roche paid us an upfront payment of $350 million in November 2020. Additionally, upon realization of a development milestone in June 2021, we received an additional $50 million from Roche.

During the term of the Roche License Agreement, Roche and we jointly developed bemnifosbuvir for COVID-19 on a worldwide-basis and equally shared the costs associated with such development activities. On February 10, 2022, the Roche License Agreement terminated.

As a result of the Roche License Agreement termination, we regained worldwide exclusive rights from Roche to research, develop, manufacture and commercialize bemnifosbuvir, products containing bemnifosbuvir or AT-511, the free base of bemnifosbuvir and related companion diagnostics in all fields of use.

Merck License Agreement

In December 2021, we entered into a license agreement with Merck (“Merck License Agreement”) for the development, manufacture and commercialization of ruzasvir. Ruzasvir is the NS5A inhibitor we are developing in combination with bemnifosbuvir for the treatment of HCV.

Pursuant to the terms of the Merck License Agreement, we obtained from Merck an exclusive (subject to certain reserved rights to conduct internal research), sublicensable, and worldwide license under certain Merck patents and know-how to research, develop, manufacture, have manufactured, use, import, export, sell, offer for sale, and otherwise commercialize ruzasvir (“Compound"), or products containing the Compound (each a “Product”) for all therapeutic or prophylactic uses in humans (“Field”).

In consideration for the rights we acquired under the Merck License Agreement, we paid Merck an upfront payment in the amount of $25 million and we will be required to pay Merck milestone payments up to $135 million in the aggregate upon our achievement of certain development and regulatory milestones

and up to $300 million in the aggregate upon our achievement of certain sales-based milestones. The first potential milestone, in the amount of $5.0 million, would be payable upon the commencement of a Phase 3 clinical trial. Additionally, we have agreed to pay Merck tiered royalties based on annual net sales of Products ranging from high single digit to mid-teens percentages, subject to certain adjustments. Our royalty payment obligations will continue on a country-by-country and Product-by-Product basis until the later of (i) the expiration of the last to expire valid claim of a licensed Merck patent claiming such Product and (ii) a period of years after the first commercial sale of such Product in such country.

Under the terms of the Merck License Agreement, we are obligated to use commercially reasonable efforts to develop and commercialize at least one Product in the Field in certain countries.

The term of the Merck License Agreement will continue, on a Product-by-Product and country-by-country basis, until expiration of all royalty payment obligations arising under the Merck License Agreement. We may terminate the Merck License Agreement for convenience upon 90 days prior written notice. Each party has the right to terminate the Merck License Agreement in the event of the other party’s material breach of the terms of the Merck License Agreement subject to a 60-day cure period and in the event of the other party’s bankruptcy or insolvency. Merck has the right to terminate the Merck License Agreement immediately if we commence any interference or opposition proceeding or other challenge to the validity or enforceability of any Merck patent licensed to us under the Merck License Agreement or if we otherwise oppose any extension of, or the grant of any supplementary protection certificate with respect to, any such Merck patent.

Upon any termination of the Merck License Agreement, the license granted to us by Merck will terminate. Upon termination of the Merck License Agreement by us for convenience other than as a result of a safety issue, or upon any termination by Merck, Merck will have an exclusive, fully paid, perpetual, sublicensable license to certain of our patents and know-how that are reasonably necessary to develop, manufacture or commercialize a Product that contains ruzasvir as the sole active agent, as such Product exists at termination. Additionally, if requested by Merck, during a period of time after delivery of the notice of termination of the Merck License Agreement by Merck or by us for convenience other than as a result of a safety issue, we will have the obligation to negotiate with Merck for the grant to Merck of a non-exclusive, royalty bearing license to certain of our patents and know-how that are reasonably necessary to develop, manufacture or commercialize a Product that is comprised of the combination of ruzasvir and bemnifosbuvir, as such Product exists at termination, with certain license terms pre-specified in the Merck License Agreement.

