10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year endedDecember 31, 2022

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, 2022, 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 $537,283,731.

The number of shares of Registrant’s Common Stock outstanding as of February 25, 2023 was 83,341,574.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s definitive proxy statement for its 2023 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, 2022, 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 52

Item 1B. Unresolved Staff Comments 122

Item 2. Properties 122

Item 3. Legal Proceedings 122

Item 4. Mine Safety Disclosures 122

PART II

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 142

Item 8. Financial Statements and Supplementary Data 142

Item 9A. Controls and Procedures 142

Item 9B. Other Information 144

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 144

PART III

Item 10. Directors, Executive Officers and Corporate Governance 145

Item 11. Executive Compensation 145

Item 14. Principal Accountant Fees and Services 145

PART IV

Item 15. Exhibits, Financial Statement Schedules 146

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,” "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 top-line 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 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, 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 becomes endemic.

These forward-looking statements are based on management’s current expectations. 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. 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 highly dependent on our management, directors and other key personnel.

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We may expend resources in anticipation of potential clinical trials and commercialization of bemnifosbuvir, which we may not be able to recover if bemnifosbuvir is not approved for the treatment of COVID-19, we are not successful at commercializing bemnifosbuvir or 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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The market for new therapeutics for the treatment of COVID-19 may be reduced, perhaps significantly, if vaccines and current therapeutics remain effective in minimizing serious consequences of the disease.

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If approved, bemnifosbuvir will face significant competition from other treatments for COVID-19 that are currently marketed or are in development.

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The COVID-19 pandemic and future variant fueled pandemic surges may materially and adversely affect our business opportunities, clinical trials and financial results.

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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 never 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, including bemnifosbuvir. If we fail to successfully develop bemnifosbuvir for the treatment of COVID-19 or the combination of bemnifosbuvir and ruzasvir for the treatment of hepatitis C 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 US 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 have only a limited number of employees, which may be inadequate to manage and operate our business.

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

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We may engage in acquisitions or strategic partnerships 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 upon whom we depend 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 focused on discovering, developing, and commercializing antiviral therapeutics to improve the lives of patients suffering from serious viral infections. We are developing our lead product candidate, bemnifosbuvir, for the treatment of COVID-19, the disease caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 ("SARS-CoV-2") and its variants. We are also developing bemnifosbuvir in combination with ruzasvir for the treatment of Hepatitis C ("HCV").

COVID-19 has caused a global health crisis resulting in millions of deaths and lingering medical issues for many survivors. While there have been many rapid advances in the prevention and treatment of COVID‐19, due to the limitations of the current vaccine and treatment options, there remains a significant unmet medical need for large numbers of high-risk individuals both in the US and globally. Our COVID-19 strategy is centered on the development of bemnifosbuvir as a monotherapy and potentially as a part of a COVID-19 therapy that combines bemnifosbuvir with another antiviral agent and focuses on these high-risk patients for whom current vaccines and treatments remain inadequate. Our goal is to deliver a safe, effective, and convenient treatment option for individuals that remain vulnerable to hospitalization and death as a result of infection with SARS-CoV-2.

Even with the availability of vaccines and therapeutics, COVID-19 is the third leading cause of mortality in the US after only heart disease and cancer. As of February 15, 2023, the CDC reported that more than 400 persons a day are dying in the US from COVID-19 or related complications. More than 75% of these persons are 65 years and older. Additionally, it has been reported as recently as February 15, 2023, persons 60 years and older account for ~70% of current US hospitalizations associated with COVID-19.

While the US government has recently announced plans to end the declaration of a public health emergency associated with COVID-19, COVID-19 is expected to remain a serious endemic threat for an indefinite future period. The reasons contributing to the likelihood of COVID-19 remaining an endemic threat include: (1) viral transmission before symptom onset; (2) uneven global rollout of vaccinations; (3) ongoing vaccine hesitancy; (4) limited duration of immunity conferred by both natural infection and vaccination; (5) limited vaccine efficacy against certain SARS-CoV-2 variants; (6) limitations of current oral antivirals such as drug-drug interactions, safety concerns and tolerability; (7) uncertain impact of vaccines on transmission; (8) continuing evolution of the virus evading endogenous and vaccine-induced immunity; and (9) diminution of virus transmission mitigation behaviors, such as wearing masks and social distancing.

The continued emergence of SARS-CoV-2 variants that may have greater transmissibility and may cause more severe disease, combined with the diminution of virus mitigation behaviors among others in the general population, together with the consequences that are expected to associate with the end of the public health emergency leave patients for whom current therapeutics are limited particularly vulnerable to the virus and related disease. In view of these factors, we are developing bemnifosbuvir as a potential therapy to meet the needs of these vulnerable patients.

As COVID-19 continues to persist as a serious global endemic disease, we believe that the COVID-19 therapeutic market will remain a multi-billion-dollar opportunity for many years to come with the US continuing to comprise the most significant commercial market. In the US, we anticipate that the COVID-19 commercial market will soon transition from a single government payer to more traditional payer channels such as Medicare, Medicaid and private commercial insurance. We anticipate a major consideration for determining reimbursement by these third party payers will be a cost/value analysis that is driven in part by the economic burden of hospitalization, especially for at-risk populations.

Bemnifosbuvir

We utilized our team’s expertise and experience, gained from decades of developing innovative antiviral treatments, to design bemnifosbuvir, an investigational, proprietary, potent, and selective, nucleotide polymerase inhibitor, which may be developed as each of a monotherapy and in combination with other antiviral agents. Bemnifosbuvir (AT-527) has been derived from our internal discovery program that combines unique nucleotide scaffolds with novel double prodrugs for the purpose of inhibiting the enzymes central to viral replication. Utilizing this double prodrug moiety approach, we believe that we have been able to maximize formation of the active metabolite of bemnifosbuvir thereby creating an oral antiviral product candidate that is designed to prevent replication of single stranded RNA (“ssRNA”) viruses while avoiding toxicity to host cells. In nonclinical studies we have demonstrated that bemnifosbuvir has a unique mechanism of action that includes both RNA-dependent RNA polymerase (“RdRp”) chain termination and inhibition of the nidovirus RdRp associated nucleotidyltransferase (“NiRAN”) of the SARS-CoV-2 virus and variants. By targeting these highly conserved sites through this unique dual mechanism of action, bemnifosbuvir has the potential to create a high barrier to resistance. Additionally, in in vitro studies we have conducted, bemnifosbuvir maintained its antiviral activity across COVID-19 variants of concern ("VOC"), including all Omicron subvariants tested.

COVID-19 Clinical Studies

In November 2022, we initiated SUNRISE-3, a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial. SUNRISE-3 is evaluating bemnifosbuvir (550 mg twice-daily ("BID") for five days) in at least 1500 high-risk non-hospitalized patients with mild or moderate COVID-19. The trial will be conducted at clinical trial sites in the US, Europe, Japan, and other regions of the world. The patient population will consist of those at the highest risk for disease progression, including patients ≥ 80 years old, patients ≥ 65 years old with one or more major risk factors, and immunocompromised patients ≥ 18 years old, all regardless of COVID-19 vaccination status.

