vir-20231231

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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FORM 10-K

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(Mark One)

For the fiscal year ended December 31, 2023

Commission File Number 1-39083

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Vir Biotechnology, Inc.

(Exact Name of Registrant as Specified in its Charter)

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(Address of Principal Executive Offices) (Zip Code)

Registrant’s telephone number, including area code: (415) 906-4324

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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, $0.0001 par value VIR 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. Yesx No o

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes oNox

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. Yesx No o

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). Yesx No o

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

Large accelerated filer x Accelerated filer o

Non-accelerated filer o Smaller reporting company o

Emerging growth company o

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. o

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. x

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. o

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). o

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

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant as of June 30, 2023 was approximately $1.8 billion based upon the closing price of its Common Stock on June 30, 2023 of $24.53 per share, as reported by The Nasdaq Global Select Market.

The number of shares of the Registrant’s Common Stock outstanding as of February 16, 2024 was 135,032,268.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the definitive proxy statement, or the Proxy Statement, for the Registrant’s 2024 Annual Meeting of Stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K. The Proxy Statement will be filed with the Securities and Exchange Commission within 120 days of the Registrant’s fiscal year ended December 31, 2023.

Auditor PCAOB ID: 42 Auditor: Ernst & Young LLP Address: San Mateo, California

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PART I

Item 1. Business 2

Item 1A. Risk Factors 53

Item 1B. Unresolved Staff Comments 91

Item 1C. Cybersecurity 91

Item 2. Properties 94

Item 3. Legal Proceedings 94

Item 4. Mine Safety Disclosures 94

PART II

Item 6. [Reserved] 96

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 110

Item 8. Financial Statements and Supplementary Data 111

Item 9A. Controls and Procedures 145

Item 9B. Other Information 147

Item 9C. Disclosure Regarding Foreign Jurisdiction that Prevent Inspections 147

PART III

Item 10. Directors, Executive Officers and Corporate Governance 148

Item 11. Executive Compensation 148

Item 14. Principal Accounting Fees and Services 148

PART IV

Item 15. Exhibits, Financial Statement Schedules 149

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CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATA

This Annual Report on Form 10-K contains forward-looking statements about us and our industry that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this Annual Report on Form 10-K, including statements regarding our strategy, future financial condition, future operations, research and development, potential of, and expectations for, our pipeline and technology platforms, the timing, potential of and expectations for planned clinical trials and preclinical studies, the timing and likelihood of regulatory filings and approvals for our product candidates, our ability to commercialize our product candidates, the potential benefits of collaborations, projected costs, prospects, plans, objectives of management, expected market size and growth for our potential products, the timing of availability of clinical data, program updates and data disclosures, and our plans for our hepatitis B virus, hepatitis delta virus, influenza, COVID-19 and human immunodeficiency virus portfolios, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “might”, “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology.

We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of known and unknown risks, uncertainties and assumptions described in the sections titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in this report. Other sections of this report may include additional factors that could harm our business and financial performance. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Moreover, we operate in a very competitive and rapidly changing environment. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements.

In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although we believe that we have a reasonable basis for each forward-looking statement contained in this report, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur at all. You should refer to the section titled “Risk Factors” for a discussion of important factors that may cause our actual results to differ materially from those expressed or implied by our forward-looking statements. Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. Except as required by law, we undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industry publications and research, surveys, and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this Annual Report on Form 10-K involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third-party research, surveys, and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research, and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions.

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PART IPAR

Item 1. Business.

Overview

Powering the Immune System to Transform Lives.

Vir Biotechnology, Inc. (including its subsidiaries, referred to as “Vir,” “the Company,” “we,” “our” or “us”) is an immunology company focused on combining cutting-edge technologies to treat and prevent serious infectious diseases and other serious conditions, including viral-associated diseases. At Vir, we have a bold vision – powering the immune system to transform lives. We aim to achieve this in two fundamental ways – first, through developing powerful antibody therapeutics and second, by generating unique T cell responses in vivo through our T cell-based viral vector platform. Our growth and pursuit of scientific innovation is fueled by our world-class leading monoclonal antibody (mAb) platform that has a proven track record and is further strengthened by our artificial intelligence-led mAb optimization and engineering capabilities.

Our current clinical development pipeline consists of product candidates targeting hepatitis delta virus (HDV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV). The most advanced preclinical candidates in our pipeline include those targeting influenza A and B, coronavirus disease 2019 (COVID-19), respiratory syncytial virus (RSV), human metapneumovirus (MPV), and human papillomavirus (HPV). We have assembled two technology platforms that modulate the immune system by exploiting critical observations of natural immune processes— a mAb discovery platform and a T cell-based viral vector platform. Additionally, Vir is evaluating small interfering RNA (siRNA) through a collaborationwith Alnylam Pharmaceuticals, Inc., or Alnylam, in our hepatitis clinical trials. We have established our own internal process development, analytical development, manufacturing, supply chain and quality capabilities and work with contract development and manufacturing organizations (CDMOs) to develop, manufacture, test and supply our early- and late-stage product candidates.

We have an industry-leading management team and board of directors with significant immunology and infectious diseases experience, including a proven track record of progressing product candidates from early-stage research through clinical development, and worldwide regulatory approval and commercialization experience. Given the global impact of infectious diseases and other serious conditions, we are committed to providing broad access to our therapeutics.

Our Strategy

We are leveraging our core capabilities to drive patient impact and growth in infectious disease treatments and beyond to areas such as viral-associated and immune-mediated diseases, focusing our capital and resources on areas where Vir can be best-in-class.

Our core capabilities include our deep immunology and virology expertise. In addition, our proven world-class mAb platform with artificial intelligence (AI) driven protein engineering capabilities allows us to discover and engineer next-generation antibodies with enhanced properties. Our cytomegalovirus (CMV) based viral vector platform is designed with the goal of generating unique, potent and long-lasting T cell responses.

The core elements of our business strategy include:

•Advancing our pipeline. We are conducting multiple clinical trials in multiple therapeutic areas including hepatitis and HIV.

•Expanding our pipeline. We are leveraging our two platforms(mAbs and CMV) to discover anddevelop novel product candidates targeting HDV, HBV, HIV, influenza A & B viruses, COVID-19, RSV/MPV, precancerous HPV lesions, and additional viral-associated and immune-mediated diseases. We anticipate moving additional preclinical candidates into the clinic in the next 12 to 24 months.

•Disciplined approach to capital allocation. We are thoughtfully leveraging our strong balance sheet to ensure advancement of our multiple product candidates through major inflection points and invest in our people, processes and systems across the Company, while maintaining the ability to invest in external innovation.

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•Augmenting our pipeline and capabilities by accessing external assets and innovation. We actively monitor the external innovation landscape to identify technologies and assets to license or acquire that could complement our existing pipeline and enhance our capabilities.

•Partnering for success. We have established relationships with organizations such asthe Bill & Melinda Gates Foundation (BMGF), the Biomedical Advanced Research and Development Authority (BARDA), the National Institute of Health (NIH), and the National Health Service (NHS) to further facilitate access to our potential future medicines and to support our clinical development efforts. We will continue to pursue similar alliances that help achieve our strategy with a focus on patient impact and value creation.

Our Pipeline

Our current product and product candidates are summarized by disease are in the chart below:

PEG-IFN-α = peg-interferon alfa-2a; HVTN = HIV Vaccine Trials Network; NIAID= National Institute of Allergy and Infectious Diseases

1MARCH trial (Part B); 2GS-9688; 3nivolumab

*Per the collaboration agreement announced in February 2021, Vir and GSK are continuing to advance new monoclonal antibody therapeutics for other respiratory viruses, including RSV

† Sotrovimab for early treatment by IV currently has marketing approval, temporary authorization or emergency use authorization in >30 countries. In April 2022, the FDA deauthorized sotrovimab’s use in all U.S. regions. Sotrovimab incorporates Xencor’s XtendTM technology. Tobevibart incorporates Xencor’s XtendTM and other fragment crystallizable technologies.

Our Clinical Product Portfolio

HDV

Summary

According to a 2020 article in the Journal of Hepatology and the World Health Organization’s July 2023 hepatitis D Factsheet, approximately 12 million people globally are infected with HDV, representing approximately 5% of the HBV population, and other studies show up to an estimated 72 million people living with HDV globally, many of which are likely undiagnosed. HDV is considered the most severe and aggressive form of viral hepatitis leading to increased rates of cirrhosis, hepatocellular carcinoma, hepatic decomposition, and liver failure. People with HDV are four times more likely to develop liver cancer than people with HBV and more than half of people with HDV will die of liver disease within 10 years of diagnosis. There are no approved therapies for HDV in the U.S. Hepcludex (bulevirtide), a once daily subcutaneous injection, has approval in the European Union (EU) and the United Kingdom (U.K.). Pegylated interferon alpha (IFN-α) has been used off-label with limited success due to its tolerability profile and low rates of sustained virologic response. Our current internal estimates project the HDV treatment market could be as large as $2 billion annually.

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We are developing tobevibart, a monoclonal antibody also known as VIR-3434, and elebsiran, an siRNA also known as VIR-2218, for the treatment and suppression of chronic HDV. Hepatitis B surface antigen (HBsAg) is a critical component necessary for the HDV lifecycle and both tobevibart and elebsiran act independently to inhibit the replication of HDV by targeting HBsAg. Tobevibart binds to a conserved region of HBsAg, which helps eliminate HDV virions from the blood and also blocks the infection of hepatocytes with HDV. Elebsiran targets a conserved region of the HBV genome and inhibits production of all HBV proteins including HBsAg.

In September 2022, we initiated the Phase 2 SOLSTICE trial evaluating tobevibart and elebsiran as monotherapy and in combination for the chronic treatment of people living with HDV. The trial is assessing the safety and ability of the regimens to reduce HDV viremia and normalize alanine aminotransferase (ALT): endpoints that may indicate improved clinical outcomes. The current endpoint for regulatory approval is a combined endpoint consisting of a 2 log10 decline in HDV RNA or undetectable HDV RNA and ALT normalization. Initial data presented in November 2023 demonstrated median HDV RNA reductions of -2.0 log10 and -1.4 log10 with once monthly subcutaneous (SC) doses of tobevibart and elebsiran monotherapy, respectively, for 12 weeks. Once monthly SC combination therapy after 12 weeks of monotherapy with either tobevibart or elebsiran achieved -4.3 log10 reduction. As of January 2024, of the participants entering combination therapy with tobevibart and elebsiran, data on 6 participants through week 20 of combination therapy was available. Of these, 6/6 achieved HDV RNA < lower limit of quantitation (LLOQ) and 5/6 achieved HDV RNA < limit of detection (LOD) 12 weeks after starting combination therapy, which was maintained through week 20. One participant in the tobevibart monotherapy arm achieved the combined endpoint with ALT normalization and two participants receiving combination therapy achieved the combined endpoint at week 12, which was maintained through week 20. These data support continued evaluation of tobevibart and elebsiran for the chronic treatment of chronic hepatitis delta (CHD).

Tobevibart + elebsiran for HDV

Molecular Characteristics and Preclinical Data. Tobevibart is an investigational neutralizing mAb that has been engineered for immune engagement and targets a conserved region on HBsAg that allows it toneutralize strains from all 10 HBV genotypes. Tobevibart specifically targets the antigenic loop (AGL) on HBsAg. The AGL helps the virus bind to hepatocytes and subsequently infect these liver cells. By binding to the AGL, tobevibart prevents viral entry, which prevents the spread of HDV to uninfected hepatocytes. Tobevibart’s proprietary fragment crystallizable (Fc) Gamma engineering enhances its ability to engage immune cells, promoting the removal of antibody-virion complexes. Tobevibart also incorporates Xencor’s XtendTM neonatal Fc receptor technology, which extends its half-life. Tobevibart was identified using Vir’s proprietary mAb discovery platform.

Elebsiran is an investigational HBV-targeted siRNA that reduces HBsAg, a protein which is required for the HDV viral life cycle. Elebsiran is a single siRNA targeting a conserved sequence of HBV that allows for predicted activityagainst 99.7% of the strains of HBV, including all 10 HBV genotypes. Because this conserved sequence falls within a specific region of the X gene of HBV that exists within all four HBV RNA transcripts, elebsiran is able to degrade each transcript, and consequently decrease the expression of all proteins produced by the virus: X, polymerase, S, and core. Elebsiran is thus potentially a potent antiviral.

HBV DNA can become integrated into human DNA as intDNA. Because elebsiran targets a region of HBV that is conserved in the large majority of HBV intDNA, this single siRNA is predicted to be able to prevent the production of HBV proteins derived from intDNA, as well as the production of all other HBV proteins from covalently closed circular DNA (cccDNA).

MOA = mechanism of action; NRTI = nucleotide reverse transcriptase inhibitor; RNP = ribonucleoprotein; SVP = subviral particle

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Tobevibart has been shown to neutralize HDV infection with pan-genotypic activity. Single and combination treatments with tobevibart and elebsiran of HBV/HDV-co-infected primary human hepatocytes in vitro reduced HBV antigens as well as secreted infectious HDV virions. In vivo, the parental molecule of tobevibart reduced the levels of HBsAg, HDV and HBV viremia in HBV/HDV-co-infected liver-chimeric mice. These data support the clinical evaluation of tobevibart and elebsiran in HDV.

Phase 2 Trial of tobevibart in combination with elebsiran. In September 2022, we initiated the Phase 2 SOLSTICE trial evaluating tobevibart and elebsiran as monotherapy and in combination for the chronic treatment of people living with HDV. The trial is assessing the safety and ability of the combination to reduce HDV viremia (2 log10 decline in HDV RNA or undetectable HDV RNA) and normalize ALT, the current combined endpoints used for regulatory approval. The SOLSTICE trial initially evaluated once monthly SC injections of either tobevibart or elebsiran as monotherapy for 12 weeks. If participants did not achieve the primary endpoint of virologic response (2 log10 IU/mL decline or undetectable HDV RNA) and ALT normalization, participants were eligible to initiate combination therapy. Median decline of HDV RNA in participants receiving tobevibart or elebsiran as monotherapy were -2.0 log10 and -1.4 log10 IU/mL, respectively after 12 weeks of treatment.