Manufacturing

We do not currently own or operate manufacturing facilities for the production of preclinical or clinical product candidates, nor do we have plans to develop or operate our own manufacturing operations in the future. We currently rely upon third-party contract manufacturing organizations (“CMOs”) to produce our product candidates for both preclinical and clinical use and anticipate to rely upon these or other CMOs or other third parties for commercial supply if any of our product candidates is successfully developed and approved for sale. While we expect that we will be able to enter into such arrangements, we do not currently have long term agreements in place for manufacture of product at commercial scale quantities. As a result, there are no assurances that our manufacturing and supply chain infrastructure will remain uninterrupted and reliable or that our CMOs or other third parties will be able to satisfy demand in a timely manner. While there are a limited number of companies that can produce raw materials and active pharmaceutical ingredients in the quantities and with the quality and purity that we require for our product candidates, based on our diligence to date, we believe our current network of manufacturing partners are able to fulfill these requirements, and are capable of continuing to expand capacity as needed. Additionally, we have, and will continue to evaluate further relationships with additional suppliers to increase overall capacity as well as further reduce risks associated with reliance on a limited number of suppliers for manufacturing.

Our employees who have extensive manufacturing and supply chain experience oversee the relationships with our CMOs.

Competition

As a clinical-stage biopharmaceutical company, we face competition from a wide array of companies in the pharmaceutical and biotechnology industries. These include both small companies and large

companies with much greater financial and technical resources and far longer operating histories than our own. We may also compete with the intellectual property, technology, and product development efforts of academic, governmental, and private research institutions.

Our competitors may have significantly greater financial resources, established presence in the market, expertise in research and development, manufacturing, preclinical and clinical testing, obtaining regulatory approvals and reimbursement, and marketing approved products than we do. These competitors also compete with us in recruiting and retaining qualified scientific, sales, marketing, and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

The key competitive factors affecting the success of any product candidates that we develop, if approved, are likely to be their efficacy, safety, convenience, price, and the availability of reimbursement from government and other third-party payors. The commercial opportunity for any product candidate we develop, if any are approved, could be reduced or eliminated if such product fails to achieve market acceptance from patients, prescribers and payors, our competitors develop and commercialize products that are more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours and may commercialize products more quickly than we are able to.

SARS-CoV-2

Many therapies and vaccines are approved or authorized for emergency use for the treatment and prevention, respectively of COVID-19 in the US and multiple additional countries. In addition to approved or authorized products, there are other agents in development for the treatment of COVID-19 both within and outside the US.

Direct acting antiviral therapies for the treatment of COVID-19 that are currently approved or authorized by the FDA for use include:

•

PaxlovidTM (nirmatrelvir tablets; ritonavir tablets) (Pfizer Inc.), which includes nirmatrelvir, a SARS-CoV-2 main protease inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, approved for the treatment of mild-to-moderate COVID-19 in adults who are at high-risk for progression to severe COVID-19, including hospitalization or death; and authorized for emergency use in pediatric patients (12 years of age and older weighing at least 40 kg) at high-risk for progression to severe COVID-19, including hospitalization or death.

•

LagevrioTM (molnupiravir) (Ridgeback Biotherapeutics LP/Merck & Co., Inc.), a ribonucleoside analog authorized for emergency use for the treatment of adults with mild-to-moderate COVID-19 who are at high-risk for progression to severe COVID, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate.

•

Veklury® (remdesivir) (Gilead Sciences, Inc.), a SARS-CoV-2 nucleotide analog RdRp inhibitor approved for the treatment of COVID-19 in adults and pediatric patients (28 days of age and older and weighing at least 3 kg) who are (i) hospitalized, or (ii) not hospitalized and have mild-to-moderate COVID-19, and are at high-risk for progression to severe COVID-19, including hospitalization and death.

These antiviral therapies are also approved or authorized for use in many countries outside the US.