SUNRISE-3 is designed to evaluate bemnifosbuvir as monotherapy (primary analysis) but will also explore the effect of combination therapy in a smaller sub-set of patients who receive an antiviral drug along with bemnifosbuvir (secondary analysis). The trial will include two populations derived from the type of standard of care ("SOC") received: 1) “supportive care population” (those patients who do not qualify for an approved antiviral treatment or where antivirals are not locally available) which will assess bemnifosbuvir given as monotherapy (primary analysis) and 2) “combination antiviral population” which will assess 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 at least 1,300 patients in the supportive care population and is powered to detect a clinically meaningful reduction in hospitalization/death versus placebo in this population. By enriching the patients enrolling in the trial with those who are at the highest risk for disease progression, we are targeting rates of hospitalization/death of ~4-6%. An interim analysis will be conducted by an independent data safety monitoring board ("DSMB") after 60% patient enrollment in the arm of the study enrolling the supportive care population. Secondary endpoints in each of the supportive care patient population and the combination antiviral population include COVID-19 complications, medically attended visits, symptom rebound/relapse and viral load rebound.

Data from prior studies of bemnifosbuvir that we have relied upon to support the design of SUNRISE-3 includes results from the Phase 3 clinical trial referred to as MORNINGSKY that was closed out early along with results from Phase 1 drug-drug interaction ("DDI") studies. While the primary endpoint of the MORNINGSKY study, time to symptom alleviation, was not achieved, the results from MORNINGSKY demonstrated a 71% reduction in hospitalization (2.9% versus 10%) (p=0.047, unadjusted, exploratory; secondary endpoint) in the bemnifosbuvir arm (n=137) versus placebo (n=70). The patients enrolled in the MORNINGSKY trial consisted of a broad outpatient population including 47% who were high risk, 28% who were vaccinated, and 56% who were seropositive at baseline. In a subgroup analysis in

patients greater than 40 years old, the reduction in hospitalization in the bemnifosbuvir arm of the MORNINGSKY trial was even greater at 82%.

To date, five clinical DDI studies have been completed and demonstrated an overall low DDI 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 many drugs that are commonly prescribed to patients at high risk for COVID-19.

In these DDI 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.

In parallel to conducting our SUNRISE-3 clinical trial, we are engaging in efforts to discover a protease inhibitor product candidate that we may combine with bemnifosbuvir for the treatment of specific COVID-19 patient populations that are unable to mount immune response and require combination therapy. We have conducted in vitro studies that have demonstrated an additive antiviral effect when bemnifosbuvir was combined with antivirals from the protease inhibitor class, including nirmatrelvir. The data that we anticipate obtaining from the SUNRISE-3 clinical trial in the subset of patients who receive combination therapy will be, we believe, the first clinical data evaluating the combination of bemnifosbuvir and certain other currently authorized antiviral treatments.

Combination Therapy

Combination therapy utilizing multiple direct acting antivirals with differing mechanisms of action is an established strategy that has been historically successful in treating many life-threatening viral diseases, including human immunodeficiency virus (“HIV”), hepatitis B virus (“HBV”) and HCV. Nucleos(t)ide analogs are the backbone of many of these successful combination therapies. Advantageously, drug combinations can simultaneously target multiple points in the viral replication cycle with the effect of increasing antiviral activity and can also combat resistance that may develop over time with use of single agent drugs.

Hepatitis C Virus (HCV) Clinical Studies

For the treatment of chronic HCV infection, we are advancing the combination of bemnifosbuvir and ruzasvir, an investigational NS5A inhibitor. Approximately 58 million people globally, including ~2.4 million in the US, are living with chronic HCV infection. The World Health Organization ("WHO") reports a global incidence of 1.5 million cases per year and 399,000 deaths per year. The US HCV prevalence is expected to remain constant over the coming years as rising HCV incidence offsets the number of new patients treated.

We believe that the combination of bemnifosbuvir and ruzasvir has the potential to improve upon the current standard of care by offering a differentiated short duration, pan-genotypic protease-sparing regimen for HCV-infected patients with or without cirrhosis.

During the second quarter of 2023, we plan to initiate 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 the pan-genotypic combination consisting of 550 mg once daily ("QD") of bemnifosbuvir and 180 mg QD of ruzasvir after eight weeks of treatment. Approximately 280 HCV-infected, treatment-naïve patients across all genotypes, 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 sustained virologic response ("SVR") at Week 12 post-treatment. Other virologic endpoints include virologic failure, SVR at Week 24 post-treatment and resistance.

Our Development Pipeline

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

Dengue and RSV

In February 2023, after advancing AT-752 to a Phase 2 clinical trial, we have determined 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 estimated resource burdens, including substantial costs, associated with the further clinical development of an antiviral for each of the treatment and prophylaxis of dengue.

We have also recently determined not to further pursue our discovery efforts to identify a product candidate for the treatment of respiratory syncytial virus ("RSV"). This action was taken to facilitate enhanced focus of our management team and to deploy our other resources on those therapeutic indications where our programs are more advanced.

We believe we are well capitalized to advance our current programs. We had $646.7 million in cash, cash equivalents and marketable securities at December 31, 2022. Based on our current plans, we anticipate these financial resources will allow us to advance our current and planned clinical programs to and through key inflection points and to fund our activities into 2026.

Our Strategy

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

Deploy our expertise and experience particularly our depth of knowledge with respect to nucleos(t)ide analogs to discover and develop novel or differentiated direct acting antivirals that have the potential to meet unmet medical needs or improve the current standard of care. We have assembled and are utilizing the expertise and experience of a team with a demonstrated track

record of efficiently and successfully discovering, developing, obtaining global regulatory approvals and commercializing innovative direct acting oral antiviral therapeutics. Our team has very specific expertise in the identification of unmet patient needs, virology, medicinal chemistry, particularly nucleos(t)ide chemistry and optimization, drug discovery, preclinical and clinical development, regulatory affairs and commercialization. We have relied on that expertise to:

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discover bemnifosbuvir, an investigational, novel, double prodrug nucleotide analog, which we are developing for the treatment of COVID-19 and HCV; and

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identify and in-license ruzasvir, an investigational NS5A inhibitor, that we intend to evaluate in combination with bemnifosbuvir for the treatment of HCV.

Additionally, we are using that expertise to:

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conduct our clinical trials, including the Phase 3 clinical trial SUNRISE-3, for the treatment of COVID-19, which is currently enrolling patients, and a Phase 2 clinical trial that we expect will initiate enrollment of patients in the second quarter of 2023 for the treatment of HCV; and

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design an optimized second-generation protease inhibitor that we anticipate to combine with bemnifosbuvir for the treatment of COVID-19.

Develop bemnifosbuvir (AT-527) as monotherapy for COVID-19 to address key limitations of current therapies and explore combination therapy for specific patient populations. Bemnifosbuvir, is an investigational, orally administered, non-mutagenic, non-teratogenic, direct-acting antiviral agent being evaluated in our Phase 3 SUNRISE-3 clinical trial as monotherapy and in combination with other antivirals as a part of the locally available SOC. Supportive data from MORNINGSKY showed a 71% lower risk of hospitalization in the bemnifosbuvir arm versus placebo (p=0.047, unadjusted, exploratory; secondary endpoint). In a subgroup analysis in patients greater than 40 years old, the reduction in hospitalization was even greater at 82%.

We are developing bemnifosbuvir for COVID-19 to address the current highest unmet medical need. Specifically, we are targeting the most vulnerable patient populations who are at the greatest risk for disease progression to severe COVID-19 or mortality, and for whom there are currently the fewest treatment options. With currently available oral antivirals, there are serious limitations that minimize or eliminate the suitability of use in certain patient populations and monoclonal antibodies are no longer effective against COVID-19 variants and subvariants. These limitations include DDIs with commonly prescribed medicationssuch as seizure medications, anti-psychotics and anti-coagulants. In addition, currently available vaccines have also presented limitations, including waning immunity and failure to mount immune response in specific populations.