Six participants entered combination treatment. As of the January 2024 data cutoff, data was available on all 6 participants through week 20 of combination therapy or day 225 of any therapy. At week 12 of combination therapy, a median reduction in HDV RNA of -4.29 log10 from baseline was observed. At that time, 6/6 achieving HDV RNA <LLOQ and 5/6 participants achieving HDV RNA <LOD, which has continued through Week 20. One participant in the tobevibart monotherapy arm achieved the combined endpoint with ALT normalization and 2 participants also achieved the combined endpoint after the initial 12 weeks of combination therapy, which was maintained through week 20. No serious adverse events (SAEs) were reported with few treatments emergent adverse events across cohorts with most being Grade 1 and 2. No ALT elevations above baseline were observed to Week 20 with the tobevibart/elebsiran combination therapy regardless of baseline HBsAg or HDV RNA. Additional cohorts evaluating the combination of tobevibart and elebsiran and tobevibart monotherapy are currently ongoing with additional data anticipated to be available in 2024.

LLOQ = 63 IU/mL; LOD = 14 IU/mL

1Cohort 2C has 6 total participants enrolled. As of January 2024, from the 6 participants who have reached day 225 (week 20 of combination therapy), 5 participants achieved HDV RNA < LLOQ.

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HBV

Summary

According to the Hepatitis B Foundation, approximately 300 million people globally are chronically infected with HBV and approximately900,000 die from HBV-associated complications each year. There is a significant unmet medical need for more effective therapies that lead to life-long control of the virus after a finite duration of therapy, which is the definition of a functional cure. Currently, a year-long course of IFN-α is the best available curative therapy and has a low functional cure rate of approximately 3% to 7%. Alternatively, suppressive therapy with daily nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) is commonly used, but patients often require a lifetime of therapy and NRTI therapy does not eliminate the risk of cirrhosis or hepatocellular carcinoma.

Our two therapeutic candidates, tobevibart and elebsiran, are both antivirals and potential immunomodulators. We believe that a functional cure for HBV will require an effective immune response, in addition to antiviral activity, based on the observation that severe immunosuppression can reactivate HBV disease. Our hypothesis is that the large amount of HBV protein that is transcribed in liver cells can suppress the immune system. There are at least two potential mechanisms by which suppression occurs. The first mechanism is T cell tolerance and exhaustion by the presentation of intracellular HBV antigens on hepatocytes. The second is the large quantities of HBV proteins that are released into the blood, especially HBsAg, which may also be immunosuppressive. We therefore believe that tobevibart and elebsiran have the potential to play a critical rolein interrupting the mechanisms of immunosuppression and reactivating the immune response to deliver high functional cure rates.

Tobevibart and elebsiran demonstrated declines in HBsAg and were generally well tolerated in dose-escalation Phase 1 studies in healthy volunteers and adults with HBV. Phase 2 clinical trials evaluating tobevibart and elebsiran are in progress and described below.

A Phase 2 clinical trial evaluating elebsiran in combination with PEG-IFN-α for 24 and up to 48 weeks showed that 25.8% (8/31) of the participants receiving up to 48 weeks of elebsiran plus IFN-α treatment achieved higher rates of HBsAg seroclearance with hepatitis B surface antibodies (anti-HBs) seroconversion by the end of treatment, with 16.1% (5/31) maintaining seroclearance 24 weeks after end of treatment. The treatment regimens were generally well tolerated and resulted in no new safety signals. These initial results support our hypothesis of combining an antiviral with an immunomodulator to achieve HBsAg seroclearance and seroconversion.

In July 2021 we initiated a two-part study to evaluate the combination of tobevibart and elebsiran in virally suppressed HBV patients. Part A evaluated short treatment courses of tobevibart and elebsiran to rapidly evaluate safety, PK and HBsAg suppression when tobevibart is given weekly concomitantly with or after pre-treatment with elebsiran. Results from MARCH Part A in 2022 showed that the combination of tobevibart and elebsiran resulted in an approximate 3 log10 IU/mL decline in HBsAg with no safety signals. In November 2022, we announced end of treatment data for all MARCH Part A that the combination of tobevibart and elebsiran achieved mean HBsAg reductions >2.7 log10 IU/mL in all cohorts, absolute HBsAg levels <10 IU/mL were achieved in most participants, and no safety signals. Follow-up data after end of treatment showed rebounds in HBsAg levels over time.

MARCH Part B includes cohorts treated for 24- and 48-weeks with monthly doses of tobevibart plus elebsiran with and without PEG-INF-α. In November 2023, we announced initial 24-week treatment arm results from MARCH Part B that evaluated the combination of tobevibart and elebsiran with and without IFN-α. End of treatment results at 24-weeks demonstrated 15.0% (3/20) and 14.3% (3/21) of participants achieving HBsAg seroclearance in the tobevibart+elebsiran and tobevibart+elebsiran+IFN-α arms, respectively. This was higher than what was observed with elebsiran+IFN-α in which 5.6% of participants achieved HBsAg seroclearance after 24 weeks, demonstrating that tobevibart improved the rate of HBsAg seroclearance. At 12 weeks after end of treatment, all participants who achieved HBsAg seroclearance in the tobevibart+elebsiran arm had rebounded while 2 of 3 participants in the tobevibart+elebsiran+IFN-α arm maintained HBsAg seroclearance. End of treatment data from the 48-week arms of tobevibart+elebsiran and tobevibart+elebsiran+IFN-α are expected in the fourth quarter of2024.

The Phase 2 PREVAIL platform trial evaluating the efficacy and safety of tobevibart and elebsiran in participants with chronic HBV infection is ongoing evaluating inactive carriers and immune active, treatment-naïve patients.

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Elebsiran is also being evaluated in additional Phase 2 clinical trials with collaborators. Brii Bio is the sponsor for the Phase 2 trial of elebsiran in combination with BRII-179, an investigational therapeutic vaccine, for the treatment of chronic HBV infection. Treatment has completed in this trial. Treatment with elebsiran alone or in combination with BRII-179 with and without coadjuvant IFN-α was generally well tolerated. Although the combination of elebsiran and BRII-179 had greater anti-HBs responses and improved HBsAg-specific T-cell responses, comparable HBsAg reduction was observed in all cohorts at end of treatment (-1.7-1.8 log10 IU/mL). As described in further detail below under the heading “Our Collaboration, License and Grant Agreements,” we granted Brii Bio an option to obtain exclusive rights to develop and commercialize elebsiran and tobevibart in China, Taiwan, Hong Kong and Macau, or collectively the China Territory, for the treatment, palliation, diagnosis, prevention or cure of acute and chronic diseases of infectious pathogen origin or hosted by pathogen infection, or the Field of Use. In December 2021, we and Gilead (study sponsor) initiated a Phase 2 clinical trial of elebsiran in combination with GS-9688 (selgantolimod), Gilead’s investigational TLR-8 agonist, and nivolumab in both NRTI-suppressed patients and viremic patients. Patients with HBV treatment experience also may receive tenofovir alafenamide, or TAF. In February 2023, nivolumab was discontinued in cohorts evaluating nivolumab in combination with elebsiran and GS-9688 due to immune-related adverse events associated with nivolumab, which are consistent with the safety profile of the class.

HBV Life Cycle and Undetectable HBsAg as a Clinical Endpoint

After infecting a cell, the virus forms cccDNA. This form of HBV DNA is located in the nucleus of hepatocytes and acts like a mini-chromosome. HBV DNA can also integrate into the patient’s DNA. This form of HBV DNA is known as integrated DNA, or intDNA.

HBV releases infectious virions and subviral particles (SVPs) from infected cells. Both virions and SVPs include forms of an HBV protein called HBsAg, a blood biomarker that indicates that the HBV cccDNA and/or intDNA in that patient’s hepatocytes are actively making HBV RNA and HBV proteins. The formal endpoint accepted by the FDA for functional cure is undetectable HBsAg, defined as less than 0.05 IU/mL, as well as HBV DNA less than the lower limit of quantification, in the blood six months after the end of therapy. Achievement of this endpoint has been shown to predict improved clinical outcomes and the lack of need for further therapy.

Limitations of Current Standard of Care

There is a significant unmet medical need for finite versus chronic therapies that achieve functional cure. The most commonly used therapy for chronic HBV is life-long suppressive therapy with daily oral NRTIs, like tenofovir or entecavir. However, NRTIs rarely achieve functional cure, defined as the sustained loss (seroclearance) of detectable HBsAg and HBV DNA in serum, after a finite course of treatment. NRTIs prevent HBV ribonucleic acid, or RNA, from being transcribed into HBV DNA, which is a process known as reverse transcription. NRTIs therefore have little to no direct impact on covalently closed circular DNA(cccDNA) the reservoir for HBVor HBsAg production. It has been reported that after a year of therapy with NRTIs, zero to 3% of patients experience a functional cure. Additionally, NRTIs reduce, but do not eliminate, the risk of HBV associated liver failure and liver cancer. Despite its low utilization rate, suppressive therapy with NRTIs for HBV represented approximately $500 million in the U.S. alone in 2022, according to IQVIA (Midas data).

An alternative treatment option for chronic HBV is a year-long course of IFN-α therapy, which has poor tolerability and low functional cure approximately 3% to 7% of the time. The mechanisms by which IFN-α, an immune cytokine, achieves a functional cure are not known, but there is additional evidence supporting the need for immune stimulation to achieve a functional cure.

Of the hundreds of millions of people with chronic HBV worldwide, only about 10% are diagnosed, and of those diagnosed, only about 22% are treated. New, functional cure therapies have potential to increase diagnosis and treatment rates. Our current internal estimates project the global HBV functional cure market could be as large as $10 billion annually.

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Tobevibart for HBV

Molecular Characteristics and Preclinical Data. Tobevibart is an investigational neutralizing mAb that has been engineered for immune engagement and targets a conserved region on the antigenic loop (AGL) of HBsAg that allows it to neutralize strains from all 10 HBV genotypes. The AGL helps the virus bind to hepatocytes and subsequently infect these liver cells. By binding to the AGL, tobevibart prevents viral entry, which prevents the spread of HBV to uninfected hepatocytes. Tobevibart, through a process called opsonization, also helps remove HBV virions and SVPs from the blood. Hepatitis B immunoglobulin (HBIG) an approved therapy for preventing reinfection after transplantation and which consists of polyclonal antibodies against HBV, acts by similar mechanisms. In vitro, tobevibart demonstrates approximately 5,000-fold greater potency than HBIG in neutralization assays.

Tobevibart also has the potential to activate the immune system, via three different processes. First, due to specialized mutations in the Fc domain, tobevibart, has the potential to act as a T cell vaccine. Tobevibart has been engineered with mutations that enhance binding to the Fc receptor (FcR) IIa activating receptor and diminish binding to the FcR IIb inhibitory receptor. As such, tobevibart is designed to capture virions and SVPs, deliver such virions and SVPs to dendritic cells (DCs), and instruct these DCs to mature and stimulate T cells that can eliminate HBV infected hepatocytes. Second, tobevibart has the potential to act via antibody-dependent cell cytotoxicity (ADCC). In this process, by binding to HBsAg at the cell surface, tobevibart recruits natural killer cells to eliminate infected hepatocytes. The Fc domain of tobevibart has been engineered to promote ADCC. Third, by reducing the amount of HBsAg in the blood, tobevibart has the potential to remove a brake on the immune system by decreasing the ability of HBV to suppress it. Additionally, tobevibart, incorporates Xencor’s XtendTM to extend serum half-life.

Phase 1 Trial of tobevibart. The trial was an adaptive clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and antiviralactivity of tobevibart. The Phase 1 clinical trial had four parts.

Part A was a single ascending dose design in healthy volunteers, with Parts B and C as single ascending dose designs in adults with chronic HBV on NRTIs. Part B included patients with HBsAg levels less than 1,000 IU/ml for the 6 mg cohort and less than 3,000 IU/mL for the other dose cohorts. Part C included patients with HBsAg levels greater than or equal to 3,000 IU/mL. Part D included patients with HBV DNA greater than or equal to 1,000 IU/mL who were not receiving NRTI therapy.

The primary endpoints across all parts of the trial were safety and tolerability. The key secondary endpoint in Parts B and C was the maximum reduction of serum HBsAg from baseline. In Part D, an additional key secondary endpoint was the maximum change of HBV DNA from baseline.

Across all study parts, tobevibart up to 3,000 mg intravenously, or IV, was generally well tolerated with no clinical safety concerns observed. In Part B, most participants achieved a ≥1 log10 IU/mL reduction from baseline in HBsAg within 1-3 days. Mean HBsAg reductions in the 6 mg, 18 mg, 75 mg, and 300 mg groups were 1.30, 1.27, 1.96, and 2.21 log10 IU/mL, respectively, at nadir. All participants who received 75 mg or 300 mg of tobevibart achieved HBsAg <100 IU/mL and 5/6 (83%) in the 300 mg group achieved HBsAg <10 IU/mL. In Part D, single doses of 75 mg or 300 mg was associated with rapid reductions in HBsAg and HBV DNA in the majority of participants. Across both cohorts, 11/12 participants receiving tobevibart achieved a >1 log10 IU/mL decline in HBsAg and 11/12 achieved a >1 log10 IU/mL decline in HBV DNA with the changes in HBsAg and HBV DNA showing similar kinetics. Across all parts of the study, tobevibart was generally well tolerated with the majority of adverse events being mild to moderate in severity. The rapid reductions in HBsAg after just one dose and the safety profile supported further evaluation in Phase 2.

Elebsiran for HBV

Molecular Characteristics. Elebsiran is an investigational, single siRNA targeting a conserved sequence of HBV that allows for predicted activityagainst 99.7% of the strains of HBV, including all 10 HBV genotypes. Because this conserved sequence falls within a specific region of the X gene of HBV that exists within all four HBV RNA transcripts, elebsiran is able to degrade each transcript, and consequently decrease the expression of all proteins produced by the virus: X, polymerase, S, and core. Elebsiran is thus potentially a broad-spectrum, potent antiviral.

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We believe that the large amount of HBV protein that is transcribed in liver cells can suppress the immune system. There are at least two potential mechanisms by which suppression occurs. The first mechanism is T cell tolerance and exhaustion by the presentation of intracellular HBV antigens on hepatocytes. The second is the large quantities of HBV proteins that are released into the blood, especially HBsAg, which may also be immunosuppressive. By directly reducing the amount of HBV proteins made, elebsiran has the potential to decrease the ability of HBV to suppress the immune system—in effect removing a brake on the immune system. In mice models, siRNAs that are able to reduce HBsAg expression can transform an otherwise ineffective therapeutic HBV vaccine into one that can functionally cure such mice of HBV, suggesting that HBsAg suppression has the ability to enhance the immune response against HBV.