In addition to bemnifosbuvir, other orally administered antiviral agents that are currently in later stage development in the US for the treatment of COVID-19 include:

Investigational Therapy Company Mechanism of Action Phase of Development

Ensitrelvir (S-217622) Shionogi Protease inhibitor Phase 3

Ibuzatrelvir (PF-07817883) Pfizer Protease Inhibitor Phase 2

In addition to the antivirals listed above, both within and outside the US, several monoclonal antibodies were previously authorized for emergency use for the prophylaxis or treatment of COVID-19. While these authorizations were rescinded in the US, it is possible that monoclonal antibodies which have effectiveness against future SARS-CoV-2 variants may be developed and authorized or approved for the treatment of COVID-19.

Vaccines that are approved or authorized for emergency use for the prevention of COVID-19 in the US include:

•

Comirnaty® (COVID-19 Vaccine, mRNA) (Pfizer-BioNTech), 2023-2024 formula FDA-approved vaccine for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12 years of age and older.

•

Pfizer-BioNTech (COVID-19 Vaccine, monovalent), 2023-2024 formula vaccine authorized for all doses administered to individuals 6 months through 11 years of age to prevent COVID-19.

•

Spikevax® (COVID-19 Vaccine, mRNA) (Moderna), 2023-2024 formula FDA-approved vaccine for active immunization to prevent COVID-19 in individuals 12 years of age and older.

•

Moderna (COVID-19 Vaccine, monovalent), 2023-2024 formula vaccine authorized for all doses administered to individuals 6 months through 11 years of age to prevent COVID-19.

•

Novavax COVID-19 Vaccine, Adjuvanted, 2023-2024 formula monovalent vaccine authorized to prevent COVID-19 for individuals 12 years of age and older.

The potential treatments and vaccines for COVID-19 continue to evolve and the lists above are not comprehensive lists of every or all treatments and vaccines that are in development for COVID-19. These lists include the products or product candidates approved or authorized for emergency use and the direct acting antivirals in late stage clinical development in the US as of the date of this Annual Report on Form 10-K that we believe would be the most competitive with bemnifosbuvir.

HCV

Since 2014, many direct-acting antiviral therapies have been approved for use for the treatment of HCV in the US and globally. Orally administered, FDA-approved treatments for patients with chronic HCV include:

•

Sovaldi® (sofosbuvir) (Gilead Sciences, Inc.), an HCV nucleotide analog NS5B polymerase inhibitor approved for the treatment of adult patients with GT-1, -2, -3, -4, -5, -6 chronic HCV infection without cirrhosis or with compensated cirrhosis as a component of a combination antiviral treatment regimen; pediatric patients ≥3 years old with HCV GT-2 or -3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin.

•

Epclusa® (sofosbuvir and velpatasvir) (Gilead Sciences, Inc.) fixed dose combination regimen of sofosbuvir and velpatasvir, an HCV NS5A inhibitor, approved for the treatment of adults and pediatric patients ≥3 years old with chronic HCV GT-1, -2, -3, -4, -5, or -6 infection without cirrhosis or with compensated cirrhosis, or for use in combination with ribavirin with decompensated cirrhosis.

•

Harvoni® (ledipasvir and sofosbuvir) (Gilead Sciences, Inc.) a fixed dose combination of ledipasvir, an HCV NS5A inhibitor, and sofosbuvir approved for the treatment of adult and pediatric patients ≥3 years old with HCV GT-1, -4, -5 or -6 infection without cirrhosis or with compensated cirrhosis.

•

Vosevi® (sofosbuvir, velpatasivir, and voxilaprevir) (Gilead Sciences, Inc.) a fixed dose triple combination of sofosbuvir, velpatasvir and voxilaprevir, an HCV NS3/4A protease inhibitor

approved for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who have HCV GT-1, -2, -3, -4, -5, or -6 infection and have previously been treated with an HCV regimen containing an HCV NS5A inhibitor; HCV GT-1a or -3 infection who have previously been treated with an HCV regimen containing sofosbuvir without an HCV NS5A inhibitor.