We believe the potential product profile we are targeting for bemnifosbuvir with potential low risk for DDIs would fulfill an unmet need for an oral antiviral for COVID-19. If realized in clinical studies and if bemnifosbuvir is approved, we believe this potential profile may enable bemnifosbuvir to become a cornerstone of both monotherapy and combination oral therapy for the treatment of COVID-19.

In addition to the development of bemnifosbuvir as a monotherapy, we are advancing the development of COVID-19 combination therapy for specific immunocompromised populations. In vitro combinations of bemnifosbuvir with authorized direct acting antivirals, including protease inhibitors, have demonstrated additive antiviral activity and we continue to advance our internal protease inhibitor program for future combination therapy with bemnifosbuvir.

Advance a pan-genotypic regimen of bemnifosbuvir and ruzasvir for HCV that has the potential to improve the standard of care. Despite the availability of direct acting antiviral oral combination regimens for the treatment of HCV, there remains a large, underserved, HCV patient population which continues to grow in the US. A large portion of this increase in incidence is attributable to the opioid crisis, IV drug use, and HCV reinfection, especially among younger adults. Clinical studies that Merck conducted with ruzasvir and clinical studies of bemnifosbuvir we have conducted each demonstrated potent antiviral activity and were well tolerated by HCV-infected patients. Synergy of the combination of bemnifosbuvir and ruzasvir in inhibiting HCV replication has also been observed in vitro. We expect to initiate enrollment

of a Phase 2 clinical trial evaluating the combination of bemnifosbuvir and ruzasvir during the second quarter of 2023. We believe that the combination of bemnifosbuvir and ruzasvir with a short treatment duration and protease inhibitor-free regimen, if successfully developed and approved,has the potential to benefit the expanding populations of HCV-infected patients in the US and globally.

Maximize the value of our product candidates by retaining rights and selectively seeking advantageous collaborations to enhance our global commercialization reach. We generally intend to retain global development and commercialization rights to our product candidates, which we believe will allow us to retain the greatest potential value of our product portfolio. However, we may opportunistically enter into commercialization license agreements or collaborations when and where we believe there is an opportunity, particularly outside the US, to gain specific market expertise and other commercialization resources without requiring us to build significant commercial infrastructure.

Remain opportunistic for in-licensing opportunities to augment our pipeline. In addition to our internal research activities which are currently focused on the potential discovery and preclinical development of a second-generation protease inhibitor product candidate, we plan to remain opportunistic in the evaluation of third party clinical-stage antiviral drug candidates that we may in-license to augment our existing pipeline. Utilizing our scientific expertise, we will continue to evaluate in-licensing opportunities that would allow us to address significant unmet medical need or where we anticipate we could substantively improve upon the current standard of care.

Our Team

Our management team has significant experience discovering, developing, and commercializing antiviral therapies for life-threatening viral infections. Our Founder, Chairman, and Chief Executive Officer, Jean-Pierre Sommadossi, Ph.D., has over 30 years of scientific, operational, strategic, and management experience in the biopharmaceutical industry. Dr. Sommadossi has authored over 180 peer-reviewed publications and holds more than 135 US patents related to antiviral and cancer therapeutics. Dr. Sommadossi was the principal founder of Idenix Pharmaceuticals, Inc. (“Idenix”), which was acquired by Merck in 2014, and a co-founder of Pharmasset, Inc. (“Pharmasset”), which was acquired by Gilead Sciences, Inc. in 2012.

We have assembled an experienced management and scientific team with a track record of success in the field of antiviral drug development, many of whom have worked together previously. Our team has significant expertise in nucleos(t)ide chemistry, biochemistry and virology and has applied that expertise towards the discovery and development of innovative antiviral treatments, including Epivir, Sovaldi, Tyzeka, Valtrex, Wellferon, Videx, Reyataz, Sustiva, Mavyret, Xofluza, Relenza, Zerit, Zepatier, Epclusa, Harvoni and Veklury. Members of our team have held senior positions at AstraZeneca plc, Merck, GlaxoSmithKline plc, Chiron, Novartis International AG, Biogen, F. Hoffmann La Roche, Abbvie, Bristol Myers Squibb, Shire, Biohaven Pharma, Pharmasset, Idenix, Valeant Pharmaceuticals International, Gilead Sciences, Inc. and Alnylam Pharmaceuticals.

Antiviral Therapy

Background on viruses

Viruses are cellular parasites that lack the machinery required to survive and replicate on their own and can only replicate using a host cell’s replication process. Unlike living organisms, such as humans, that use DNA as the basis for their genetic material, viruses can use either DNA or RNA. Approximately 70% of all viruses are RNA viruses. RNA viruses can be single stranded (ssRNA) viruses or double-stranded (dsRNA), viruses, depending on the type of RNA used as the genetic material.

Viruses have two primary components: nucleic acid (single or double stranded RNA or DNA) and a protective shell (the capsid). Some viruses may also have a lipid bilayer (the envelope) surrounding the capsid, an additional membrane derived from host cell membranes that contains viral proteins. A virus encased within a lipid bilayer is known as an enveloped virus, while a virus without this bilayer is called a non-enveloped virus. Enveloped ssRNA viruses are the more prevalent cause of severe human viral disease. Each of SARS-CoV-2, a coronavirus belonging to the coronaviridae family, and hepatitis C virus, a flavivirus, are enveloped ssRNA viruses.

Viral infection occurs and the viral replication process begins when a virus attaches itself to a specific receptor site on the host-cell membrane through attachment proteins. The viral replication mechanism is dependent upon whether the virus is an RNA or DNA virus. Most DNA viruses use host cell proteins and enzymes to make additional DNA that is used to copy the viral genome or is transcribed to messenger RNA (“mRNA”). RNA viruses use their RNA as a template for synthesis of viral genomic RNA and mRNAs. The mRNAs encode both nonstructural proteins responsible for viral replication and transcription and structural proteins responsible for viral assembly. Finally, the newly created virus particles (“virions”), are released from the host cell in order to repeat the infection and replication cycle. RNA viruses can be particularly challenging to treat, as the error rates around the viral RNA polymerase directed RNA synthesis cause high mutation rates during replication, creating variants and resistance challenges for antiviral therapies.

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 across different viruses, making drugs targeted to the polymerase less susceptible to the effects of viral mutation and resistance. There are four types of viral polymerase, depending upon the virus and its genomic makeup:

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RNA-dependent RNA polymerase (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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DNA-dependent DNA polymerase (“DdDp”): DdDp is used by DNA viruses to replicate their genome.

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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.

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DNA-dependent RNA polymerase (DdRp): DdRp is used by DNA viruses to transcribe mRNA from DNA templates during replication.

As viral RNA polymerase-based synthesis does not occur in human host cells, antiviral drug development for RNA viruses focuses on identifying selective drug-like molecules that target viral RNA polymerase. 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 nidovirus RdRp associated nucleotidyltransferase (NiRAN) and have opened avenues for the development of new and more effective antiviral therapies.

Viral resistance and variants

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 and become less susceptible to certain antiviral therapies over time. In the case of RNA viruses, which 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.