We believe that elebsiran is the only HBV-targeting siRNA currently in development that includes enhanced stabilization chemistry (ESC+) technology and preclinical, modeling and initial clinical data suggest this technology may be able to enhance the potential safety of elebsiran.

Phase 1/2 Trial of elebsiran. The trialwas an adaptive clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and antiviralactivity of elebsiran. It evaluated single ascending doses(50 mg to 900 mg) of elebsiran in healthy volunteers and multiple ascending doses(50 mg to 200 mg for 2 doses) in adults with chronic HBV suppressed on NRTI therapy.

Across healthy volunteers and chronic HBV patients, elebsiran has been generally well-tolerated. No clinically significant ALT abnormalities, which are a marker of liver inflammation, have been observed. In the Part A 900 mg cohort, asymptomatic Grade 1 ALT elevations with no associated changes in bilirubin, or other markers of liver function, have been observed. Three SAEs have been reported, all in Part B. The first, a Grade 2 headache, resolved with IV fluids and non-opioid pain medications. This patient had additional symptoms of fever, nausea, vomiting and dehydration, assessed by us as consistent with a viral syndrome. The second SAE, a Grade 4 depression, occurred over 50 days after the last drug dose was administered, and was assessed by us as not related to elebsiran. The third SAE, a patient suicide, occurred 241 days after the last dose of study drug and was assessed by us as not related to elebsiran. Three Grade 3 adverse events of upper-respiratory tract infection, chest pain and low phosphate levels in the blood have also been reported. We did not consider any of these Grade 3 events as related to elebsiran.

Antiviral activity of elebsiran was assessed by changes in HBsAg. The activity of elebsiran through Week 48 for each dose level is shown in the graph below. For Parts B and C, the mean baseline HBsAg levels were 3.3 log10 IU/mL and 3.9 log10 IU/mL, respectively. The mean decline in HBsAg across hepatitis B e-antigen (HBeAg) negative and HBeAg positive subjects at Week 16 was 1.5 log10, or an approximately 32-fold reduction. The declines observed in HBsAg at Week 16 ranged from 0.97 log10 to 2.2 log10, or an approximately nine to 160-fold reduction, after two 200 mg doses of elebsiran given four weeks apart. The mean HBsAg level at Week 16 was 314 IU/mL, with half of the patients achieving HBsAg values < 100 IU/mL and 5/6 achieving HBsAg values < 1000 IU/mL. Five of the 12 patients that achieved HBsAg values of <100 IU/mL maintained it through Week 48. Therefore, even though HBsAg levels gradually rebounded, overall, a durable effect was observed.

The ability of elebsiran to result in substantial and durable declines in HBsAg after only two doses suggests that elebsiran has the potential to play an important role in the functional cure of chronic HBV. We have initiated additional clinical trials evaluating elebsiran in combination with other immunomodulatory agents.

Change from Baseline in HBsAg following administration of elebsiran. Each line represents the mean decline from baseline in HBsAg for elebsiran for each dosing level or pooledplacebo in Parts B and C.

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HBV Combinations and New Product Candidates

Phase 2 Trial of elebsiran in combination with IFN-α. This is a clinical trial evaluating the safety, tolerability,pharmacokinetics and antiviral activity of elebsiran alone and in combination with IFN-α in adults with chronic HBV infection on NRTIs. The trial is evaluating multiple doses of elebsiran 200 mg, alone or in combination with IFN-α for 24 to 48 weeks. The trial cohorts are shown below.

EOT = end of treatment; LLOD = lower limit of detection; QD = daily; QW = every week

aHBsAg assay LLOQ and LLOD are 0.05 IU/mL.

Elebsiran in combination with IFN-α for 24 weeks from Day 1 (Cohort 3) resulted in a more rapid and substantial decline in HBsAg compared to elebsiran alone (Cohort 1) and elebsiran lead-in followed by concomitant administration with IFN-α from Week 12-24 (Cohort 2). Through Week 24, mean HBsAg change from baseline were -1.9, -2.0, and -2.4 log10 IU/mL in Cohorts 1, 2, and 3, respectively, with greater than 1 log10 decline in HBsAg maintained at Week 48. Cohorts 4 and 5 evaluated treatment beyond 24 weeks. In both Cohorts 4 and 5, participants took elebsiran and IFN-α from Day 1 through Week 24. In Cohort 4, participants were eligible to continue IFN-α up to 48 weeks if they did not achieve HBsAg less than the lower limit of quantitation, or LLOQ, and participants in Cohort 5 were able to continue elebsiran and IFN-α up to Week 48 if they did not achieve HBsAg <LLOQ. If a participant in Cohorts 4 or 5 achieved HBsAg <LLOQ at 2 consecutive visits, they were eligible to stop therapy. Through Week 48, mean HBsAg change from baseline were -1.8 and -2.9 log10 IU/mL in Cohorts 4 and 5, respectively. Overall, 10 participants achieved HBsAg seroclearance by Week 48 across all cohorts with the majority occurring in Cohorts 4 and 5. Importantly, nine out of these 10 participants, including all four in Cohort 5, also achieved seroconversion defined as anti-HBsAb > 10 mIU/mL, which suggests the potential for durability of response after stopping therapy. Participants in Cohorts 4 and 5 were able to maintain HBsAg seroclearance 24 weeks after end of treatment at 16.7% (3/18) and 15.4% (2/13), respectively. Among participants who had HBsAg seroclearance by end of treatment, 4/4 had anti-HBs levels >500 mIU/mL at end of treatment had sustained HBsAg seroclearance 24 weeks post end of treatment. All participants (3/3) who had anti-HBs levels <100 mIU/mL at end of treatment experienced rebound in HBsAg. Three participants had anti-HBs between 100-500 mIU/mL; 2 experienced a rebound and 1 sustained HBsAg seroclearance through 24 weeks post end of treatment. The treatment regimens were generally well tolerated and resulted in no new safety signals.

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We believe the data from this study provides us proof of concept of our approach to achieving a functional cure in HBV and that anti-HBs titers >500 mIU/mL at end of treatment were associated with sustained HBsAg seroclearance at 24 weeks post end of treatment.

Preliminary 48-week safety and efficacy data from novel investigative cohorts of elebsiran alone and in combination with IFN-α in participants with chronic HBV infection. All participants are virally suppressed on NRTIs.

1 Two participants withdrew from study prior to Week 16; 1 participant had HBsAg seroclearance at Week 32, stopped PEG-IFN per protocol, and had a rebound in HBsAg by Week 48.

Phase 2 Trial of tobevibart and elebsiran with and without IFN-α (MARCH). In July 2021, we initiated the Phase 2 MARCH trial to evaluate the combination of tobevibart and elebsiran as a functional cure regimen for chronic HBV infection. Tobevibart and elebsiran have the potential to act in concert by inhibiting virion production, removing potentially tolerogenic HBV proteins, and stimulating new HBV specific T cells. All patients were virally suppressed on NRTIs. The MARCH trial is being conducted in two parts. Part A is the first evaluation of the combination of tobevibart and elebsiran and is primarily assessing the safety of the combination as well as efficacy. Part B of the trial is evaluating 24- and 48-week regimens of the tobevibart and elebsiran combination with and without IFN-α.

Q4W = every 4 weeks

* Not exhaustive – does not include monotherapy arms for tobevibart. Additional cohorts may be added.

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Part A of the MARCH trial evaluated the safety of the combination of tobevibart and elebsiran. Cohort 1 was a lead-in with elebsiran followed by coadministration of tobevibart from Week 16-20. Cohort 2 and 3 evaluated the concomitant administration of tobevibart and elebsiran and from Day 1 through Week 12, evaluating 18 mg and 75 mg tobevibart administered weekly. Cohort 1 demonstrated a mean 3.1 log10 decline in HBsAg at end of treatment while Cohorts 2 and 3 demonstrated a 2.7 log10 decline in HBsAg. Although no participants achieved HBsAg <LLOQ, most participants achieved HBsAg <10 IU/mL. Tobevibart in combination with elebsiran was generally well tolerated with most adverse events being mild. Follow-up data showed rebound of HBsAg after end of therapy but HBsAg levels remained -0.8 to -0.9 log10 IU/mL below baseline 48 weeks post end of treatment.

Preliminary data from the ongoing open-label Phase 2 MARCH trial evaluating the safety, tolerability and antiviral activity of tobevibart in combination with elebsiran in virally suppressed participants with chronic HBV infection who received continuous NRTI therapy for two months or more. All participants are virally suppressed on NRTIs.

Part B of the MARCH trial is evaluating the combination of tobevibart and elebsiran with and without IFN-α for 24 and 48 weeks. Initial 24-week data from Part B demonstrated that tobevibart+elebsiran and tobevibart+elebsiran+IFN-α achieved HBsAg seroclearance in 15.0% (3/20) and 14.3% (3/21) of participants, respectively. All participants who received tobevibart+elebsiran and achieved HBsAg seroclearance had rebound in HBsAg. Of the three participants who received tobevibart+elebsiran+IFN-α and achieved HBsAg seroclearance, only one had rebound in HBsAg. Participants who had sustained HBsAg seroclearance had higher anti-HBs antibodies levels compared to those who did not. All treatment emergent adverse events in the tobevibart+elebsiran cohort were Grade 1-2 in severity. Of those treated with tobevibart+elebsiran+IFN-α, treatment-emergent adverse events were generally consistent with those expected for IFN-α with Grade 3 treatment-emergent adverse events reported in five participants. 48 week cohorts of tobevibart+elebsiran and tobevibart+ elebsiran+IFN-α are ongoing with end of treatment data expected in the fourth quarter of 2024.

*Denotes participants who sustained HBsAg loss at 12 weeks post-EOT

Anti-HBs concentrations in the VIR-2218-1001 and VIR-2218-1006 studies were determined using the Anti-HBs2 Assay IVD Kit on the Siemens ADVIA Centaur instrument and the Elecsys Anti-HBs II assay on the Roche Cobas instrument, respectively. The laboratory developed test using the Elecsys Anti-HBs II assay incorporated the addition of a VIR-3434 binding blocker (anti-idiotype Fab fragment) to the samples prior to analysis, preventing assay interference by VIR-3434.

Values <LLOQ were imputed as 1 mIU/mL

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Summary of Phase 2 Combination Trials. Data from VIR-2218-1001 and the MARCH trial support our approach to achieving functional cure in HBV. In the VIR-2218-1001 trial, we were able to demonstrate that the combination of elebsiran+IFN-α was able to increase HBsAg seroclearance rates to 25.8% compared to what has been observed with siRNAs (0%) and IFN-α as monotherapy (3-7%) at end of treatment. In addition, we were able to observe an approximate 5-fold increase in HBsAg seroclearance rates between Week 24 and 48. From MARCH Part B, 24 weeks of tobevibart+elebsiran and tobevibart+elebsiran+IFN-α resulted in HBsAg seroclearance rates about 3-fold higher compared to elebsiran+IFN-α alone demonstrating the additional activity of tobevibart. Data expected in the fourth quarter of 2024 should inform whether a similar increase in HBsAg seroclearance rates will be observed between Week 24 and Week 48 as was observed in VIR-2218-1001.

2 HBsAg > 10 mIU/mL; Tx = Treatment

Other Collaborators. In April 2021, Brii Bio initiated a Phase 2 trial of elebsiran in combination with BRII-179, an investigational therapeutic vaccine, for the treatment of chronic HBV infection. Treatment has been completed in this trial. Treatment of elebsiran alone or in combination with BRII-179 with and without coadjuvant IFN-α was generally well tolerated. Although the combination of elebsiran and BRII-179 had greater anti-HBs responses and improved HBsAg-specific T cell responses, comparable HBsAg reduction was observed in all cohorts at EOT (-1.7-1.8 log10 IU/mL).

In December 2021, we and Gilead initiated a multi-center, open-label Phase 2 clinical trial designed to evaluate thesafety, tolerability and efficacy of various combinations of elebsiran, GS-9688 (selgantolimod), Gilead’s investigational TLR-8 agonist, nivolumab and TAF in adults with chronic HBV. The trial enrolled approximately 120 patients ages 18 to 65 who were either viremic or are NRTI-suppressed. Patients who were HBeAg-positive (an indicator of acute viral replication), as well as those who were HBeAg-negative, were enrolled. The primary efficacy endpoint is the proportion of patients who achieve a functional cure (defined as HBsAg loss and HBV DNA <20 IU/mL at follow-up week 24). In February 2023, nivolumab was discontinued in cohorts evaluating nivolumab in combination with elebsiran and GS-9688 due to immune-related adverse events associated with nivolumab, which are consistent with the safety profile of the class.

The Phase 2 PREVAIL platform trial and its THRIVE/STRIVE sub-protocols of tobevibart and/or elebsiran and/or IFN-α in viremic patients with chronic HBV infection was initiated in the first half of 2023. The THRIVE sub-protocol is evaluating the safety and efficacy of regimens containing combinations of an NRTI with tobevibart and/or elebsiran in inactive carriers defined as adults with chronic HBV that are HBeAg negative with HBV DNA ≤2000 IU/mL and ALT ≤ upper limit normal (ULN). The STRIVE sub-protocol is evaluating the safety and efficacy of regimens containing combinations of an NRTI with tobevibart and/or elebsiran and/or IFN-α in adults with chronic HBV infection who have not received prior NRTI or IFN-α treatment. Participants will be HBeAg positive or negative with HBV DNA >2000 IU/mL, ALT>ULN and ≤ 5× ULN.

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HIV

Summary

Forty years after the start of the epidemic, HIV remains one of the world’s most serious public health challenges. With approximately 1.5 million new cases of HIV worldwide each year, there remains a strong need for prophylactic vaccine. We are taking a different immunologic approach to HIV prevention using human cytomegalovirus (HCMV) as a vector designed to maximize T cell immunity. Based on in vivo data, we hypothesize an HCMV-based vaccine may be able to “program” unique T cell responses against HIV, which is different from other vaccine approaches. HCMV as a vector is a weakened version of the virus designed to deliver the HIV vaccine material to the immune system without itself causing disease in the trial participants. HCMV has been present in much of the global population for centuries. Most people living with HCMV experience no symptoms and are unaware that they are living with the virus. HCMV remains detectable in the body for life, which suggests it has the potential to deliver and then safely help the body retain HIV vaccine material for a long period of time, potentially overcoming the waning immunity observed with more short-lived vaccine vectors.