•

Mavyret® (glecaprevir and pibrentasvir) (AbbVie, Inc.) a fixed-dose combination of glecaprevir, an HCV NS3/4A protease inhibitor and pibrentasvir, an HCV NS5A inhibitor, approved for the treatment of adult and pediatric patients ≥3 years old with chronic HCV GT-1, -2, -3, -4, -5, or -6 infection without cirrhosis or with compensated cirrhosis. Mavyret as an eight-week treatment is approved for patients who have not been previously treated. Longer treatment durations (up to 16 weeks) are indicated for some treatment-experienced populations. Mavyret is not approved for use in patients with decompensated cirrhosis.

•

Zepatier® (elbasvir and grazoprevir) (Merck & Co., Inc.) a fixed-dose combination of elbasvir, an HCV NS5A inhibitor and grazoprevir, an HCV NS3/4A protease inhibitor approved for the treatment of chronic HCV GT-1 or -4 infection in adult and pediatric patients ≥12 years old or weighing at least 30 kg. Zepatier is indicated for use with ribavirin in certain patient populations.

In addition to the branded products, Gilead Sciences, Inc. markets authorized generic copies of Epclusa and Harvoni through its subsidiary, Asegua Therapeutics, LLC. We are not aware of any investigational agents in late-stage development in the US although there may be other investigational agents for HCV in various stages of clinical development in other parts of the world.

Commercialization

We currently believe that we can maximize the value of our product portfolio by retaining global development rights to our product candidates. However, to further maximize the value of product candidates that are authorized or approved for sale, we may seek collaborations that allow us to access and leverage commercialization expertise and resources of collaborators in certain markets. To assist in the commercialization in the US of any product candidates we successfully develop, we may enter into arrangements with third parties that have existing commercial infrastructure including primary care sales force and expertise in managed care. Outside the US, we anticipate that commercialization of our products, if approved or authorized for use, would be undertaken by third party collaborators. Currently, we do not have any sales, marketing or commercial product distribution infrastructure and we do not have any existing arrangements with third parties to commercialize our product candidates in the US or elsewhere.

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain proprietary protection for our nucleotide therapeutic products for viral diseases, including our purine nucleotide compounds for SARS-CoV-2 and HCV. We seek to protect our proprietary compounds and methods of treatment for viral diseases using our nucleotide compounds, alone and in combination with other therapeutic agents, in addition to dosage forms, dosing regimens and formulations for their administration. We also seek protection on the manufacturing process for the production of our nucleotide compounds. Our success also depends on our ability to operate without infringing, misappropriating or otherwise violating the proprietary rights of others and to prevent others from infringing, misappropriating or otherwise violating our proprietary rights.

Our policy is to seek to protect our proprietary position by filing US and foreign patent applications covering our proprietary technologies, inventions, and improvements that are important to the development and implementation of our business. In addition, we currently plan to seek patent term adjustments, restorations, and/or patent term extensions where applicable in the US, Europe and other jurisdictions. We also rely on trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietary position. Additionally, we expect to benefit, where appropriate, from statutory frameworks in the US, Europe and other countries that provide a period of regulatory data exclusivity to compensate for the time required for regulatory approval of our drug products.

As of February 1, 2024, we are the sole owner of fourteen patent families covering our product candidates and proprietary nucleotide compounds, which include composition of matter, pharmaceutical compositions, methods of use, and processes of manufacture as described in more detail below. Our owned patent estate as of February 1, 2024, on a worldwide basis, includes more than 300 pending, granted, or allowed patent applications with eighteen issued US patents, nine pending US non-provisional applications, two pending international patent applications filed under the Patent Cooperation Treaty (“PCT”), and more than 250 pending or granted patent applications that have entered the national phase of prosecution in countries outside the US.

As of February 1, 2024, we are the exclusive licensee of three patent families from Merck covering composition of matter, process of preparation, and formulations of the NS5A inhibitor ruzasvir (MK-8408), which collectively include two issued US patents, granted patents in France, Great Britain, and Germany and one pending US patent application and one pending patent application in the European Patent Office ("EPO").