SARS-CoV-2 has proven to be able to mutate quickly with more than six million variants identified since fall 2020. A number of these variants have been designated by WHO and Centers for Disease Control and Prevention ("CDC") as Variants of Interest ("VOI") because there is evidence of increased transmissibility, more severe disease, reduced effectiveness of vaccines or antibodies, or diagnostic detection failures. However, these strains may only appear in isolated regions and have not yet spread to

other countries. WHO and CDC have also identified a number of VOC 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 and descendent lineages.

Globally, from January 10, 2023 to February 6, 2023 it was reported that 99.6% of SARS-CoV-2 sequences were the Omicron VOC. Among the Omicron VOC, BA.5 and its descendent lineages dominated globally, accounting for 53.9% prevalence of all submitted sequences during the January 16 to January 22 January 2023 timeframe. In light of the widespread transmission of the Omicron VOC across the globe, WHO has added a new category to its variant tracking system, “Omicron subvariants under monitoring,” which may require prioritized attention and monitoring. Current Omicron subvariants under monitoring include BF.7, BQ.1, BA.2.75, CH.1.1, XBB, XBB.1.5, and XBF.

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 evolving from a pandemic to an endemic threat where the virus will still be circulating, with surges from time to time.

Nucleos(t)ide analogs and prodrugs

Nucleic acids are composed of naturally occurring chemical compounds termed nucleosides and nucleotides and are the main information-carrying molecules of the cell that determine the inherited characteristics of human and viral genetic material by directing the process of protein synthesis. The two main classes of nucleic acids are DNA and RNA. Nucleos(t)ide analogs are synthetic compounds that mimic the structure of naturally occurring nucleosides and nucleotides that target the viral polymerase directly so that it mistakenly incorporates these analogs into nascent nucleic acids, causing inhibition of viral replication. Nucleos(t)ide analogs, compared to other classes of antiviral therapies, have a high barrier to viral resistance due to the conservation of the structure of the polymerase that is required to produce viable virions.

Prodrugs are biologically inactive compounds which are employed to improve drug delivery, bypass rate limiting activation steps, decrease toxicity, and improve the oral bioavailability and permeation of cell membranes by the nucleos(t)ide analog. Prodrugs of nucleos(t)ide analogs have become the backbone of single-drug and combination-drug therapies to treat life threatening viral infections, including HIV, HBV, and HCV.

Bemnifosbuvir

Bemnifosbuvir is an investigational, novel, proprietary, orally administered double prodrug of a guanosine nucleotide analog. More specifically, it 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 in an effort 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 may 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.

Because bemnifosbuvir targets viral RNA polymerase, a highly conserved enzyme critical to viral replication and transcription, via a dual mechanism, we expect it to maintain antiviral activity against emerging variants with mutations in the spike protein which is responsible for the receptor recognition and host cell membrane fusion process. In fact, the few amino acid substitutions (Y273H, P323L, and G671S) in the polymerase that emerged in past and present VOCs are all remote from the nucleoside triphosphate ("NTP") binding site and nucleos(t)ide analogs resistance sites. They belong to functionally distinct clusters providing general adaptation to the evolving virus in its human host, unlikely to confer drug resistance. Additionally, since all the enzymes involved in the metabolic pathway of bemnifosbuvir to the active triphosphate are ubiquitous host cell enzymes and not virally encoded proteins, we believe that the high rate of viral mutation does not affect the activation of bemnifosbuvir.

Development Programs

SARS-CoV-2

Background

SARS-CoV-2 is a coronavirus, belonging to the coronaviridae family, and is an enveloped virus with a positive sense ssRNA genome which encodes 29 viral proteins. It is one of six other human coronaviruses that exist, with four responsible for one third of common cold infections.

SARS-CoV-2 is structurally similar to two other life-threatening coronaviruses: SARS-CoV and Middle East Respiratory Syndrome coronavirus (“MERS-CoV-1”).

SARS-CoV-2 is a spherical virus that carries four different structural proteins: spike protein, envelope protein, membrane glycoprotein and nucleocapsid protein. As shown in the illustration below, the infection cycle begins when the spike proteins bind to the angiotensin-converting enzyme 2 cellular receptor (“ACE2”), on the surface of the target cells. A second cell surface protein, transmembrane serine protease 2 (“TMPRSS2”), enables the virion to enter the cell, where it releases its RNA. Some of this RNA is translated into new proteins using the host cell’s machinery—these proteins include the four structural proteins, as well as a number of Non-structural proteins (“Nsps”), that form the replication complex. Within this complex, RdRps catalyze the synthesis of the approximately 30,000-nucleotide RNA viral genome. The proteins and RNA are then assembled into a new virion in the Golgi and released through exocytosis.

COVID-19 – Disease Overview

Coronavirus disease 2019 ("COVID-19"), the disease caused by infection with SARS-CoV-2 and its variants, has given rise to a global pandemic that swept rapidly throughout the world beginning in 2020 and continues to cause infection and disease due to waning immunity and continued emergence of SARS-CoV-2 variants. As of February 15, 2023 according to the CDC, there have been more than 100 million confirmed cases reported and over 1.1 million deaths in the US alone and the WHO reported more than 754 million confirmed cases of COVID-19 and over 7 million deaths worldwide. In 2022, the CDC reported that COVID-19 was the third leading cause of death in the US after only heart disease and cancer with the majority of deaths occurring in patients aged 65 and older. Older adults and individuals who have risk factors are at a higher risk for developing more serious complications from COVID-19 leading to hospitalization and death.

Infection with SARS-CoV-2 may be asymptomatic or it may cause a wide spectrum of illness ranging from a mild upper respiratory tract infection to severe life-threatening sepsis and multiorgan failure. Commonly reported symptoms include fever, cough, shortness of breath, loss of taste or smell, sore throat, fatigue, headaches, muscle aches, and gastrointestinal ("GI") disturbance. Symptoms typically last two to three weeks, but many patients continue to experience symptoms for many weeks or develop new symptoms, which is now recognized as the post-acute COVID-19 syndrome, or Long COVID. COVID-19 affects people of all ages; however, people who are immunocompromised, elderly, or have certain underlying medical conditions (e.g., chronic heart, lung, and kidney disease; diabetes, obesity, and cancer) are at increased risk of poor outcomes.

The elderly (with or without comorbidities) and the immunocompromised at any age, are well documented to be unlikely to be able to mount an adequate immune response to the virus, and also seem to be unsuccessful in mounting an adequate antibody response even when vaccinated. Furthermore, many of these people are likely to be receiving concomitant medications which are recognized to have drug-drug interactions with ritonavir, meaning that they are contraindicated to receive nirmatrelvir/ritonavir. In this same population, there is considerable reluctance to use molnupiravir because of its mutagenicity and the perceived downstream consequences that may induce. With the ongoing evolution of the virus and the continual emergence of new variants, the utility of monoclonal antibodies has also been abrogated. The net result of this is that these patients currently have no access to effective outpatient therapies, are likely to need intravenous remdesivir as therapy and are also more likely to be hospitalized because of more severe disease.

oral antivirals such as drug-drug interactions, safety concerns and tolerability; (7) uncertain impact of vaccines on transmission; (8) continuing evolution of the virus evading endogenous and vaccine-induced immunity; and (9) diminution of virus transmission mitigation behaviors, such as wearing masks and social distancing.

Current Approaches for Prevention and Treatment of COVID-19 and Their Limitations

At the outset of the COVID-19 pandemic, unprecedented progress was made with both vaccines and treatment options for this novel disease. Despite this progress, there remain substantial limitations 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 (which have increased transmissibility and the ability to evade neutralizing antibodies). Limitations of current oral antivirals include DDIs with commonly prescribed medications such as seizure medications, anti-psychotics, anti-coagulants and more, and safety concerns.