VIR-1111, a prototype HIV vaccine, was evaluated in a Phase 1 first-in-human study that demonstrated no safety signals and no vector shedding or viremia. No sustained HIV-insert-specific T cell responses were observed. VIR-1388 has incorporated modifications that have the potential to enhance HIV-specific immunogenicity compared to VIR-1111 and provide broader coverage against circulating strains of HIV. The VIR-1388 Phase 1 study was initiated in 2023.

Disease Overview and Limitations of the Current Standard of Care

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), each year there are approximately 700,000 HIV-related deaths globally. Unless treated, infection with HIV results in an almost universally fatal disease, acquired immune deficiency syndrome, or AIDS. According to the World Health Organization (WHO), almost 36 million people have died from HIV-related illnesses globally since cases were first reported in 1981.

Highly effective HIV treatments are now available, but these medicines only suppress HIV and are not curative. They require life-long administration and carry the risk for viral breakthrough and resistance. Furthermore, while HIV prevention programs based on behavioral modification, pharmacological intervention, use of barrier devices and other methods continue to be developed, such approaches have had at most a modest effect on HIV transmission globally in high-risk populations. Although pre-exposure prohylaxis (PrEP) with antiretroviral therapy has been available for several years, it requires daily administration to be effective. Long-acting antiretroviral PrEP has recently been approved but still requires injections every 2 months to be effective. Therefore, we believe the most effective means of curbing the worldwide HIV epidemic would be a safe and effective vaccine for individuals who are or may become sexually active.

VIR-1111 and VIR-1388 for HIV

Molecular Characteristics and Preclinical Data. VIR-1111 is a prototype T cell vaccine using an engineered HCMV vector designed to elicit T cells thatrecognize HIV epitopes different from those recognized by prior HIV vaccines, to exploit the capacity of HCMV to induce persistently high frequencies of T cells pre-programmed to migrate into tissues, and to stimulate a different type of immune response to HIV, known as an human leukocyte antigen E (HLA-E ) restricted cluster of differentiation (CD) 8 T cell response. VIR-1388 contains a novel immunogen intended to provide broader coverage against circulating strains of HIV compared to the clade A Gag immunogen in VIR-1111. Genetic modifications of the HCMV vector used for VIR-1388 recapitulate those of rhesus CMV vectors that elicited an HLA-E restricted immune response and protected more than 50% of nonhuman primates (NHPs) from repeated exposure to simian immunodeficiency viruses (SIV).

Phase 1 Trial of VIR-1111. The trial was a multiple ascending dose clinical trial designed to evaluate the safety, tolerability, reactogenicity andimmunogenicity of VIR-1111 in CMV-positive healthy adult volunteers, initiated in December 2020 and completed in December 2022. The immunogenicity evaluation included an assessment of the breadth and nature of the T cell response to the vaccine. In November 2022, we announced that safety and immunology data from the initial two cohorts of the trial showed no safety signals and no vector shedding or viremia reported to date. In addition, no sustained HIV insert-specific T cell responses were observed in the first two cohorts. Safety and immunology data reported in 2023 from the highest dose cohort 3 were consistent with the data from cohorts 1 and 2. The manufacture and early clinical development of VIR-1111 was funded by the Bill & Melinda Gates Foundation.

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Phase 1 Trial of VIR-1388. Learnings from VIR-1111 have informed the vector and trial design of VIR-1388. We initiated a Phase 1 trial of VIR-1388 in September 2023. The trialis a multiple ascending dose clinical trial designed to evaluate the safety, tolerability, reactogenicity and immunogenicity of VIR-1388 in CMV-positive healthy adult volunteers. VIR-1388 is a subcutaneously administered HIV T cell vaccine using HCMV as a vector. Like VIR-1111, VIR-1388 has beendesigned to elicit T cells that recognize HIV epitopes that are different from those recognized by prior HIV vaccines and to stimulate a different and specific type of T cell immune response to HIV, known as an HLA-E restricted immune response. VIR-1388 has additional modifications that have the potential to enhance immunogenicity compared to VIR-1111. This trial is supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation, and is being conducted by the HIV Vaccine Trials Network. Initial data from the trial is expected in the second half of 2024.

COVID-19

Summary

In response to the COVID-19 pandemic, we moved rapidly to address this global health challenge. Our focus has been on treating and preventing COVID-19, as well as potential future coronavirus outbreaks. To do so, together with our collaborator GSK, we developed the mAb sotrovimab for the treatment and prophylaxis of COVID-19. Sotrovimab is based on a parent antibody, S309, which was derived from samples previously gathered for research on pan-coronavirus-neutralizing mAbs. Data suggest that sotrovimab has the potential for ‘dual-action’, or the ability to block viral entry into healthy cells and an enhanced ability to clear infected cells.

In May 2021, the FDA granted an emergency use authorization (EUA) to sotrovimab for the early treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and at high risk for progression to severe COVID-19, including hospitalization or death. In December 2021, the European Commission granted marketing authorization to Xevudy® (sotrovimab) in the EU for the treatment of adults and adolescents at increased risk of progressing to severe COVID-19. In March 2022, the FDA de-authorized sotrovimab’s use in all U.S. regions due to increases in the proportion of COVID-19 cases caused by non-susceptible new variants. Sotrovimab has obtained emergency authorization, temporary authorization or marketing approval (under the brand name Xevudy®) for early treatment of COVID-19 in more than 30 countries. Over 2.1 million doses of sotrovimab have been delivered as of December 31, 2022. We continue to conduct in vitro testing of sotrovimab against new variants and subvariants as they emerge, and to collect and evaluate real-world evidence, both of which are being shared with regulatory authorities.

Sotrovimab is also being evaluated in two additional indications: (1) to determine if sotrovimab can prevent symptomatic COVID-19 infection in uninfected immunocompromised adults, and (2) to evaluate if sotrovimab treatment can improve clinical outcomes in patients hospitalized with COVID-19.

In addition, Vir is preparing for future pandemics by developing coronavirus mAbs that we believe have the potential to have even broader application and be more potent than sotrovimab.

Disease Overview and Limitations of Current Standard of Care

The FDA has granted either EUAs or marketing approvals to multiple vaccines, drugs and/or antibodies to prevent or treat COVID-19 in the U.S. For prophylaxis, despite the high efficacy of the COVID-19 vaccines, there are still populations in whom vaccine immunogenicity is suboptimal, such as the elderly with comorbidities, immunocompromised persons, or those who may not want or be able to tolerate vaccines. For early treatment, both mAbs and small molecules have shown strong efficacy data and have pros and cons around convenience and compliance. For example, for some patients and their physicians, intramuscular, or IM, or IV mAbs may be preferred to small molecules due to administration in a single treatment visit (“one and done”), concerns about compliance with small molecules (multiple pills, multiple times per day, over multiple days), and concerns about oral treatment initiation requirements. For hospitalized patients, there is still significant unmet need. Data suggest that COVID-19 mAbs may have a role in improving clinical outcomes such as decreasing intensive care unit stays and/or mortality in hospitalized patients who have severe or critical COVID-19. Importantly, the ongoing durability of current vaccines, small molecules, and mAbs in the setting of the continued emergence of variants is uncertain.

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Sotrovimab for COVID-19

Molecular Characteristics

Sotrovimab is an engineered human immunoglobulin 1 (IgG1) neutralizing anti-SARS-CoV-2 monoclonal antibody that has Fcmodifications designed to improve bioavailability in the respiratory mucosa and increase half-life, and incorporates Xencor’s XtendTM technology. Sotrovimab binds with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein. It is designed to have dual-actions of neutralizing the virus by blocking viral entry into healthy cells, while also enhancing the ability to clear infected cells. Sotrovimab potently neutralizes live SARS-CoV-2 in vitro and in vivo, and binds to a highly conserved epitope that is shared with SARS-CoV-1.

Early Treatment

In August 2020, we initiated the lead-in phase of our Phase 2/3 trial COVID-19 Monoclonal antibody Efficacy Trial - Intent to Care Early, or COMET-ICE, for the treatment of adults at high risk of hospitalization or death from COVID-19 via IV administration. This trialwas a Phase 2/3, randomized, double-blind, multi-center, placebo-controlled trial investigating IV infusion of 500 mg of sotrovimab in adults with mild to moderate COVID-19 at high-risk of progression to severe disease, who were not hospitalized and did not require oxygen. The trial included a lead-in phase to evaluate the safety and tolerability of sotrovimab, followed by an expansion phase with 1:1 randomization of sotrovimab and placebo. The final COMET-ICE trial results in the full trial population of 1,057 participants demonstrated an adjusted relative risk reduction of 79% (p<0.001) in all-cause hospitalization for more than 24 hours or death due to any cause by day 29 compared to placebo, meeting the primary endpoint of the trial.

In May 2021, the FDA granted an EUA to sotrovimab for the early treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and at high risk for progression to severe COVID-19, including hospitalization or death. In December 2021, the European Commission granted marketing authorization to Xevudy® (sotrovimab) in the European Union (EU) for the treatment of adults and adolescents at increased risk of progressing to severe COVID-19. In March 2022, the FDA de-authorized sotrovimab’s use in all U.S. regions due to increases in the proportion of COVID-19 cases caused by the Omicron BA.2 subvariant. Sotrovimab has obtained emergency authorization, temporary authorization or marketing approval (under the brand name Xevudy®) for early treatment of COVID-19, supplying more than 30 countries.

We continue to conduct in vitro testing of sotrovimab’s ability to neutralize new variants and subvariants as they emerge, and to collect and evaluate real-world evidence, both of which are being shared with regulatory authorities.

Prophylaxis

In August 2022, sotrovimab entered the Phase 3 PROphylaxis for paTiEnts at risk of COVID-19 infecTion, or PROTECT-V, platform trial sponsored by Cambridge University Hospitals National Health Service, or NHS, Foundation Trust assessing the use of a 2 g dose of sotrovimab administered IV in uninfected, high-risk immunocompromised individuals. This is a randomized, double-blinded, placebo-controlled trial that is currently enrolling participants. The primary endpoint is PCR-confirmed symptomatic COVID-19 infection at three months. Key secondary endpoints include PCR-confirmed symptomatic COVID-19 infection at subsequent timepoints, time to confirmed SARS-CoV2 infection, safety, mortality and disease severity. Due to significant uncertainty in the anticipated infection rate, the sample size will be monitored and reviewed regularly by the independent Data Monitoring Committee (IDMC). Timing of initial data will depend on continued rate of enrollment.

Hospitalized treatment

In December 2021, sotrovimab entered the Randomized Evaluation of COVID-19 Therapy, or RECOVERY, trial, a Phase 3 trial in the UK evaluating standard of care alone versus usual standard of care plus a single 1 g dose of sotrovimab given IV. This is a randomized, controlled, open-label, platform trial assessing several possible treatments in patientshospitalized with COVID-19 in the UK. Trial participants who are hospitalized with COVID-19 are eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus a single dose of sotrovimab given IV. Timing of initial data will depend on continued rate of enrollment.

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Influenza

Summary

There remains medical need for prevention of serious influenza illness. The variability in the efficacy of influenza vaccines could be due to incomplete coverage against seasonal strains and the lack of an effective immune response in many individuals after receiving the vaccine. We are developing influenza mAbs as a universal prophylactic for influenza to address the limitations of flu vaccines. In May 2021, we signed a definitive collaboration agreement, or the 2021 GSK Agreement, with Glaxo Wellcome UK Limited to expand our existing collaboration to include the research and development of new therapies for influenza and other respiratory viruses. See the section titled “Our Collaboration, License and Grant Agreements—Collaboration Agreements with GSK” for a description of the 2021 GSK Agreement.

Disease Overview and Limitation of Current Standard of Care

According to the WHO, on average, each year the influenza virus is estimated to infect one billion individualsand to result in 290,000 to 650,000 deaths globally. According to the Centers for Disease Control and Prevention (CDC), in the 2018-2019 flu season, despite the availability of the flu vaccine, approximately 36 million people were diagnosed with influenza, 500,000 people were hospitalized, and 34,000 people died from influenza in the U.S. alone. Influenza vaccines have historicallyhad limited success, with an average efficacy of 40% overall, across all populations. This limited efficacy results from incomplete coverage against seasonal strains and the lack of an effective immune response in many individuals after receiving the vaccine. We are developing influenza mAbs as a universal prophylactic for influenza to address the limitations of existing flu vaccines, which we believe will lead to meaningfully higher levels of protection against seasonal and pandemic strains of influenza.

VIR-2482 for Influenza A

Molecular Characteristics

VIR-2482 is an investigational mAb targeting a functionally conserved epitope on the influenza Ahemagglutinin protein located within the stem region. In preclinical studies, we demonstrated that in vitro VIR-2482 covers all the major strains of influenza A that have arisen since 1918. In addition, in prophylactic lethal challenge studies of influenza A in mice, VIR-2482 was able to protect mice from death at VIR-2482 exposures we believe to be clinically relevant. We engineered the parent form of VIR-2482 to extend its half-life to create VIR-2482, which incorporates Xencor’s XtendTM technology.

Phase 1 and 2 Clinical Studies

VIR-2482-3001 was a Phase 1 first-in-human, randomized, double-blinded, placebo-controlled single ascending dose trial in healthy adult volunteers with endpoints of safety, tolerability, and pharmacokinetics, or PK, when VIR-2482 is administered intramuscular (IM) in four different doses: 60 mg, 300 mg, 1200 mg, and 1800 mg. This trial was initiated in August 2019 and is now complete. The trial showed VIR-2482 was well-tolerated up to 1800 mg and is estimated to have a half-life of 58 days based on preliminary clinical data.

In October 2022, we initiated PENINSULA (PrevENtIoN of illnesS dUe to InfLuenza A), a Phase 2 randomized, double-blind, placebo-controlled, dose-ranging trial in healthy adult volunteers aged 18 to 64 to evaluate the safety, tolerability and efficacy of two different intramuscularly administered doses of VIR-2482 in preventing illness due to influenza A. The primary efficacy endpoint is the proportion of trial participants with protocol-defined influenza illness1, requiring one systemic symptom and one respiratory symptom with polymerase chain reaction (PCR) confirmed influenza A infection, compared to placebo. Secondary endpoints included the proportion of participants with CDC-defined influenza-like-illness with PCR-confirmed influenza A infection2, and the proportion of participants with WHO-defined influenza-like-illness with PCR-confirmed influenza A infection3. This study enrolled ~3,000 healthy adults aged 18-64 randomized 1:1:1 into placebo, 450 mg, and 1200 mg of VIR-2482 arms. The results showed that the primary and secondary efficacy endpoints were not met. Specifically, there was a non-statistically significant reduction in influenza illness of approximately 16% at 1,200 mg using the primary endpoint. In this same group, an approximate 57% reduction in influenza A illness was observed when illness was defined according to CDC criteria. Post-hoc analyses showed that the relative risk reduction in CDC-defined criteria increases further to 65% when excluding the confirmed flu cases that occurred within a few days of dosing. VIR-2482 was generally well tolerated and no safety signals were identified. The PENINSULA trial was funded in part with federal funds from the Department of Human Services (HHS); the Administration for Strategic Preparedness (ASPR); and the BARDA, under OT number 75A50122C00081.