The exclusivity terms of our patents depend upon the laws of the countries in which they are obtained. In the countries in which we currently file, the patent term is 20 years from the earliest date of filing of a non-provisional patent application. The term of a US patent may be extended to compensate for the time required to obtain regulatory approval to sell a drug (a patent term extension) or by delays encountered during patent prosecution that are caused by the US Patent and Trademark Office (referred to as patent term adjustment). For example, the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act, permits a patent term extension for FDA-approved new chemical entity drugs 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 and diligence during the review process. Patent term extensions in the US cannot extend the term of a patent beyond a total of 14 years from the date of product approval, only one patent covering an approved drug, or its method of use may be extended, and only those claims covering the approved drug, or an approved method for using it may be extended. A similar kind of patent extension, referred to as a Supplementary Protection Certificate, is available in the European Union ("EU"). Legal frameworks are also available in certain other jurisdictions to extend the term of a patent. We currently intend to seek patent term extensions on any of our issued patents in any jurisdiction where we have a qualifying patent and the extension is available; however, there is no guarantee that the applicable regulatory authorities, including the FDA in the US, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions. Further, even if our patent is extended, the patent, including the extended portion of the patent, may be held invalid or unenforceable by a court of final jurisdiction in the US or a foreign country.

Current issued patents and patent applications covering the composition of matter for our present clinical candidates AT-511 and bemnifosbuvir will expire on dates ranging from 2036 to 2038, if the applications are issued and held valid by a court of final jurisdiction if challenged, and without regard to any possible patent term adjustments or extensions. Current patent applications covering the use of AT-511 and bemnifosbuvir for the treatment of SARS-CoV-2 will expire on dates ranging from 2040 to 2041, if the applications are issued and held valid by a court of final jurisdiction if challenged, and without regard to any possible patent term adjustments or extensions. Current issued patents and patent applications covering the use of AT-511 and bemnifosbuvir for the treatment of HCV will expire on dates ranging from 2036 to 2042, if the applications are issued and held valid by a court of final jurisdiction if challenged, and without regard to any possible patent term adjustments or extensions.

However, any of our patents, including patents that we may rely on to protect our market for approved products, may be held invalid or unenforceable by a court of final jurisdiction. Alternatively, we may decide that it is in our interest to settle a litigation in a manner that affects the term or enforceability of our patent. Changes in either the patent laws or in interpretations of patent laws in the US and other jurisdictions may diminish our ability to protect our inventions and enforce our intellectual property rights. Accordingly, we cannot predict the breadth or enforceability of claims that have been or may be granted on our patents or on third-party patents. The pharmaceutical and biotechnology industries are characterized by extensive litigation regarding patents and other intellectual property rights. Our ability to obtain and maintain our proprietary position for our nucleotide compounds and the use of these compounds will depend on our success in enforcing patent claims that have been granted or may grant.

We do not know whether any of the pending patent applications that we have filed or may file or license from third parties will result in the issuance of any additional patents. The issued patents that we own or may receive in the future may be challenged, invalidated, or circumvented, and the rights granted under any issued patents may not provide us with sufficient protection or competitive advantages against competitors with similar technology. Furthermore, our competitors may be able to independently develop and commercialize drugs with similar mechanisms of action and/or duplicate our methods of treatments or strategies without infringing our patents. Because of the extensive time required for clinical development and regulatory review of a drug we may develop, it is possible that, before any of our drugs can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent. For more information regarding risks relating to intellectual property, see Part I, Item 1A. “Risk Factors—Risks Related to Intellectual Property.”

Our patent families, as of February 1, 2024, are further described below.