As a result, there remains a continued urgent need to develop novel, safe, efficacious, convenient, oral, therapies with low risk of drug-drug interaction 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 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 becomes endemic with the potential for 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. Approved and authorized vaccines include, among others, mRNA vaccines such as Pfizer/BioNTech’s Comirnaty and Moderna’s mRNA-1273, each monovalent vaccines which, were approved for the prevention of symptomatic COVID-19 caused by the original strain. These vaccines have been available in the US and globally since December 2020. More recently, in August 2022, bivalent mRNA vaccines from each of Pfizer/BioNTech and Moderna were authorized by the FDA for the prevention of symptomatic COVID-19 caused by the Omicron subvariants BA.4 or BA.5.

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.While COVID-19 vaccines have demonstrated meaningful efficacy in preventing infection by the original strain of COVID-19, evidence shows significantly lower levels of protection against variants. Multiple clinical and real-world studies have demonstrated reduced vaccine effectiveness against the Omicron variants and subvariants.

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Limited durability of response impacting the ability to achieve long term immunity. Due to a combination of waning antibody titers overtime, the emergence of SARS-CoV-2 variants that display significantly reduced susceptibility to vaccine and infection-induced antibodies, and the limited level of mucosal immunity conferred by systemically administered vaccines, protection against symptomatic COVID-19 is relatively short-lived. As long as significant numbers of people globally are not protected against infection and transmission, SARS-CoV-2 variants will continue to circulate and cause disease.

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Failure of certain patient populations to mount immune response to vaccines. The elderly (with or without comorbidities) and the immunocompromised at any age, are well documented to be unlikely to be able to mount an adequate immune response to the virus, and may also be unsuccessful in mounting an adequate antibody response even when vaccinated. The levels of pre-existing antibodies in transplant patients who had been vaccinated at least twice and

received boosters, but who required hospitalization for severe COVID-19 infection were found to be undetectable.

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Delayed onset of protection. The peak neutralizing antibody response conferred by currently available vaccines is usually 10 to 14 days after the final dose or booster vaccination, resulting in a period of time during which an individual is susceptible to SARS-CoV-2 infection and COVID-19 disease, despite having received the vaccine. Furthermore, given that certain vaccines require two doses, three to four weeks apart, full protection may not be achieved for several weeks after the initial dose.

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Vaccine hesitancy.Numerous surveys attribute vaccine hesitancy to a constellation of perceived safety, side effect and quality concerns. Asof February 15, 2023, according to the CDC, only 69% of the total US population has completed the primary series of vaccines and only 16.0% have received the latest (bivalent) booster. Globally, vaccine adoption and hesitancy are generally consistent with the US figures.

Monoclonal Antibodies ("mAbs") for the treatment 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. However, the use of mAbs for the treatment of COVID-19 has been 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.The clinical utility of mAbs has varied over time due to the emergence of SARS-CoV-2 variants demonstrating partial or full resistance to neutralization. Currently, in the US, with the recent revocation of the EvusheldTM EUA, the authorizations for all mAbs have been rescinded due to the high frequency of circulating SARS-CoV-2 variants that are able to evade the available neutralizing antibodies. 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.

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Inconvenience of administration. All mAbs that were previously authorized for the treatment of COVID-19 were administered intravenously. This required specialized facilities that were properly equipped to accommodate IV infusions in actively infected patients.

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 including the treatment of outpatients at high risk of progression to severe COVID-19. Additionally, each of LagevrioTM (molnupiravir), an orally administered direct-acting antiviral for the treatment of adults with mild to moderate COVID-19 in the outpatient setting, and PaxlovidTM (ritonavir boosted nirmatrelvir), an orally administered protease inhibitor for the treatment of adults with mild to moderate COVID-19 in the outpatient setting are authorized for use under an EUA in the US and many additional countries globally.

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, 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 IV infusion which minimizes the convenience of administration.

Our COVID-19 strategy

We are developing bemnifosbuvir, an investigational, orally administered, novel antiviral product candidate, for the treatment of COVID-19.

Data from the Phase 3 MORNINGSKY clinical trial that was closed out early did not meet the primary endpoint of time to symptom alleviation but the results demonstrated a 71% reduction in hospitalization (2.9% versus 10%) (p=0.047, unadjusted, exploratory; secondary endpoint) in the bemnifosbuvir arm (n=137) versus placebo (n=70). The patients enrolled in the MORNINGSKY trial consisted of a broad outpatient population including 47% who were high risk, 28% who were vaccinated, and 56% who were seropositive at baseline. In a subgroup analysis in patients greater than 40 years old, the reduction in hospitalization in the bemnifosbuvir arm of the MORNINGSKY trial was even greater at 82%. There was also a trend for clinical benefit (all-cause mortality) observed in the global phase 2 study in hospitalized patients. Although low background rates of disease progression precluded completion of the study as initially designed, all three deaths in the study occurred in placebo recipients compared to no deaths in patients receiving bemnifosbuvir. Additionally, bemnifosbuvir has demonstrated low risk of DDIs in five phase 1 clinical studies, antiviral activity against all tested VOC in in vitro studies, no mutagenicity or teratogenicity in in vitro studies and, given its mechanism of action, a high barrier to resistance.

We believe bemnifosbuvir as 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. We have initiated SUNRISE-3, a global Phase 3 randomized, double-blind, placebo-controlled clinical trial evaluating bemnifosbuvir (550 mg BID for 5 days) in at least 1500 high-risk non-hospitalized patients with mild or moderate COVID-19.

While SUNRISE-3 is principally designed to evaluate bemnifosbuvir as monotherapy (primary analysis) it is also designed to explore of 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 also advancing an internal discovery program focused on identifying a second generation protease inhibitor that we may potentially combine with bemnifosbuvir for combination treatment of COVID-19. We are seeking to discover a protease inhibitor that is highly potent and well tolerated with limited DDIs and does not require a Pharmacokinetic ("PK") booster (e.g., ritonavir). The optimization of lead compounds is ongoing with a target of late 2023 to submit an IND for the selected clinical candidate.

Our rationale for advancing this potential combination is based upon both historical precedents for treating serious viral diseases with combination treatments that include agents with different mechanisms of action targeting different points in the viral replication cycle and the results from the in vitro study we have conducted in an HCoV-229E surrogate model. In this in vitro study, we evaluated the antiviral activity of AT-511, the free base of bemnifosbuvir in combination with the protease inhibitor, nirmatrelvir, and the results showed an additive antiviral effect.

We believe these data suggest a potential benefit of the combination of bemnifosbuvir and a protease inhibitor for the treatment of SARS-CoV-2 infection.

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 Nsps 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, a 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.

SARS-CoV RNA Polymerase

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.

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. Current COVID-19 variants have lessened the effectiveness of vaccines and eliminated the effectiveness of monoclonal antibodies due to the mutations in the viral spike protein. It is expected that future variants may also impact the effectiveness of vaccines and monoclonal antibodies.

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

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 history

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 with the termination of the Roche License Agreement in November 2021, we prematurely discontinued each of the Phase 3 MORNINGSKY and MEADOWSPRING clinical trials 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 the SUNRISE-3 Phase 3 clinical trial of bemnifosbuvir for the treatment of COVID-19.