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Efficacy Analyses

Occurrence of Influenza-Like-Illness (ILI) with PCR-Confirmed Influenza A

Relative Risk Reduction (%) - 3.78% 15.85%

Relative Risk Reduction (%) - 11.45% 57.23%

Number of Participants with WHO-Defined ILI3 11 (1.12%) 12 (1.22%) 6 (0.60%)

Relative Risk Reduction (%) - -9.80% 44.13%

Note: Percentages are calculated relative to the number of participants in the full analysis set.

1 Protocol-defined ILI is defined as PCR-confirmed influenza A infection with at least one respiratory symptom: sore throat, cough, sputum production, wheezing, or difficulty breathing and at least one systemic symptom: fever (temperature >37.8°C), chills, weakness, or myalgias.

2 CDC-ILI is defined as fever (temperature >37.8°C) and cough and/or sore throat.

3 WHO-ILI is defined as fever (temperature >38°C) and cough.

We are continuing to develop next generation antibodies that we believe have the potential to have even broader applications in treating both influenza A and B.

Our Preclinical Programs

We continue to advance next-generation mAbs based on our proprietary platform and enabled by AI and machine learning to deliver high-quality drug candidates more efficiently.

We expect to file multiple investigational new drug applications (INDs) in the next 12-24 months, including:

•VIR-1949, an investigational therapeutic T cell vaccine based on our HCMV vector platform that is designed to treat precancerous lesions caused by human papillomavirus;

•VIR-7229, an investigational mAb against COVIDwith exceptional breadth and potency against SARS-CoV variants and related animal coronaviruses;

•VIR-2981, an investigational neuraminidase-targeting mAb against both influenza A and B viruses;

•VIR-8190, an investigational mAb with dual specificity against RSV and MPV; and

•HIV Cure: potential cocktail of broadly neutralizing antibodies with Fc modifications to control viral load and achieve a functional cure of HIV.

HPV: VIR-1949

HPVs cause primary infections acquired in childhood or by sexual transmission. Persistent HPV infections may result in cervical or anal dysplasia that can progress to cancer. HPV also causes head and neck and other less common cancers. Most pre-cancerous cervical and anal dysplasia and HPV-related cancers are due to HPV 16 and 18 types. Cancer is caused by the viral oncogenes, E6 and E7. Licensed vaccines are protective, but the HPV disease burden is expected to remain for decades due to pre-existing infections and poor vaccine uptake.

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Building upon our CMV vectored vaccine platform, Vir’s CMV-HPV vaccine candidate (VIR-1949) offers a novel approach to therapy for HPV-associated diseases because the CMV vector has the potential to stimulate high frequencies of HPV-specific CD4+ and CD8+ T cells that are predominantly effector memory T cells pre-programmed to traffic into tissues. Proof of biology studies using rhesus CMV vaccines demonstrate T cell homing to tissues, clearance of simian immunodeficiency virus and TB and long-term persistence of immunity. The CMV-HPV immunogen is a multi-component fusion protein designed for breadth against HPV 16 and 18, and other cancer causing HPV types. CMV-HPV is anticipated to generate high frequencies of HPV-specific T cells with the potential to eliminate pre-cancerous disease and limit HPV tumor progression. Notably, cervical high-grade squamous intra-epithelial lesion (HSIL) regression has been associated with a local CD8+ T cell response. The benefits of an HPV therapeutic vaccine are as an alternative to the risks of surgery for dysplasia and to improve often poor outcomes of HPV cancer.

VIR-1949 is our first oncology program that expands our pipeline beyond infectious disease into viral-associated cancer.

COVID: VIR-7229

COVID-19 continues to be a disease area with high unmet medical need and currently there are no FDA approved or authorized products for Pre-exposure Prohylaxis (PREP) for immunocompromised individuals who may not respond sufficiently to vaccines. We have leveraged our mAb platform 2.0 to develop VIR-7229, an investigational, pre-clinical COVID mAb, which was optimized using data AI structure and antibody (dAIsYTM), our proprietary AI-driven design of fragment antigen binding (Fab) and FC mAb variants, to improve potency, breadth, and resistance to viral escape. In vitro data show that VIR-7229 can neutralize all historical and current variants of SARS-CoV-2 as well as related animal coronaviruses with potency compatible with intramuscular injection. Our goal for VIR-7229 is to provide a next-gen COVID mAb with exceptional breadth against future variants for prophylaxis in individuals who do not mount an adequate response to vaccines. We have validated that this potentially prophylactic mAb continues to be efficacious even as the virus evolves and is potent enough for intramuscular administration.

In September 2023, we received approximately $50 million in new BARDA funding, including $40 million in Project NextGen funding, which supports the development of VIR-7229 through Phase 1 in the context of developing alternative mAb delivery technologies.

Influenza: VIR-2981

VIR-2981, is an investigational neuraminidase-targeting mAb that has been shown in in vitro and in vivo models to neutralize both flu A and flu B, including seasonal and zoonotic strains with pandemic potential. Because it inhibits the neuraminidase enzyme – similar to flu antiviralscurrently used to prevent or treat influenza symptoms – VIR-2981’s mechanism of action has been clinically validated. Vir-2891 is being developed as a single administration for season-long prophylaxis of influenza in individuals at risk of severe disease. The passive immunization approach planned for VIR-2981 has been effective in other acute viral respiratory diseases such as RSV and COVID-19. Compared to Vir’s previous candidate for influenza A prophylaxis, Vir-2482, Vir 2981 has been shown to have higher potency in in vivo studies, in addition to extended breadth.

RSV and MPV: VIR-8190

We are identifying and refining human antibodies with antiviral activity against RSV alone and those that also have dual specificity against RSV and MPV. Both RSV and MPV cause significant medical burden in young children and individuals with a variety of immune deficits. The passive immunization concept of using antibodies to prevent respiratory viral infections, and/or reduce disease associated with infection, has been successfully demonstrated for RSV (nirsevimab) and other respiratory viruses such as COVID-19.

HIV: mAb combination (cure)

Despite recent advances in the availability of antivirals to control HIV, treatments still require frequent, if not daily administration over a lifetime. Notably, there is precedent indicating that in a subset of patients, the administration of bNAbs subsequent to antiretroviral interruption can mediate sustained suppression of HIV-1 replication. This effect may result from the elicitation of enduring HIV-specific T cell responses, offering a rationale for exploring bNAbs as a candidate for enduring HIV-1 functional cure. With the support of the Bill and Melinda Gates Foundation, we are selecting and engineering bNAbs to optimize their breadth, potency, half-life, effector functions and manufacturability. This aims to develop a unique and innovative HIV-1 therapy approach for both long-acting therapy and functional cure of HIV-1 infected individuals.

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Our Technology Platforms

Our technology platforms are designed to modulate the immune system by exploiting critical observations of natural immune processes. We are using our platforms to advance our current product candidates and generate additional product candidates for multiple indications.

Platforms for the Creation of Transformative Medicines

We have purposefully assembled a portfolio of technology platforms that we believe will, individually or in combination, allow us to modulate the immune system in innovative ways and to exploit the vulnerabilities of pathogens. Our current platforms are focused on antibodies and T cells. We have assembled these platforms through internal development, collaborations and acquisitions. We are using our platforms, and continue to evaluate others, to advance our current product candidates and generate additional product candidates for multiple indications.

We follow the science to select the modality, or combination of modalities, that gives us the highest chance of success for a specific pathology in a given patient population. The diversity of our different platforms allows us to select the best modality or modalities for a given clinical need.

Antibody Platform

We have established robust methods for identifying rare antibodies with unique breadth/potency/resistance profile and development potential. We then improve on their properties with AI-enabled protein engineering. Our antibody platform capitalizes on successful immune responses occurring in (i) peoplewho have recovered from infectious diseases or (ii) transgenic mice expressing human-IgG following immunization. In both approaches, we select rare and highly potent antibodies that can be developed to treat and prevent rapidly evolving and/or previously untreatable pathogens or to treat disorders beyond infectious diseases. We have applied this platform to identify mAbs for a range of pathogens including SARS-CoV-2, HBV, HDV, influenza A and influenza B virus, Ebola, HIV, RSV, MPV, malaria, rabies, clostridium difficile, Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter spp. Examples of the power of this platform are sotrovimab, our anti-SARS-CoV-2 mAb, which has been granted Emergency Use Authorization or marketing authorization under the brand name Xevudy® in multiple regions,and EbangaTM(ansuvimab), the anti-Ebola virus mAb identified by our scientists in collaboration with the NIH and others and marketed by Ridgeback Biotherapeutics LP. The fully-human antibodies that we discover may also be modified via our proprietary AI-driven protein engineering technology platform, dAIsYTM, to enhance their therapeutic potential by further improving affinity, resistance profile, PK and/or manufacturability properties.

Overview

We are developing antibody-based therapies for the treatment or prevention of infections by rapidly evolving and/or previously untreatable pathogens, as well as of disorders beyond infectious diseases, for which we believe we can make an impact. mAbs rely on multiple mechanisms of action, including neutralization, killing of target cells (i.e., virus-infected cells, tumor cells, immune cells), as well as modulation of the immune response. We combine high-throughput, rapid isolation of rare, highly potent, broad-spectrum and fully human antibodies with targeted AI-enhanced engineering to increase their therapeutic potential.

We expect the following benefits from mAb candidates identified using our antibody platform:

•Effective regardless of an individual’s ability to generate their own immune response;

•Diminished likelihood of self-reactivity (e.g., off-target binding) because our mAbs are fully human and purged from autoreactivity by the host immune system;

•For infectious disease mAbs, broad coverage of most or all strains of a pathogen, or even multiple pathogens and high affinity binding to conserved antigen epitopes characterized by structural/functional constraint, resulting in a high barrier to resistance from viral escape;

•Longer half-life than naturally occurring antibodies through Fc engineering;

•Potential to induce a vaccinal effect, i.e. to elicit endogenous adaptive immune response that may provide durable protection even after the mAb is no longer present;

•Antibody-mediated cell killing affects against infection and tumors; and

•Tunable potency/affinity for inhibitory or agonist properties

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Sotrovimab, ansuvimab, tobevibart,VIR-2482 as well as other mAbs in early preclinical development such as VIR-7229 were generated using our antibody platform.

Our Approach

Hu-Ig = humanized immunoglobulin

We use a proprietary antibody screening technology that allows us to screen the antibodies produced from hundreds of millions of B cells derived from survivors of an infection or from human-Ig immunized mice to identify those rare mAbs that have the characteristics needed to create an effective medicine. Rare characteristics include, for example, the ability to bind to a highly conserved antigen within a pathogen, to neutralize multiple different pathogens or to selectively bind host target proteins. We refer to this technology as High Throughput Isolation since we are able to screen hundreds of millions of B cells to find rare antibodies in just a few weeks.

After identification of top mAb development candidates, our proprietary AI-driven protein engineering technology, dAIsYTM, is used to generate libraries of mAb variants which are further screened using functional assays, as well as screened for favorable pharmacokinetic and manufacturability properties. Top mAb variants may be recombined as the basis for new libraries, in iterative cycles to identify the lead antibody sequence.

Precision Antibody Engineering to Create the Best Medicines

Our strategy is to optimize both the Fab and Fc domains of mAbs using our proprietary AI-driven engineering approach to generate the best medicine to treat or prevent a broad range of infectious and non-infectious diseases. Once we isolate a rare, fully human antibody via High Throughput Isolation, we then engineer the Fab and Fc domains, to enhance expected efficacy, potency and manufacturability. The Fab portion binds to the target antigen of interest. The Fc portion binds to effector proteins and cells in the body to engage the immune system in killing and clearing targeted cells.

Fab engineering is performed to further increase mAb potency and breadth of coverage. MAb potency and breadth depend on the epitope targeted, affinity of binding and valency. In some cases, it may be valuable to create mAbs that bind to more than one epitope, so-called “multi-specific” mAbs, by engineering the Fab region using a wide range of proprietary and non-proprietary formats.

Effector functions can be enhanced or reduced via Fc mutations that alter the binding affinity of the Fc domain of a mAb to the various FcRs, based on a detailed understanding of the role of individual FcRs in immunity. Fc engineering selects and optimizes the specific ways in which mAbs engage FcRs, which in turn govern properties such as the half-life of the antibody as well as “effector functions,” i.e. the way that the immune system is recruited by the mAb to fight infection or kill other target cells. The Fc engineering of our mAbs fine tune the interactions with activating and inhibiting FcRs, which are differentially expressed on immune cells, and takes into account the FcgR polymorphisms in the human population, to generate mAbs tailored for specific indications.

Examples of immunity that can be altered via Fc engineering include the recruitment of serum proteins to infected areas, phagocytosis and destruction of viruses and viral particles, the killing of target cells through a process known as ADCC and the presentation of antigens to elicit potentially long-lasting B and T cell immunity.

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Antibodies as T Cell Vaccines

We are using Fc engineering to create antibodies that are designed to not only directly treat or prevent infection but also to elicit an effective adaptive immune response against chronic viral infections, such as HBV or HIV. We refer to this property as a vaccinal effect, i.e., eliciting continued protection even after the mAb is no longer present. This technology benefits from the fact that FcRs on specialized antigen-presenting cells, which are called dendritic cells, or DCs, internalize complexes of antibody and antigen. Our strategy leverages the observation that different FcRs on antigen presenting cells can bind differentially to the Fc portion of the mAb. By engineering the Fc region, we can therefore select which FcRs preferentially interact with the antibody-antigen complex to generate activated DCs that we believe can mediate an effective and durable T cell immunity.