AT-511 and bemnifosbuvir

We own a first patent family that describes AT-511 or a pharmaceutically acceptable salt thereof (for example, bemnifosbuvir), pharmaceutical compositions of AT-511 or the pharmaceutical salts thereof, and methods to treat HCV using AT-511 or a salt thereof. This family consists of seven issued US patents (US Pat. Nos. 9,828,410; 10,000,523; 10,005,811; 10,239,911; 10,815,266; 10,870,672; 10,870,673) covering AT-511 or a pharmaceutically acceptable salt thereof, related compounds and their pharmaceutical compositions. This patent family is now also in the national stage of prosecution or granted in the African Regional Intellectual Property Organization (“ARIPO”), Australia, Brazil, Canada, China, Colombia, the Eurasian Patent Office (“EAPO”), Egypt, the EPO, Georgia, Hong Kong, Indonesia, Israel, India, Japan, Korea, Mexico, Macao, Malaysia, Nigeria, New Zealand, the Philippines, Russia, Saudi Arabia, Singapore, Thailand, Vietnam, Ukraine, South Africa, and the United Arab Emirates. We have more than 30 foreign patents granted or allowed, and more than 20 pending patent applications. The expected year of expiration for this patent family, where issued, valid and enforceable, is 2036, without regard to any extensions, adjustments, or restorations of term that may be available under national law.

We also own a second patent family that specifically covers bemnifosbuvir (the hemisulfate salt for AT-511), pharmaceutical compositions, process of preparation, and methods to treat HCV using bemnifosbuvir. This family includes two issued US patents (US Pat. No. 10,519,186, and US Patent No. 10,906,938,) and one allowed US application covering bemnifosbuvir. This family is currently in the national phase of prosecution in Argentina, ARIPO, Australia, Brazil, Canada, China, Colombia, the EAPO, the EPO, Georgia, Hong Kong, Indonesia, Israel, India, Japan, Korea, Mexico, Malaysia, Nigeria, New Zealand, the Philippines, Russia, Singapore, Taiwan, Thailand, Vietnam, Ukraine, Uzbekistan, and South Africa. We have over 25 granted foreign patents and over 25 pending applications. The expected year of expiration for this patent family, if issued, valid and enforceable, is 2038, without regard to any extensions, adjustments, or restorations of term that may be available under US or other national laws.

We own two patent families that disclose methods for the treatment of SARS-CoV-2 using AT-511 or bemnifosbuvir. These families include four granted US patents (US Patent Nos. 10,874,687, 11,707,480, 11,783,038, and 11,813,278) and two pending US applications. A patent application in this family has been allowed in Japan and applications are pending in Argentina, ARIPO, Australia, Bahrain, Brazil, Canada, Chile, China, Columbia, Ecuador, Egypt, the EPO, the EAPO, Georgia, India, Israel, Japan, Jordan, Kuwait, Libya, Malaysia, Mexico, Morocco, New Zealand, Nicaragua, Nigeria, Oman, Philippines, Russia, Saudi Arabia, Singapore, South Africa, South Korea, Taiwan, Thailand, Tunisia, Uzbekistan, and Vietnam. The expected year of expiration for patents issued from these families, if valid and enforceable, is 2040 or 2041, without regard to any extensions, adjustments, or restorations of term that may be available under US or other national laws.

We own a fifth patent family that discloses the use of AT-511 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a positive-stranded RNA virus infection, including a Flaviviridae viral infection such as dengue, West Nile, or yellow fever. This family consists of one allowed application and one issued patent (US Patent No. 10,946,033) and is currently pending or granted in Australia, Brazil, Canada, China, the EAPO, the EPO, Hong Kong, Indonesia, Japan, Korea, Malaysia, Nigeria, Russia,

Singapore, Thailand, Vietnam, and South Africa. We have over 30 foreign patents granted and over 20 pending patent applications. The expected year of expiration for this patent family, if issued, valid and enforceable, is 2037, without regard to any extensions, adjustments, or restorations of term that may be available under US or other national laws.

We own a sixth patent family that discloses the use of AT-511 and bemnifosbuvir for the treatment of HCV in patients with cirrhosis of the liver. This family includes one granted US application (US Patent No. 11,690,860). The expected year of expiration for this patent family, if issued, valid and enforceable, is 2039, without regard to any extensions, adjustments, or restorations of term that may be available under US or other national laws.