SUNRISE-3 – Global Phase 3 clinical trial

SUNRISE-3 is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating bemnifosbuvir (550 mg BID for 5 days) in at least 1,500 high-risk non-hospitalized patients with mild or moderate COVID-19. The trial will be conducted at clinical trial sites in the US, Europe, Japan, and other regions of the world. The patient population will consist of those at the highest risk for disease progression, including patients ≥ 80 years old, patients ≥ 65 years old with one or more major risk factors, and immunocompromised patients ≥ 18 years old, all regardless of COVID-19 vaccination status.

The trial is designed to evaluate bemnifosbuvir as monotherapy (primary analysis) but will also explore the impact of combination therapy in a smaller sub-set of patients who receive a compatible antiviral drug along with bemnifosbuvir (secondary analysis). The trial will include two populations derived from the type of standard of care received 1) “supportive care population” (patients who do not qualify for an approved antiviral treatment or where antivirals are not locally available) which will assess bemnifosbuvir given as monotherapy (primary analysis) and 2) “combination antiviral population” which will assess 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 twice-daily 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 at least 1,300 patients in the supportive care population and is powered to detect a clinically meaningful reduction in hospitalization/death versus placebo in this population. By enriching the patients enrolling in the trial with those who are at the highest risk for disease progression, we are targeting rates of hospitalization/death of ~4-6%. An interim analysis will be conducted by a DSMB after 60% patient enrollment in the arm of the study enrolling the supportive care population. Secondary endpoints in each of the supportive care patient population and the combination antiviral population include COVID-19 complications, medically attended visits, symptom rebound/relapse and viral load rebound.

MORNINGSKY - Global Phase 3 trial

The Phase 3 MORNINGSKY study was a randomized, placebo-controlled study 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. The study, which was initiated in collaboration with Roche, was discontinued in December 2021 prior to completion as a result of the termination of the collaboration with Roche. Patients were randomized (2:1) to receive 550 mg BID bemnifosbuvir or placebo for five days. The primary endpoint was time to alleviation/improvement of COVID-19 symptoms. Secondary endpoints included hospitalization, all-cause mortality, and change in viral load. At the time of discontinuation, 216 patients had been randomized (2:1; active:placebo), with 207 patients who comprised the efficacy evaluable population. The study enrolled a broad outpatient population, including 47% who were high risk, 28% who were vaccinated, and 56% who were seropositive 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 demonstrated a 71% reduction in hospitalization (2.9% versus 10%) (p=0.047, unadjusted, exploratory; secondary endpoint) in the bemnifosbuvir arm (n=137) versus placebo (n=70). In a subgroup analysis in patients greater than 40 years old, the reduction in hospitalization in the bemnifosbuvir arm of the MORNINGSKY trial was even greater at 82%.

There were no deaths in the study. There was no meaningful difference in the change from baseline in viral load between the bemnifosbuvir arm and the placebo arm. The 550 mg BID dose was generally well tolerated compared to placebo. There were no drug-related SAEs reported, and proportions of patients with adverse events 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 also closed out in March 2022 after enrolling only 72 patients that had taken part in MORNINGSKY, a smaller number of patients than planned. As a result, firm conclusions about the long-term symptoms of COVID-19 could not be drawn from this study.

Global Phase 2 study in hospitalized patients with COVID-19

This 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 impact of bemnifosbuvir (550 mg BID; Part A) on Progressive Respiratory Insufficiency (PRI), however, low background rates of disease progression precluded completion of the study as initially designed. The protocol was amended to explore higher doses of bemnifosbuvir (1100 mg BID; Part B), however the study was prematurely discontinued in January 2022 due to the changing COVID-19 treatment landscape. 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.

After bemnifosbuvir 550 mg BID dosing for five days, rapid reduction in viral load levels were observed. At Day 2, patients receiving bemnifosbuvir experienced a 0.6 log10 greater mean reduction from baseline viral load versus placebo. A sustained difference in viral load reduction was maintained through Day 8.

Bemnifosbuvir’s SARS-CoV-2 antiviral activity was also observed in patients with baseline viral loads above the median of 5.35log10 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 12% 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 serious adverse events. Non-serious adverse events were equally distributed across treatment arms. Most were mild-to-moderate in severity and assessed as not related to bemnifosbuvir.

MOONSONG - Global Phase 2 trial

This study was a randomized, double-blind, multi-center, placebo-controlled trial, that evaluated the antiviral activity, safety and pharmacokinetics of sequential doses of bemnifosbuvir 550 mg (Cohort A, n=30) and 1,100 mg (Cohort B, n=30) with BID dosing in adult outpatients with mild or moderate COVID-19 versus placebo (n=40). 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 pooled 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 adverse event ("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 serious adverse events ("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

In addition to the MORNINGSKY Phase 3 clinical trial and the Phase 2 clinical trials, supporting Phase 1 and clinical pharmacology studies, including a bronchoalveolar lavage study, multiple DDI 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 5 days in healthy subjects.

Results from the bronchoalveolar lavage 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 DDI studies were completed with topline results demonstrating an overall low DDI potential associated with bemnifosbuvir.

Phase 1 - DDI Studies

A series of Phase 1 studies suggest a favorable drug-interaction profile, 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 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 may be co-administered with commonly prescribed therapeutics that are often taken for other conditions by 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, supporting clinical pharmacology studies in special populations (e.g., subjects with hepatic and renal impairment) are ongoing.

Phase 1 - PK Study – Second-generation bemnifosbuvir tablet

In the SUNRISE-3 clinical trial, we are using a second-generation formulation 275 mg tablet of bemnifosbuvir. We have evaluated this formulation in a Phase 1 study in healthy subjects who were administered bemnifosbuvir (fasted and with a low-fat meal) for ten days at 550 mg BID (2 x 275 mg). The results of this study demonstrated that the second-generation tablet had higher plasma exposures of AT-273, the active surrogate metabolite of bemnifosbuvir, than the plasma exposures obtained with the first-generation tablet which was used in the MORNINGSKY study. Additionally, the second-generation tablet achieved higher plasma trough concentrations of AT-273 (> EC90 of bemnifosbuvir in inhibiting SARS-CoV-2 replication) without food effect and regardless of fat content. In this study, bemnifosbuvir was generally well-tolerated in healthy subjects.

Bemnifosbuvir and Ruzasvir for the Treatment of Hepatitis C

Hepatitis C virus (HCV)

Background

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 genotypes. Hepatitis C becomes chronic Hepatitis C in 75% to 85% of acute cases, with an incubation period lasting from two to 26 weeks.

HCV is classified into seven genotypes and 67 subtypes, with genotype 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. Approximately 290,000 people die every year from HCV related liver diseases, with the majority of deaths related to cirrhosis and hepatocellular carcinoma.

The incidence rate of acute HCV has more than doubled since 2013 (124% 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

Despite significant advances in treatment beginning in 2013, there remains a large, underserved, HCV patient population which continues to grow dramatically in the US. While a portion of this rise in incidence results from increased diagnosis of HCV that began following the 2013 CDC issuance of guidelines for screening of all Americans born between the years 1945 and 1965, a large portion of this increase in incidence is attributable to the opioid crisis, IV drug use and HCV reinfection.

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. Estimated at approaching $4 billion in global sales in 2022, with approximately 50% attributable to the US, the HCV market remains large.

Current treatment landscape

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 genotype, 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/velpatasvir): a combination regimen consisting of an NS5B inhibitor and an 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 genotype one through six infection, either without cirrhosis or with compensated cirrhosis. For patients with decompensated cirrhosis, Epclusa is approved for use in combination with ribavirin (a purine nucleoside analog). Patients on Epclusa require 12 weeks of treatment.