Specific vaccinal mutations in the Fc domain can enhance immune responses to a pathogen in two ways. First, the mAb can deliver increased amounts of antigen to DCs. Second, FcRs deliver signals that activate DCs. In turn, activated DCs can stimulate T cells specific to the delivered antigen, resulting in T cell immunity. In this way, an antibody with vaccinal Fc mutations can potentially actively immunize infected patients. The in vivo data supporting enhancement of the vaccinal effect through Fc mutants has been demonstrated by others, e.g. in a CD20 positive tumor model, using mice with humanized Fc receptors. In this experiment, anti-CD20 mAbs and CD20 tumor cells were administered to mice months before being later rechallenged with a lethal dose of CD20 tumor cells. Most of the mice (80%) who received a mAb with Fc mutants that enhanced binding to activating FcRs IIa and IIIa survived. Conversely, 70% or more mice who received a mAb without the enhancing Fc mutations died. This durable protection is believed to be the result of the induction of a protective T-cell response. We have also generated similarly compelling animal data in the context of influenza infection, in which vaccinal antibodies induced CD8 T cell responses. We are testing this technology in chronic HBV infection with tobevibart, and if it performs as expected at mediating HBV functional cure, we believe the technology could be used similarly with other mAbs to control other chronic infections, including HIV.

T Cell-Based Viral Vector Platform

We are exploiting the unique immunology of HCMV, a commonly occurring virus in humans, as a vaccine vector to potentially prevent and treat infection by pathogens refractory to current vaccine technologies. HCMV infects a large proportion of the human population and causes a life-long asymptomatic infection that typically causes no harm. This is due to millions of years of co-evolution between the virus and host in which the virus evades sterilizing immunity using specialized viral genes, while at the same time allowing the generation of certain T cell responses that prevent HCMV infection from becoming lethal.

Overview

We have modified the HCMV genome to express proteins from HIV and HPV. This approach is based on fundamental observations made in NHPs, with vaccine vectors made from rhesus cytomegalovirus, or RhCMV. HCMV is the most potent known inducer of T cell responses of any human virus and may induce potent and long-lasting T cell responses to a broader range of epitopes than observed for other viral vaccines. In addition, we can make proprietary modifications in the HCMV genome that we expect will elicit different types of pathogen-appropriate T cell responses. We term this approach “immune programming.” We believe this platform may also have applicability beyond infectious diseases, potentially to cancers that can be controlled by T cells that recognize tumor antigens.

We expect the following benefits from using HCMV as a platform:

•Highly potent and long-lived T cell responses throughout the body, targeting the antigens of interest;

•Induction of high numbers of specialized T cells, known as effector memory cells, that are present in tissues and allow control of infection in the first few days;

•Immune responses to three- to four-fold more antigenic epitopes in a target protein than other viral vectors;

•Programmable T cell responses allowing selection of the type of T cells elicited;

•Opportunity for repeated vaccination using the same backbone HCMV vector against different infections;

•Opportunity to use the same HCMV vector to protect against or treat multiple pathogens; and

•Potential to induce responses even to proteins that the host is tolerant of, such as self-proteins expressed in a tumor.

VIR-1111, VIR-1388 and VIR-1949 were generated using our T cell platform.

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Our Approach

We believe that the type of T cell response elicited by an HCMV-based vaccine vector can be selected by mutating certain genes in HCMV. We term this approach “immune programming.” We believe that immune programming is critical to combating infections such as HIV and TB that have proven intractable, to date, for other vaccine technologies.

The unique immunology of HCMV depends on the virus’s ability to elicit high frequencies of memory T cells, especially tissue-trafficking T cells and to regulate the normal immune processes of antigen presentation by major histocompatibility complex, or MHC proteins. The MHC proteins, class I, class II and MHC-E (called HLA proteins in humans) bind small peptide fragments on the surfaces of antigen presenting cells that are detected by T cells. HCMV contains multiple genes that regulate many of the steps in antigen presenting cells that elicit T cell immunity by altering antigen presenting cell biology, the types of antigen presenting cells infected by the viral vaccine and the mechanisms responsible for the ability of a T cell to recognize antigens together with MHC molecules. Through manipulation of the HCMV genome, we believe we can program different types of pathogen-appropriate T cell responses.

Immune programming and protection from lethal challenge were observed in NHPs vaccinated with RhCMV vectors against SIV and TB. An RhCMV vaccine with genome changes favoring T cell detection of peptide fragments bound by MHC-E protected more than half of NHPs from infection when challenged with a highly virulent form of SIV, whereas all animals in the control group became infected. RhCMV vaccines manipulated to generate T cells that detected peptides bound to MHC-I were not protective, demonstrating the potential value of a programmable T cell vaccine platform. Protection has also been observed against TB in preclinical studies of NHPs after immunization with either of two RhCMV vaccines. Modifications to one of the protective vaccines elicited T cells that recognized peptides plus MHC-II and MHC-E responses, while the other was programmed to elicit a T cell response against peptides attached to MHC-I. This shows the potential significance of being able to specifically program a vaccine to elicit T cells that will be most effective against a given infection, as the programming of a vaccine to protect against SIV can be different from the programming of a vaccine to protect against TB. These preclinical data supported our use of the HCMV T cell platform to vaccinate against HIV and TB.

The Bill & Melinda Gates Foundation is providing funds for the process development and manufacturing and early clinical development of our HIV vaccine program.

MHC-E as a Near-Universal Target for Medicines that Leverage T Cell Receptors

T cells need to be able to recognize a highly diverse set of pathogen proteins to be effective. This diversity comes from the use of multiple different host immune response major histocompatibility complex (MHC) proteins to present foreign antigens to T cells. The genes for HLA class I and to a lesser extent the HLA class II are highly variable between individuals, while HLA-E genes are less variable between individuals. The immune response MHC genes that are highly variable between individuals are responsible for eliciting most T cell responses. These MHC molecules enable T cells to recognize foreign proteins through the use of a specific T cell receptor (TCR) on the T cell surface. The programmed T cell responses elicited by HCMV vectors with certain gene modifications are predicted to use MHC -E, which may have advantages when MHC class I proteins have been blocked on infected cells and tumors. T cells with TCRs recognizing antigenic peptides together with MHC-E may be functional when typical T cell responses are not functional and potentially allow for the generation of universal TCR-based medicines beyond vaccines, such as off-the-shelf cancer T cell therapy.

Our Collaboration, License and Grant Agreements

Collaboration Agreements with GSK

2020 Collaboration Agreement with GSK

In June 2020, we entered into a definitive collaboration agreement with GSK, or the 2020 GSK Agreement, pursuant to which we agreed to collaborate to research, develop and commercialize products for the prevention, treatment and prophylaxis of diseases caused by SARS-CoV-2, the virus that causes COVID-19, and potentially other coronaviruses. The collaboration initially focused on the development and commercialization of three types of collaboration products under three programs: (1) antibodies targeting SARS-CoV-2, and potentially other coronaviruses, or the Antibody Program; (2) vaccines targeting SARS-CoV-2, and potentially other coronaviruses, or the Vaccine Program, and (3) products based on genome-wide CRISPR screening of host targets expressed in connection with exposure to SARS-CoV-2, and potentially other coronaviruses, or the Functional Genomics Program. The initial antibodies under the Antibody Program are sotrovimab and VIR-7832.

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The original 2020 GSK Agreement contained the following key terms. For a period of four years beginning April 2020, the parties agreed to conduct certain research and development activities under mutually agreed development plans and associated budgets for each of the three programs, and under the oversight of a joint steering committee, or JSC. During such period, generally, subject to certain rights granted to WuXi Biologics (Hong Kong) Limited, or WuXi Biologics, under then existing agreements between us and WuXi Biologics, the parties would have an exclusive research collaboration with respect to antibody products directed to SARS-CoV-2 or to any other coronavirus, and in connection with functional genomics CRISPR screens for drug discovery and development in connection with SARS-CoV-2 or other coronaviruses. We are primarily responsible for the development and clinical manufacturing activities for the Antibody Program, and for conducting the initial development activities directed to a vaccine in the Vaccine Program. GSK is primarily responsible for the commercialization activities for the Antibody Program (except in connection with sales of antibody products licensed to WuXi Biologics in mainland China, Hong Kong, Macau and Taiwan), the later-stage development, manufacturing and commercialization activities for the Vaccine Program and the development, manufacturing and commercialization activities for the Functional Genomics Program. We and GSK are required to use commercially reasonable efforts to conduct the activities assigned to each party under each development plan and to seek and obtain regulatory approval for collaboration products that arise from such activities in the United States and specified major markets. Subject to an opt-out mechanism, we and GSK share all development costs, manufacturing costs and costs and expenses for the commercialization of the collaboration products, with us bearing 72.5% of such costs for the antibody products, 27.5% of such costs for the vaccine products, and we and GSK sharing equally all such costs for the functional genomics products, and all profits will be shared in the same ratios. If we and GSK elect to conduct a technology transfer of manufacturing technology under our agreement with WuXi Biologics (as further described below), we will bear 72.5% of the costs related to such manufacturing technology transfer and for commercial manufacturing of the antibody products under such agreement with WuXi Biologics, and GSK will bear 27.5% of such costs. The parties will also share the committed costs for the reservation of manufacturing capacity for the drug substance for antibody products in the foregoing ratio under our agreement with Samsung Biologics as well as such costs relating to committed manufacturing capacity for antibody products as are approved by the JSC from time to time.

On a collaboration product-by-collaboration product basis, each party has the one-time right, at specified points in development, to opt out of its co-funding obligations, and the other party may, at its election, either pursue such program unilaterally, or also cease research and development activities and funding of such collaboration product. If the opt-out provisions are not exercised by either party subject to the terms of the 2020 GSK Agreement, the parties share all profits and losses arising from any collaboration product in the same ratios in which the parties bore development costs for such collaboration program. For each collaboration product as to which a party exercises its opt-out right, the commercializing party pays to the opt-out party royalties on net sales of the applicable collaboration product at rates based on factors such as the stage of development of such collaboration product at the time the opt-out party exercises such right, and whether the opt-out party is the lead party, or a portion of the sublicense revenue if the commercializing party chooses to sublicense or otherwise divest rights to such collaboration product. On an antibody product-by-antibody product basis, we have a co-promotion right for such antibody product in the United States, under which we have the right to perform up to 20% of details in connection with such antibody product. GSK will lead commercialization and book all sales and is required to use commercially reasonable efforts to commercialize each collaboration product following regulatory approval in the United States and specified major markets. This definitive agreement superseded and replaced the April 2020 preliminary agreement with GSK. In connection with the 2020 GSK Agreement, we also entered into a stock purchase agreement in April 2020, pursuant to which we issued 6,626,027 shares of our common stock to Glaxo Group Limited, or GGL, an affiliate of GSK, at a price per share of $37.73, for an aggregate purchase price of approximately $250.0 million.

The 2020 GSK Agreement as amended will remain in effect with respect to each collaboration program for as long as there is a collaboration product being developed or commercialized by the lead party, or the non-opt-out party, in such program. Either party has the right to terminate the 2020 GSK Agreement in the case of the insolvency of the other party, an uncured material breach of the other party with respect to a collaboration program or collaboration product, or as mutually agreed by the parties.

In December 2021, Beecham S.A. assigned and transferred all its rights, title, interest, and benefit in the 2020 GSK Agreement to GlaxoSmithKline Biologicals S.A., including all its rights to bring claims under such agreement.

On May 27, 2022, we entered into Amendment No. 1 to the 2020 GSK Agreement, or Amendment No. 1. Pursuant to Amendment No. 1, we and GSK acknowledged that the antibody products that had been licensed to WuXi Biologics in mainland China, Hong Kong, Macau and Taiwan and had reverted to us pursuant to the Termination Agreement (described below) and agreed with GSK that they are now included in and governed by the 2020 GSK Agreement, subject to certain amendments relating to sotrovimab.

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Under the terms of Amendment No. 1, GSK has the sole right to develop (including to seek, obtain or maintain regulatory approvals), manufacture and commercialize sotrovimab in and for mainland China, Hong Kong, Macau and Taiwan at GSK’s sole cost and expense (other than certain payments for which we remain responsible under certain of our existing agreements with third parties). GSK paid us a one-time upfront payment of $7.0 million in consideration for the rights and licenses granted to GSK under Amendment No. 1. In addition, GSK will be obligated to pay us tiered royalties on net sales of sotrovimab in mainland China, Hong Kong, Macau and Taiwan in percentages ranging from the high teens to the low thirties. Such royalties are payable to us during the term of the 2020 GSK Agreement applicable to the Antibody Program.

On February 8, 2023, we and GSK entered into Amendment No. 2 and Amendment No. 3 to the 2020 GSK Agreement. Pursuant to Amendment No. 2 to the 2020 GSK Agreement, effective as of March 31, 2022, or the Effective Date, we and GSK agreed to remove the Vaccine Program from the 2020 GSK Agreement, and to wind down and terminate the cost-sharing arrangements and all ongoing activities in relation to the Vaccine Program. As of the Effective Date, the Vaccine Program had not yet advanced to its predefined development candidate stage. We retain the right to progress development of vaccine products directed to SARS-CoV-2 and other coronaviruses independently (including with or for third parties) outside the scope of the 2020 GSK Agreement, subject to the payment of tiered royalties to GSK on net sales of any vaccine products covered by certain GSK intellectual property rights in the low single digits, subject to certain deductions in certain circumstances. Pursuant to Amendment No. 3 to the 2020 GSK Agreement, we and GSK agreed to modify the Antibody Program to remove from the collaboration all coronavirus antibodies other than sotrovimab and VIR-7832, and certain variants thereof. Sotrovimab and VIR-7832, and certain variants thereof, remain subject to the terms of the 2020 GSK Agreement, and we retain the sole right to progress the development and commercialization of the terminated antibody products independently (including with or for third parties), subject to the payment of tiered royalties to GSK on net sales of such terminated antibody products at percentages ranging from the very low single digits to the mid-single digits, depending on the nature of the antibody product being commercialized, and subject to certain deductions in certain circumstances.

2021 Expanded GSK Collaboration

In May 2021, we entered into the 2021 GSK Agreement under which the parties agreed to expand the 2020 GSK Agreement, to include collaboration on three separate programs: (1) a program to research, develop and commercialize mAbs for the prevention, treatment or prophylaxis of the influenza virus, or the Influenza Program, excluding VIR-2482 unless GSK exercises its exclusive option (the VIR-2482 Option) to co-develop and commercialize after the Company completes a Phase 2 clinical trial; (2) an expansion of the parties' current Functional Genomics Program to focus on functional genomics screens directed to targets associated with respiratory viruses, or the Expanded Functional Genomics Program; and (3) additional programs to develop neutralizing mAbs directed to up to three non-influenza target pathogens selected by GSK, or the Selected Pathogens, and such programs, or the Additional Programs.