We own a seventh patent family that describes methods to treat mutant or resistant forms of the SARS-CoV-2 virus. This family consists of pending applications in the US, the EPO, Japan, Canada and Hong Kong, as well as one application in Argentina and one application in Taiwan. The expected year of expiration for patents issued from non-provisional patent applications filed on the basis of this patent application, if valid and enforceable, is 2041, without regard to adjustments of term that may be available under US or other national laws.

We also own an eighth patent family that discloses methods for manufacturing AT-511 and bemnifosbuvir. This family consists of one pending US application. The expected year of expiration for patents issued from non-provisional patent applications filed on the basis of these provisional patent applications, if valid and enforceable, is 2041, without regard to adjustments of term that may be available under US or other national laws.

We also own a ninth patent family that discloses additional processes for the manufacture of AT-511 and bemnifosbuvir. This family consists of one pending patent application in the US in addition to pending applications in Argentina, Australia, Canada, China, the EPO Hong Kong, India, Japan, Korea, Mexico, New Zealand, and Taiwan. The expected year of expiration for patents issuing from these non-provisional patent applications, if valid and enforceable, is 2041, without regard to any adjustments of term that may be available under US or other national law.

We also own a tenth patent family that discloses new morphic forms of bemnifosbuvir. This family consists of one pending patent application in the US, as well as pending applications in Australia, Brazil, Canada, China, the EAPO, the EPO, Israel, India, Japan, Korea, Mexico, Russia, and Taiwan. The expected year of expiration for patents issued from non-provisional patent applications filed on the basis of this patent application, if valid and enforceable, is 2042, without regard to adjustments of term that may be available under US or other national laws.

Ruzasvir

We have exclusively licensed three patent families from Merck covering composition of matter, process of preparation, and formulations of ruzasvir (MK-8408), a pan-genotype NS5A inhibitor to treat HCV. The family covering the composition of matter includes one granted US patent (US Patent No. 9,555,038), and granted patents in France, Great Britain, and Germany. The expected expiration date is in 2034. The family describing a process of preparation includes one granted US patent (US Patent No. 10,457,690), with an expected expiration date in 2036. The family describing formulations includes one pending US patent application and one pending patent application in the EPO, which if granted, is expected to expire in 2039.

We also solely own a patent family covering the combination of bemnifosbuvir and ruzasvir. This family consists of one patent application in the US, in addition to patent applications in the United Arab Emirates, Argentina, Australia, Brazil, Canada, China, Colombia, the EAPO, the EPO, Indonesia, Israel, India, Japan, Korea, Mexico, Malaysia, New Zealand, the Philippines, Qatar, Russia, Saudi Arabia, Singapore, Thailand, Taiwan, and South Africa. These patent applications, if granted, will have an expiration date in 2042.

Government Regulation and Product Approval

Government authorities in the US, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of products such as those we are developing. A new drug must be approved by the FDA through the new drug application (“NDA”), process before it may be legally marketed in the US.

US Drug Development Process

In the US, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”) and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

The process required by the FDA before a drug may be marketed in the US generally involves the following:

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completion of preclinical laboratory tests, animal studies and formulation studies in accordance with FDA’s good laboratory practice requirements and other applicable regulations;

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submission to the FDA of an IND, which must become effective before human clinical trials may begin;

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approval by an independent institutional review board (“IRB”), or ethics committee at each clinical site before each trial may be initiated;

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performance of adequate and well-controlled human clinical trials in accordance with good clinical practice requirements (“GCPs”) to establish the safety and efficacy of the proposed drug for its intended use;

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submission to the FDA of an NDA after completion of all pivotal trials;

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satisfactory completion of an FDA advisory committee review, if applicable;

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satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current good manufacturing practice (“cGMP”), requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity, and satisfactory completion of potential inspections of selected clinical investigation sites to assess compliance with GCPs; and

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FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the US.