Mavyret® (glecaprevir/pibrentasvir): a combination regimen consisting of a NS3/4A protease inhibitor and an 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 genotype one through six infection, without cirrhosis or with compensated cirrhosis. Mavyret is also approved for HCV patients with genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor (but not both). Mavyret was the first eight-week treatment approved for HCV genotypes one through six 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.

Our approach – seeking to improve the standard of care

We are developing bemnifosbuvir in combination with ruzasvir for the treatment of HCV. Bemnifosbuvir is a potent inhibitor of the HCV nonstructural protein 5B ("NS5B") RdRp. Ruzasvir is an investigational oral, potent, pan‐genotypic nonstructural protein 5A ("NS5A") inhibitor for the treatment of chronic HCV infection 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 genotypes, regardless of cirrhosis status, including the difficult to treat genotype-3 population.

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

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Potential to be the first ribavirin-free therapy for decompensated cirrhosis. Ribavirin, an antiviral first approved in 1986, carries several FDA boxed warnings, including the risk of hemolytic anemia and teratogenicity.

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

Clinical development

To date, we have completed two clinical trials of bemnifosbuvir to support the treatment of chronic HCV infection.

Phase 1 clinical trial of bemnifosbuvir as a single agent

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 genotype 1b (“GT1”), HCV-infected subjects (Part C). Additional cohorts evaluated 600 mg salt form (553 mg free base) once daily for seven days in non-cirrhotic genotype 3 (“GT3”), (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 log10 IU/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 genotype 1b (“GT1b”), HCV-infected subjects, and a mean reduction of 4.5 log10 IU/mL after seven days of dosing in non-cirrhotic GT3 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, GT1 HCV-infected subjects)

Maximum HCV RNA change in Part C (multiple dose in non-cirrhotic, GT1 HCV-infected subjects)

Maximum HCV RNA change in Part D (multiple dose in non-cirrhotic, GT3 HCV-infected subjects) and Part E (multiple dose in cirrhotic HCV-infected subjects)

Maximum Reduction(log10 IU/mL) Part D – GT3 Part E – Cirrhotic

* SD = standard deviation

** QD = once daily

Phase 2 clinical trial of bemnifosbuvir in combination with daclatasvir

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 GT1 HCV-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 < lower limit of quantitation ("LLOQ") at 12 weeks after end of treatment ("EOT")). Secondary efficacy endpoints included HCV RNA< Lower Limit Of Quantitation (“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 resistance-associated variants ("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 end of treatment; 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 EC90values 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). We believe that the rapid early clearance of HCV RNA observed in this trial supports continued evaluation of bemnifosbuvir in shortened treatment regimens, ideally with a more potent, next-generation HCV NS5A inhibitor.

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

Bemnifosbuvir HCV safety

There were no serious adverse events, dose-limiting toxicities or adverse events leading to trial discontinuation observed in our HCV Phase 1 or Phase 2 clinical trials of bemnifosbuvir. 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 EC50in the sub- to low picomolar range against all HCV genotypes (<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 GT1, GT2 and GT3-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 GT1, GT2, GT4 and GT6-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 preserved dose-related clinical antiviral activity of ruzasvir in GT-3 subjects with cirrhosis.

Over 1200 HCV-infected participants have received ruzasvir at daily doses up to 180 mg for durations up to 24 weeks as part of 2-drug and 3-drug regimens with or without ribavirin. The overall safety data indicates that ruzasvir has been generally well-tolerated with no consistent treatment-related changes in labs, vital signs, or ECG parameter values. Serious adverse events and discontinuations due to adverse events were rare in all studies conducted by Merck.

Rationale supporting the combination of bemnifosbuvir and ruzasvir for HCV

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

To further support our development of the combination of bemnifosbuvir and ruzasvir in patients, we have conducted in vitro synergy experiments in HCV GT1b replicon assays (Huh-luc/neo-ET), where HCV replicon cells were treated with multiple concentrations of AT-511, the free base of bemnifosbuvir, and ruzasvir either alone or in combination. As shown in the figure below, these experiments demonstrated that the combination resulted in substantially greater inhibition of HCV replication than either agent alone, suggesting a synergistic antiviral effect between the two inhibitors.

In vitro Synergy: Assay performed in HCV GT1b replicon (Huh-luc/neo-ET)

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.

Collectively, these data support the clinical development of bemnifosbuvir and ruzasvir used in combination for the treatment of chronic HCV infection.

Planned clinical development

In the second quarter of 2023, we plan to initiate enrollment of a Phase 2 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 the pan-genotypic combination consisting of 550 mg QD of bemnifosbuvir and 180 mg QD of ruzasvir after eight weeks of treatment. Approximately 280 HCV-infected, direct-acting antiviral naive patients across all genotypes, including a lead-in cohort of approximately 60 patients are expected to be enrolled in this Phase 2 study. The primary endpoints of the study are safety and SVR at Week 12 post-treatment. Other virologic endpoints include virologic failure, SVR at Week 24 post-treatment and resistance.

Results from this study, if positive, may support future larger studies of bemnifosbuvir in combination with ruzasvir in broad patient populations for treatment durations of eight weeks or potentially less (six weeks) as well as in patients with decompensated cirrhosis for treatment durations of 12 weeks without ribavirin.

Currently we are conducting a Phase 1 clinical study in healthy subjects to evaluate the potential DDI between bemnifosbuvir and ruzasvir and the effect of food on the PK of the agents.

Roche License Agreement

In October 2020, we entered into a License Agreement with F. Hoffmann-La Roche Ltd and Genentech, Inc. (“Roche License Agreement”) in connection with the global development, manufacture and commercialization of bemnifosbuvir, AT-511, their backup compounds (including AT-752) (“Licensed Compounds”), products containing any Licensed Compound (“Licensed Products”), and related companion diagnostics (“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 following our receipt of notice of termination from Roche in November 2021. As of the termination date, our obligations under the cost sharing arrangement with Roche associated with the development of bemnifosbuvir also ended.

As a result of the termination of the Roche License Agreement, we have regained worldwide exclusive rights from Roche to research, develop, manufacture and commercialize the Licensed Compounds, the Licensed Products and the Companion Diagnostics in all fields of use.

License Agreement with Merck

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. 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 (or a Compound contained in 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. Although we rely on CMOs, we also have personnel with extensive manufacturing experience that can oversee the relationship with our manufacturing partners. We believe that any materials required for the manufacture of our product candidates could be obtained from more than one source.

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. Our commercial opportunity for any of our product candidates could be reduced or eliminated if 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.

We are aware of the following competitors in the areas that we are currently targeting:

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 a number of other agents in development for the treatment of COVID-19.

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

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PaxlovidTM (nirmatrelvir tablets and ritonavir tablets) (Pfizer Inc.), a protease inhibitor boosted by ritonavir authorized for emergency use by the FDA for the treatment of mild-to-moderate COVID-19 in adults and 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.

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LagevrioTM (molnupiravir) (Ridgeback Biotherapeutics LP/Merck & Co., Inc.), a ribonucleoside analog authorized for emergency use by the FDA for the treatment of mild-to-moderate COVID-19 in adults 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.

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Veklury® (remdesivir) (Gilead Sciences, Inc.), a nucleotide analog RdRp inhibitor approved by the FDA for the treatment of COVID-19 in adults and pediatric patients (12 years of age and older and weigh at least 40 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. Additionally, the FDA has granted an emergency use authorization for the treatment of pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 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 of death.