In connection with the 2021 GSK Agreement, we entered into a stock purchase agreement with GGL pursuant to which we issued 1,924,927 shares of our common stock to GGL for an aggregate purchase price of approximately $120.0 million. The 2021 GSK Agreement superseded and replaced the preliminary agreement entered into with GSK in February 2021, or the 2021 Preliminary Agreement.

On February 21, 2024, the Company and GSK entered into a letter agreement (the “Letter Agreement”) pursuant to which the Company and GSK agreed to remove the Influenza Program from the 2021 GSK Agreement and to wind down and terminate the cost-sharing arrangements and all ongoing activities in relation to the Influenza Program. As of the effective date of the Letter Agreement, GSK had not exercised the VIR-2482 Option.

As it relates to the Expanded Functional Genomics Program and Additional Programs, for a period of three years following the effective date of the 2021 GSK Agreement, or the Research Term, the parties will conduct certain research and development activities under mutually agreed development plans and associated budgets for the programs within the expanded collaboration. Subject to certain exceptions, we will exclusively collaborate with respect to (a) functional genomic screens for targets associated with respiratory viruses during the Research Term, and compounds or products developed through the Expanded Functional Genomics Program directed to a collaboration target for five years following the target selection (unless either party elects to opt-out earlier), and (b) products directed to Selected Pathogens during the Research Term, which ends in 2024.

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We will mutually agree upon the allocation of responsibility for the development of products under the Expanded Functional Genomics Program, and for the development and early-stage manufacturing of products under the Additional Programs if and when GSK decides which Selected Pathogens to pursue. GSK will be primarily responsible for commercial manufacturing and commercialization activities for products under the Expanded Functional Genomics Program and Additional Programs, if and when selected by GSK. For each collaboration program, upon execution of the definitive agreement, we will grant GSK certain license rights related to the development, manufacturing and commercialization of products arising from the program.

The parties will share 50% of all development costs in accordance with the budget for each of the collaboration programs, with each party having the right (on a target-by-target, or collaboration product-by-collaboration product basis, as applicable) to opt-out of its co-funding obligations at specified points in development. In such case, the party continuing with the program will pay to the opt-out party a royalty on net sales of products arising from such program at specified rates based on the stage of development at which the opt-out is exercised. Following the exercise of an opt-out right by a party the other party may, at its election, either pursue development and commercialization of such product or program unilaterally, or also cease the conduct and funding of such collaboration product or program. In the absence of any opt-out, the parties will also share 50% of all profits and losses arising from any collaboration product. Each party is required to use commercially reasonable efforts to conduct the activities assigned to it under each development plan and, where applicable, to seek and obtain regulatory approval for collaboration products that arise from such activities in the United States and specified major markets. GSK will lead commercialization and book all sales, and is required to use commercially reasonable efforts to commercialize each collaboration product following regulatory approval in the United States and specified major markets.

GSK made an upfront payment to us of $225.0 million, 50% became payable at the effective date of the 2021 Preliminary Agreement and 50% of became payable following the execution of the 2021 GSK Agreement.

In September 2022, GSK exercised its first Selected Pathogen Right, selecting RSV as its first pathogen under the Additional Programs of the 2021 GSK Agreement. GSK agreed to retroactively share the research and development costs that we had incurred under its RSV program since April 2022 in accordance with the applicable provisions of the 2021 GSK Agreement. GSK can select up to two additional non-influenza target pathogens prior to March 25, 2024.

With respect to each Additional Program, unless earlier terminated, the 2021 GSK Agreement will remain in effect for as long as there is a product from such collaboration program being developed or commercialized by the lead party in the collaboration program or by the non-opt-out party, if applicable. With respect to the Expanded Functional Genomics Program, unless earlier terminated, the 2021 GSK Agreement will remain in effect (a) until the end of the Research Term, if no targets are selected for the Expanded Functional Genomics Program prior to the end of the Research Term, or (b) if at least one target is selected for the Expanded Functional Genomics Program prior to the end of the Research Term, for as long as there is a product from the Expanded Functional Genomics Program being developed or commercialized by the lead party in the Expanded Functional Genomics Program or by the non-opt-out party, if applicable. Either party has the right to terminate the 2021 GSK Agreement in the case of the insolvency of the other party, an uncured material breach of the other party with respect to a collaboration program or a collaboration product, or as mutually agreed by the parties.

Collaboration and License Agreement with Alnylam

In October 2017, we entered into a collaboration and license agreement with Alnylam, or the Alnylam Agreement, for the development of siRNA products for the treatment of HBV and following the exercise of certain program options, the development and commercialization of siRNA products directed to up to four other infectious disease targets selected by us. The technology licensed under the Alnylam Agreement forms the basis of our siRNA technology platform.

Pursuant to the Alnylam Agreement, we obtained a worldwide, exclusive license to develop, manufacture and commercialize the HBV siRNA product candidates, including elebsiran, for all uses and purposes other than agricultural, horticultural, forestry, aquaculture and other residential applications, such excluded fields, the Excluded Fields. In addition, Alnylam granted us an exclusive option, for each of the infectious disease siRNA programs directed to our selected targets, to obtain a worldwide, exclusive license to develop, manufacture and commercialize siRNA products directed to the target of each such program for all uses and purposes other than the Excluded Fields. Our options are each exercisable during a specified period following selection of candidates for each program, or two years following the initiation of certain activities under an agreed-upon development plan, if earlier. On a product-by-product basis for each product arising from the HBV and, following our option exercise, the infectious disease programs, Alnylam has an exclusive option, exercisable during a specified period for each such product, to negotiate and enter into a profit-sharing agreement for such product.

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We and Alnylam were jointly responsible for funding the initial research and development activities for elebsiran through completion of proof of concept trials. Prior to the exercise of our option for each siRNA program directed to one of our selected infectious disease targets, Alnylam is responsible for conducting all development activities, at our expense, in accordance with an agreed-upon development plan. Following our exercise of an option for a program and payment of the program option exercise fee and any outstanding program costs due to Alnylam, we are solely responsible, at our expense, for conducting all development, manufacture and commercialization activities for products arising from each such program unless Alnylam exercises its profit-sharing option. We are required to use commercially reasonable efforts to develop and commercialize one siRNA product directed to HBV and one siRNA product directed to the target of each other infectious disease program for which we exercise our option, in each of the major markets. If Alnylam exercises a profit-sharing option for a product, such as elebsiran, we will negotiate the terms of such profit-sharing agreement.

We retain final decision-making authority with respect to which infectious disease product candidates we advance and the development programs for the HBV and infectious disease product candidates, subject to certain limitations. During the term of the Alnylam Agreement, neither we nor Alnylam may develop or commercialize any gene-silencing, oligonucleotide-based product directed to the same target as any product candidate under the Alnylam Agreement, other than pursuant to the Alnylam Agreement, subject to certain exceptions.

Pursuant to the Alnylam Agreement, we paid Alnylam an upfront fee of $10.0 million and issued to Alnylam 1,111,111 shares of our common stock. Upon the achievement of a certain development milestone, as further discussed below, we were obligated to issue shares of our common stock equal to the lesser of (i) 1,111,111 shares or (ii) a certain number of shares based on our stock price at the time such milestone was achieved. We will be required to pay Alnylam up to $190.0 million in the aggregate for the achievement of specified development and regulatory milestones by the first siRNA product directed to HBV, and up to $115.0 million for the achievement of specified development and regulatory milestones for the first product directed to the target of each infectious disease siRNA program for which we exercised our option. Following commercialization, we will be required to pay to Alnylam up to $250.0 million in the aggregate for the achievement of specified levels of net sales by siRNA products directed to HBV and up to $100.0 million for the achievement of specified levels of net sales by products directed to the target of each infectious disease siRNA program for which we exercised our option. We will also be required to pay Alnylam tiered royalties at percentages ranging from the low double-digits to mid-teens on annual net sales of HBV products, and tiered royalties at percentages ranging from the high single-digits to the sub-teen double-digits on annual net sales of licensed infectious disease products, in each case subject to specified reductions and offsets. The royalties are payable on a product-by-product and country-by-country basis until the later of the expiration of all valid claims of specified patents covering such product in such country and 10 years after the first commercial sale of such product in such country. Alnylam is also entitled to receive a portion of any consideration we receive as a result of granting a sublicense under the licenses granted to us by Alnylam under the Alnylam Agreement or an option to acquire such a sublicense, determined based on the timing of the grant of such sublicense. In November 2018, in connection with the inclusion of the HBV siRNA program as the subject of a potential grant of a sublicense to Brii Bio under the Brii Agreement, as defined under the section titled “Collaboration, Option and License Agreement with Brii Bio,” which triggered certain payment obligations under the Alnylam Agreement, we entered into a letter agreement with Alnylam, or the Alnylam Letter, making certain modifications to the payments due to Alnylam as a result of the grant of the option and potential payments that would result from Brii Bio’s exercise of rights under such sublicense. As a result of the rights granted under the Brii Agreement and pursuant to the Alnylam Letter, in February 2020 we transferred to Alnylam a specified percentage of the equity consideration allocable to the HBV siRNA program that we received from Brii Bio and its affiliated companies in connection with the entry into the Brii Agreement.

The term of the Alnylam Agreement will continue, on a product-by-product and country-by-country basis, until expiration of all royalty payment obligations under the Alnylam Agreement. If we do not exercise our option for an infectious disease program directed to one of our selected targets, the Alnylam Agreement will expire upon the expiration of the applicable option period with respect to such program. However, if Alnylam exercises its profit-sharing option for any product, the term of the Alnylam Agreement will continue until the expiration of the profit-sharing arrangement for such product. We may terminate the Alnylam Agreement on a program-by-program basis or in its entirety for any reason on 90 days’ written notice. Either party may terminate the agreement for cause for the other party’s uncured material breach on 60 days’ written notice (or 30 days’ notice for payment breach), or if the other party challenges the validity or enforceability of any patent licensed to it under the Alnylam Agreement on 30 days’ notice.

In March 2020, we achieved one of the specified development milestones relating to elebsiran pursuant to the Alnylam Agreement, as amended. As such, we paid Alnylam $15.0 million in April 2020, and issued Alnylam 1,111,111 shares of our common stock in May 2020.

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In March and April 2020, we entered into two further amendments to the Alnylam Agreement, or the Amended Alnylam Agreement, to expand our existing collaboration to include the development and commercialization of siRNA products targeting SARS-CoV-2 and potentially other coronaviruses, and up to three targeting human host factors for SARS-CoV-2, or collectively, the COVID Collaboration Targets.

In December 2020, we and Alnylam entered into a letter amendment, or the Letter Agreement, further amending the Amended Alnylam Agreement to modify certain funding and governance provisions in connection with the siRNA products directed to the COVID Collaboration Targets, including VIR-2703, or the COV Target, and to modify certain rights of each party with respect to products arising from such programs. Pursuant to the Letter Agreement, Alnylam was responsible for conducting pre-clinical research activities set forth in the existing workplan for the COV Target, or the COV Workplan, at its discretion and sole expense, and we were no longer obligated to reimburse Alnylam for any share of costs incurred by Alnylam in conducting activities under the COV Workplan after July 1, 2020. In July 2021, Alnylam elected to discontinue the development of the COV Target, and all other related research and development activities in accordance with their rights under the Letter Agreement. As a result, the COV Target and the siRNA program related thereto are no longer included within the Amended Alnylam Agreement and all rights to the siRNA program directed to the COV Target reverted to Alnylam.

License Agreements with MedImmune

2012 Sub-License and Collaboration Agreement with MedImmune

In March 2012, our subsidiary Humabs entered into a sub-license and collaboration agreement with MedImmune, LLC, or MedImmune, as amended, or the 2012 MedImmune Agreement, pursuant to which Humabs conducted certain activities under a mutually agreed research plan for the development of therapeutic antibodies directed to influenza viruses (including influenza A and influenza B) and to Klebsiella bacteria. The 2012 MedImmune Agreement was amended in April 2013, April 2015, December 2015, August 2016, July 2017, and September 2018 to designate Klebsiella as an extra target, to extend the term of the research program and provide for related payments, and to incorporate certain research activities funded by MedImmune under a specified government grant. Under the 2012 MedImmune Agreement, as amended, MedImmune obtained a worldwide exclusive license from Humabs to develop and commercialize products directed to such targets for all uses in humans and animals except for active vaccination.

In consideration for the grant of the license, MedImmune made certain upfront payments to Humabs. MedImmune is obligated to pay Humabs development, regulatory and commercial milestone payments of up to $96.5 million in the aggregate for the first product directed to influenza viruses to achieve the applicable milestones, and up to $12.0 million for the first product directed to Klebsiella to achieve the applicable milestones. MedImmune will also be obligated to pay royalties based on net sales of products directed to influenza viruses or Klebsiella at certain fixed percentages in the low to mid-single-digits, with the rate determined based on the specific target to which the product is directed, in each case subject to specified reductions and a royalty floor. The royalties are payable, on a product-by-product and country-by-country basis, until the later of the last to expire valid claim that would, but for the licenses granted under the 2012 MedImmune Agreement, be infringed by the sale of such product in such country, and 10 years from the first commercial sale of the first product in such country. MedImmune also made certain payments to Humabs in consideration for Humabs’ conduct of the research program. We will be obligated to pass through the milestone payments and royalty payments that we receive under the 2012 MedImmune Agreement, following deduction of certain expenses incurred by us or Humabs thereunder, to Humabs’ securities holders pursuant to the Humabs SPA, as defined under the section titled “—Securities Purchase Agreement with Humabs.”

The 2012 MedImmune Agreement will remain in force until MedImmune has fulfilled all of its obligations to make milestone and royalty payments. MedImmune may terminate the 2012 MedImmune Agreement in its entirety, or on a product-by-product, license-by-license or country-by-country basis, for convenience, upon 90 days’ notice. Either MedImmune or Humabs may terminate the 2012 MedImmune Agreement for the other party’s uncured material breach or in the event of bankruptcy of the other party.

2018 License Agreement with MedImmune

In September 2018, we entered into a license agreement with MedImmune, or the 2018 MedImmune Agreement, pursuant to which we obtained a worldwide, exclusive license to develop and commercialize half-life extended versions of two specified antibodies under development by MedImmune that target influenza A and influenza B, respectively, for all uses in humans and animals. The license from MedImmune includes the grant of a sublicense under MedImmune’s license to certain intellectual property controlled by Humabs that was granted to MedImmune pursuant to the 2012 MedImmune Agreement.