Prior to beginning the first clinical trial with a product candidate in the US, a sponsor must submit an IND to the FDA. An IND is a request for allowance from the FDA to administer an investigational drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies. The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the investigational product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials may begin. Once submitted, the IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30- day time period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA allowance to begin a clinical trial.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which among other things include the requirement that all research subjects provide their informed consent for their participation in any clinical

study. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Furthermore, an independent IRB or ethics committee for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the study until completed. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the investigational product has been associated with unexpected serious harm to patients.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Phase 1: The product candidate is initially introduced into healthy human subjects, and in some cases, patients with the target disease or condition. These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

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Phase 2: The product candidate is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

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Phase 3: The product candidate is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach alignment on the next phase of development.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final drug. In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

US Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, including results from preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

In addition, the Pediatric Research Equity Act (“PREA”), requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs and certain supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is deemed safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current or fails to submit a request for approval of a pediatric formulation.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA must be resubmitted with additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity. Under the Prescription Drug User Fee Act (“PDUFA”), guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications. Additionally, before approving a NDA, the FDA may inspect one or more clinical sites to assure compliance with GCPs.

After the FDA evaluates an NDA, it will issue an approval letter or a Complete Response Letter ("CRL"). An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications. A CRL indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A CRL usually describes the specific deficiencies in the NDA

identified by the FDA and may require additional clinical data, such as an additional clinical trials or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing. If a CRL is issued, the sponsor must resubmit the NDA addressing all of the deficiencies identified in the letter or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations or restrictions on the indicated uses for which such product may be marketed. For example, the FDA may approve the NDA with a Risk Evaluation and Mitigation Strategy (“REMS”), to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. The FDA may also require one or more post-approval studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-approval studies.

Emergency Use Authorization

The Commissioner of the FDA, under delegated authority from the Secretary of HHS may, under certain circumstances in connection with a declared public health emergency, allow for the marketing of a product that does not otherwise comply with FDA regulations by issuing an EUA for such product. Before an EUA may be issued by HHS, the Secretary must declare an emergency based a determination that public health emergency exists that effects or has the significant potential to affect, national security, and that involves a specified biological, chemical, radiological, or nuclear agent or agents (“CBRN”), or a specified disease or condition that may be attributable to such CBRN. On February 4, 2020, the HHS Secretary determined that there is such a public health emergency that involves SARS-CoV-2, the virus that causes the COVID-19 infection. Once the determination of the threat or emergency has been made, the Secretary of HHS must then declare that an emergency exists justifying the issuance of EUAs for certain types of products (referred to as EUA declarations). On March 27, 2020, the Secretary of HHS declared on the basis of his determination of a public health emergency that has the potential to affect national security or the health and security of US citizens living abroad that involves SARS-CoV-2 that circumstances exist justifying authorization of drugs and biologics during the COVID-19 pandemic, subject to the terms of any EUA that is issued.

Once an EUA declaration has been issued, the FDA can issue EUAs for products that fall within the scope of that declaration. To issue an EUA, the FDA Commissioner must conclude that (1) the CBRN that is referred to in the EUA declaration can cause serious or life-threatening diseases or conditions; (2) based on the totality of scientific evidence available, it is reasonable to believe that the product may be effective in diagnosing, treating, or preventing the disease or condition attributable to the CBRN and that the product’s known and potential benefits outweigh its known and potential risks; and (3) there is no adequate, approved, and available alternative to the product. Products subject to an EUA must still comply with the conditions of the EUA, including labeling and marketing requirements. Moreover, the authorization to market products under an EUA is limited to the period of time the EUA declaration is in effect, and the FDA can revoke an EUA in certain circumstances.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates. For example, the FDA Fast Track program is intended to expedite or facilitate the process for reviewing product candidates that meet certain criteria. Specifically, investigational drugs are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. The sponsor of a Fast Track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the application may be eligible for priority review. With regard to a Fast Track product candidate, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor

provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

AVIR US Equity

AVIR · 10-K · period ended 2023-12-31

Item 1. Business.

AVIR US Equity☆

AVIR · 10-K · period ended 2023-12-31

Item 1. Business.

AVIR US Equity