Other orally administered investigational agents that are currently in development for the treatment of COVID-19 include:

Investigational Therapy Company Mechanism of Action Phase of Development

GS-5245 Gilead Sciences, Inc. Nucleoside analog Phase 3

VV116 Junshi Biosciences Nucleoside analog Phase 3

Ensitrelvir (S-217622) Shionogi Protease inhibitor Phase 3

EDP-235 Enanta Pharmaceuticals Protease inhibitor Phase 2

PBI-0451 Pardes Biosciences Protease inhibitor Phase 2

Pentarlandir SyneuRx Protease inhibitor Phase 2

In addition to the antivirals listed above, a number of monoclonal antibodies were previously authorized for emergency use for the prophylaxis or treatment of COVID-19. While these authorizations have been currently 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 and associated vaccine boosters that are approved or authorized for emergency use for the prevention of COVID-19 include:

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Comirnaty® (COVID-19 Vaccine, mRNA) (Pfizer-BioNTech), an FDA-approved (August 23, 2021) monovalent mRNA vaccine for the prevention of 2019 coronavirus disease (COVID-19) in individuals six months and older.

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Pfizer-BioNTech (COVID-19 Vaccine, Bivalent) (Pfizer-BioNTech), an FDA-EUA (August 2022) bivalent mRNA bivalent vaccine for the prevention of COVID-19 in individuals 12 years of age and older as a single booster dose administered at least two months after either: 1) completion of primary vaccination with any FDA authorized or approved monovalent COVID-19 vaccine, or 2) receipt of the most recent booster dose with any FDA authorized or approved monovalent COVID-19 vaccine.

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Spikevax® (COVID-19 Vaccine, mRNA) (Moderna), an FDA-approved (January 31, 2022) monovalent mRNA vaccine for the prevention of 2019 coronavirus disease (COVID-19) in individuals 6 months and older.

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Moderna (COVID-19 Vaccine, Bivalent), FDA-EUA (January 2022) bivalent mRNA vaccine, for the prevention of COVID-19 in individuals 18 years of age or older as a single booster dose administered at least 2 months after either: 1) completion of primary vaccination with any FDA authorized or approved monovalent COVID-19 vaccine, or 2) receipt of the most recent booster dose with any FDA authorized or approved monovalent COVID-19 vaccine.

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Janssen COVID-19 vaccine, FDA-EUA (February 2021) for the prevention of COVID-19 for individuals 18 years of age and older for whom other FDA-authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and in individuals 18 years of age and older who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine. Single booster doses may be administered at least 2 months after the primary vaccination or administered as a heterologous booster dose following completion of primary vaccination with another authorized or approved COVID-19 vaccine. The dosing interval for the heterologous booster dose is the same as that authorized for a booster dose of the vaccine used for primary vaccination.

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Novavax COVID-19 Vaccine, Adjuvanted, FDA-EUA (July 2022) for the prevention of COVID-19 for individuals 18 years of age and older

The potential treatments and vaccines for COVID-19 continue to evolve. The list above addresses the products or product candidates approved or authorized for emergency use or under clinical development in the US as of the date of this Annual Report on Form 10-K that we believe could be the most competitive with a bemnifosbuvir therapy but is not a comprehensive list of every treatment that is in development for COVID-19.

HCV

FDA-approved treatments for patients with chronic HCV include Epclusa®, an orally administered fixed dose combination of sofosbuvir, an NS5B inhibitor, and velpatasvir, an NS5A inhibitor, Harvoni®, a fixed dose combination sofosbuvir and ledipasvir, an NS5A inhibitor, Vosevi®, a fixed dose triple combination of

sofosbuvir, velpatasvir and voxilaprevir, a NS3/4A protease inhibitor, and Sovaldi®, an NS5B inhibitor marketed by Gilead Sciences, Inc., Mavyret®, the combination of glecaprevir, a NS3/4A protease inhibitor, and pibrentasvir, a NS5A inhibitor, marketed by AbbVie Inc., and Zepatier®, the combination of elbasvir, a NS5A inhibitor and grazoprevir, a NS3/4A protease inhibitor, marketed by Merck & Co., Inc., In addition to the branded products, Gilead launched and 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 co-promotion arrangements with third parties that have existing commercial infrastructure. Outside the US, we may enter into commercial license agreements. 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 on 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, 2023, we are the sole owner of fifteen 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, 2023, on a worldwide basis, includes more than 250 pending, granted, or allowed patent applications with fourteen issued US patents, eight pending US non-provisional applications, four pending US provisional applications, five pending international patent applications filed under the Patent Cooperation Treaty (“PCT”), and more than 200pending or granted patent applications that have entered the national phase of prosecution in countries outside the US.

As of February 1, 2023, we are the exclusive licensee of three patent families from MSD International GmbH (Merck, Sharp & Dohme Corp.) 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 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 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, bemnifosbuvir, AT-281 (the free base of AT-752), and AT-752 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. Current patent applications covering the use of AT-281 and AT-752 for the treatment of dengue fever will expire on dates ranging from 2036 to 2043, 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, 2023, 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) and one pending US applications 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 European Patent Office (“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 20 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, pharmaceutical compositions, 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 pending 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 ten 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 one granted US patent (US Patent No. 10,874,687), three pending US applications and applications 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 pending 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 pending US application. This family is currently in the national phase of prosecution in China, the EPO, Hong Kong, Japan, Korea, Russia, and Taiwan. 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 one international application filed under the PCT, 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 international application field under the PCT. 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 international application filed under the PCT, as well as one pending application in Canada. 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.

AT-281 and AT-752

The first patent family described above also describes AT-281, a pharmaceutically acceptable salt thereof (for example, AT-752) and pharmaceutical compositions of AT-281 or a pharmaceutical salt thereof and their use to treat HCV infection, including issued US Patent No. 10,875,885.

The second patent family described above also describes AT-752 and pharmaceutical compositions of AT-752, including in US Patent No. 10,906,928. One of these pending US applications in this patent family covers AT-752 and pharmaceutical compositions of AT-752.

The fifth patent family described above also includes a disclosure of the use of AT-281 or a pharmaceutically acceptable salt thereof for the treatment or prevention of an RNA viral infection, including dengue fever (US Patent No. 10,946,033), yellow fever, and Zika virus. Therefore, we have three patent families that describe AT-281 or AT-752 and methods of treatment for viral infections using AT-281 or AT-752.

We own another patent family that consists of three provisional US applications that disclose advantageous dosage forms of AT-752, dosage regimens of AT-752, and combination therapies comprising AT-752 for the treatment of dengue fever. The expected year of expiration for patents issuing from these non-provisional patent applications, if valid and enforceable, is 2043, without regard to any adjustments of term that may be available under US or other national law.

Ruzasvir

We have exclusively licensed three patent families from MSD International GmbH (Merck, Sharp & Dohme Corp.) 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 an international application filed under the PCT covering the combination of bemnifosbuvir and ruzasvir, which 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 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 authorization from the FDA to administer an IND 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 authorization 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 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:

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.

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.

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 approval.

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 agreement on the next phase of development. Sponsors typically use the meeting at the end of the Phase 2 trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.

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, 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.

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 the 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

AVIR US Equity

AVIR · 10-K · period ended 2022-12-31

Item 1. Business.

AVIR US Equity☆

AVIR · 10-K · period ended 2022-12-31

Item 1. Business.

AVIR US Equity