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Under certain circumstances and during certain periods of time we have the right to nominate up to two variants of each of these antibodies for inclusion under the license. MedImmune retained the rights to continue to develop and to commercialize the two specified antibodies that target influenza A and influenza B, in each case that are not the half-life extended versions that are licensed to us. Additionally, we obtained a worldwide, exclusive license under MedImmune’s antibody half-life extension technology to develop and commercialize half-life extended antibodies directed to up to two additional targets selected by us for all uses in humans or animals for the prevention, treatment or diagnosis of infectious diseases and had the right to nominate such additional targets during a specified period following the effective date of the 2018 MedImmune Agreement. We are solely responsible, at our sole cost, for the development of products containing half-life extended versions of antibodies directed to the influenza targets and any additional selected targets, and are obligated to use commercially reasonable efforts to develop and obtain regulatory approval for at least one product containing half-life extended versions of antibodies directed to each of influenza A, influenza B and any additional targets, if applicable, in the United States and specified markets in Europe and Asia. We are also obligated to use commercially reasonable efforts to commercialize products containing half-life extended versions of antibodies directed to such targets in such markets. .

In consideration for the grant of the licenses under the 2018 MedImmune Agreement, we made an upfront payment to MedImmune of $10.0 million. We will be obligated to make development and regulatory milestone payments to MedImmune of up to $92.0 million, of which $5.0 million was paid in the third quarter of 2019, in the aggregate for products containing half-life extended versions of antibodies directed to influenza A that we licensed, up to an additional $39.2 million in the aggregate for such products directed to influenza B that we licensed, and up to $250,000 in the aggregate for certain specified products directed to the additional selected targets, if applicable. We will also be required to make sales-related milestone payments to MedImmune following commercialization up to an aggregate of $200.0 million for the achievement of specified levels of aggregate annual net sales of products containing half-life extended versions of antibodies directed to influenza A and/or influenza B. MedImmune will also be entitled to receive tiered royalties based on net sales of products containing half-life extended versions of antibodies directed to influenza A and/or influenza B at percentages ranging from the mid-single-digits to sub-teen double-digits and a royalty based on net sales of products containing half-life extended versions of antibodies directed to any additional selected targets, if applicable, at a percentage in the low single-digits, in each case subject to specified reductions. These royalties are payable, on a product-by-product and country-by-country basis, until the latest to occur of expiration of the last to expire valid claim covering such product in such country, expiration of regulatory exclusivity for such product in such country, and 12 years after the first commercial sale of such product in such country. Additionally, we are responsible for paying any royalties due under the 2012 MedImmune Agreement as a result of our commercialization of products under the 2018 MedImmune Agreement.

The 2018 MedImmune Agreement will remain in force until the expiration on a country-by-country and product-by-product basis of all of our obligations to pay royalties to MedImmune. We may terminate the 2018 MedImmune Agreement in its entirety or on a product-by-product basis, for convenience, upon 120 days’ notice. Either party may terminate the 2018 MedImmune Agreement for cause for the other party’s uncured material breach on 60 days’ notice or immediately in the event of bankruptcy of the other party. Additionally, MedImmune may terminate the 2018 MedImmune Agreement for cause on 30 days’ written notice if we challenge the validity or enforceability of the patents to which we have obtained a license under the 2018 MedImmune Agreement.

Master Exclusive License Agreement with OHSU

In June 2012, our subsidiary TomegaVax, Inc., or TomegaVax, entered into a master exclusive license agreement, or the OHSU Agreement, with Oregon Health & Science University, or OHSU. The OHSU Agreement was revised and restated in August 2014 and again in August 2019, at which time we assumed TomegaVax’s rights and obligations as licensee under the OHSU Agreement. Under the OHSU Agreement, we obtained a worldwide exclusive license under certain patent rights and a non-exclusive license under certain know-how to make, have made, use, offer to sell, sell, have sold and import certain products relating to CMV vectors in all fields of use. The OHSU Agreement provides for us to include within the license grant additional patent or know-how rights covering certain inventions arising at OHSU and relating to the use of CMV vaccine vectors through the execution of technology addenda, each such addendum, a Technology Addendum. Each Technology Addendum relates to one or more invention disclosures and their corresponding patent family or know-how rights. During the term of the OHSU Agreement to date, we have entered into 17 such Technology Addenda. We must use reasonably diligent efforts to develop and commercialize the CMV vector products consistent with its reasonable business practices and judgment, including by achieving certain specified development and regulatory milestones within certain periods. We use technology licensed under the OHSU Agreement in our T cell platform and in our product candidate VIR-1111.

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Pursuant to the initial entry into the OHSU Agreement and certain of the Technology Addenda, TomegaVax issued a specified percentage of its then outstanding common stock to OHSU, which was subsequently exchanged for shares of our common stock as a result of our acquisition of TomegaVax in September 2016. In connection with the second revision and restatement of the OHSU Agreement in August 2019, we issued an additional specified number of shares of our common stock to OHSU. We are obligated to pay OHSU up to $1.3 million upon the achievement of certain development and regulatory milestones for each CMV vector product, and up to $2.0 million upon the achievement of certain aggregate annual net sales milestones for all CMV vector products. We will also be required to pay OHSU a royalty in the low single-digits on net sales of licensed products on a product-by-product basis, subject to specified reductions and offsets, and specified minimum annual royalty payments. The royalties are payable, on a product-by-product and country-by-country basis, until the later of (a) the expiration of all valid claims in the licensed patents covering such product in the country of sale or country of manufacture, as applicable, and (b) 10 years after the first commercial sale of such product in the country of sale. OHSU is also entitled to receive a specified percentage of any consideration received by us as a result of the grant of a sublicense under the rights granted under the OHSU Agreement, with the applicable percentage based on the development stage of the applicable program at the time of the grant of the sublicense.

The OHSU Agreement will remain in force until the expiration of all licensed patent rights or 10 years after the effective date of the last Technology Addendum, whichever is the later. Each individual Technology Addendum remains in force until the expiration of the patent rights to which it applies, or 10 years after the effective date of such Technology Addendum, whichever is later. Either party may terminate the OHSU Agreement, or any individual Technology Addendum, for the other party’s uncured material breach on 60 days’ written notice, which may be extended by an additional 120 days under certain conditions. The OHSU Agreement and each Technology Addendum also terminate in the event of bankruptcy of either party. We may also terminate the OHSU Agreement in its entirety, or any Technology Addendum individually, upon 60 days’ notice. OHSU may immediately terminate the OHSU Agreement if we or our sublicensees bring any action or proceeding against OHSU, subject to certain exceptions.

Exclusive License Agreement with the Institute for Research in Biomedicine

In December 2011, Humabs Holdings GmbH, or Humabs Holdings, the former parent company of our subsidiary Humabs, entered into an exclusive license agreement, or the IRB Agreement, with the Institute for Research in Biomedicine, or IRB. The IRB Agreement amended and restated an original 2004 exclusive license agreement between the parties in connection with IRB’s proprietary technologies relating to human monoclonal antibodies and the discovery of unique epitopes recognized by such antibodies. In May 2008, Humabs entered into an exclusive license agreement with IRB, or the Humabs IRB Agreement, and together with the IRB Agreement, the Current IRB License Agreements. Pursuant to the Humabs IRB Agreement, IRB granted to Humabs an exclusive license under certain intellectual property rights for the development of certain monoclonal antibodies. Following the entry into the Humabs IRB Agreement, in February 2012, Humabs and IRB entered into a research agreement, or the IRB Research Agreement, concurrently with the termination of an original research agreement dated July 2004 between Humabs Holdings and IRB, to provide for a continuing research collaboration between Humabs and IRB, and to coordinate the exploitation of intellectual property rights arising from the IRB Research Agreement with the rights granted under the Current IRB License Agreements. Under the terms of the IRB Research Agreement, IRB performs certain research activities for Humabs, and all intellectual property rights arising under the IRB Research Agreement are either owned by Humabs, or included in and licensed to Humabs pursuant to the terms of the Current IRB License Agreements. In August 2017, we acquired all of the share capital of Humabs as described further below. Prior to the closing of such acquisition, Humabs Holdings was consolidated into Humabs, such that Humabs Holdings ceased to exist as a separate legal entity, and Humabs became the successor-in-interest to Humabs Holdings’ rights under the IRB Agreement. As a result, Humabs is the licensee under each of the Current IRB License Agreements.

We use technology licensed under the Current IRB License Agreements in our antibody platform and in our product candidates VIR-2482 and tobevibart.

Pursuant to the Current IRB License Agreements, IRB granted to Humabs an exclusive, worldwide, royalty-bearing, sublicensable license under patent and know-how rights covering or associated with IRB’s proprietary technology platform relating to antibody discovery, as well as rights in certain antibodies, including as a result of activities under the IRB Research Agreement, in each case for all purposes, including to practice the licensed technology platform, and to develop, manufacture and commercialize any drug, vaccine or diagnostic product containing such licensed antibodies.

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Humabs is required to use commercially reasonable efforts to develop and commercialize licensed products, and must maintain an active program to commercialize licensed products. Humabs is required to pay to IRB a flat royalty on net sales of licensed products approved for non-diagnostic use in the low single-digits, and a flat royalty on licensed products for diagnostic use at 50% of the non-diagnostic product rate, in each case subject to standard reductions and offsets. A single royalty stream is payable on products that include the licensed antibodies (including antibodies that are owned by Humabs, but developed using the licensed technology), irrespective of whether a given product is covered by patents under both of the Current IRB License Agreements. Humabs’ obligation to pay royalties to IRB, on a country-by-country basis, is reduced upon the expiration of the relevant patents in such country, and expires 10 years after the date of first commercialization of a licensed product in such country. Humabs is also required to pay to IRB a specified percentage in the sub-teen double-digits of consideration received in connection with the grant of a sublicense to a non-affiliate third party, subject to a specified maximum dollar amount for the first up front or milestone payment received under such sublicense for each licensed product, and a lower specified maximum dollar amount for subsequent up front or milestone payments for such licensed product.

Each of the Current IRB License Agreements remains in force until the expiration of all valid claims of the licensed patent rights and trade secrets included in the licensed IRB know-how. Humabs may terminate the IRB Agreement at will on 90 days’ written notice to IRB, and either party may terminate either of the Current IRB License Agreements on 60 days’ written notice for the uncured material breach of the other party.

Exclusive License Agreement with The Rockefeller University

In July 2018, we entered into an exclusive license agreement with The Rockefeller University, or Rockefeller, which was amended in May 2019, in September 2020, and in March 2021, or the Rockefeller Agreement. Pursuant to the Rockefeller Agreement, Rockefeller granted us a worldwide exclusive license under certain patent rights, and a worldwide non-exclusive license under certain materials and know-how covering certain antibody variants relating to a specified mutation leading to enhanced antibody function and utility, to develop, manufacture and commercialize infectious disease products covered by the licensed patents, or that involve the use or incorporation of the licensed materials and know-how, in each case for all uses and purposes for infectious diseases. The licenses granted to us are freely sublicensable to third parties. Rockefeller retains the right to use the licensed patents outside the field of use, and within the field of use solely in connection with educational, research and non-commercial purposes, as well as for certain research being conducted in collaboration with us. We are obligated to grant sublicenses to third parties with respect to products that are not being pursued and are not of interest to us following a specified anniversary of the May 2019 amendment date. Pursuant to the Rockefeller Agreement, we are required to use commercially reasonable efforts to develop and commercialize infectious disease products as soon as reasonably practicable, including by achieving certain specified development milestone events within specified time periods for products arising from our HBV and influenza programs.

We use technology licensed under the Rockefeller Agreement in our antibody platform and in our product candidates tobevibart.

We paid Rockefeller an upfront fee of $0.3 million for entry into the Rockefeller Agreement, and are required to pay annual license maintenance fees of $1.0 million, which will be creditable against royalties following commercialization. In addition, for the achievement of specified development, regulatory and commercial success milestone events, we will be required to pay up to $80.3 million, in the aggregate, for up to six infectious disease products. Any follow-on products beyond six products may result in additional milestone event payments. We will also be required to pay to Rockefeller a tiered royalty at a low single-digit percentage rate on net sales of licensed products, subject to certain adjustments. Our obligation to pay royalties to Rockefeller will terminate, on a product-by-product and jurisdiction-by-jurisdiction basis, upon the latest of the expiration of the last valid claim of a licensed patent in such jurisdiction, the expiration of all regulatory exclusivity in such jurisdiction or 12 years following the first commercial sale of the applicable licensed product in such jurisdiction. If we grant a sublicense to a non-affiliate third party under the Rockefeller technology, we will be required to pay to Rockefeller a specified percentage of the consideration received from such sublicensee for the grant of the sublicense, depending on the date of receipt of the applicable sublicense income from such sublicensee.

The Rockefeller Agreement will remain in force, absent earlier termination, until the expiration of all of our obligations to pay royalties to Rockefeller in all jurisdictions. We have the right to terminate the Rockefeller Agreement in its entirety, or in part, for any reason on 60 days’ written notice to Rockefeller. Rockefeller may terminate the Rockefeller Agreement on 90 days’ written notice for our uncured material breach, or if we challenge the validity or enforceability of any of the licensed patents, or immediately in the event of our insolvency. Rockefeller may also terminate the Rockefeller Agreement if we cease to carry on business with respect to the rights granted to us under the agreement.

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Collaboration, Option and License Agreement with Brii Bio

In May 2018, we entered into a collaboration, option and license agreement with Brii Biosciences Limited (previously named BiiG Therapeutics Limited), or Brii Bio Parent, and Brii Bio, and such agreement, the Brii Agreement, pursuant to which we granted to Brii Bio, with respect to up to four of our programs (excluding mAbs in Vir’s active research and development program against coronaviruses), an exclusive option to obtain exclusive rights to develop and commercialize compounds and products arising from such programs in China, Taiwan, Hong Kong and Macau, or collectively the China Territory, for the treatment, palliation, diagnosis, prevention or cure of acute and chronic diseases of infectious pathogen origin or hosted by pathogen infection, or the Field of Use. Our HBV siRNA program being developed under the Amended Alnylam Agreement (described above) is included within the Brii Agreement as a program for which Brii Bio may exercise one of its options. Brii Bio may exercise each of its options following the achievement by us of proof of concept for the first product in such program. In partial consideration for the options granted by us to Brii Bio, Brii Bio Parent and Brii Bio granted us, with respect to up to four of Brii Bio Parent’s or Brii Bio’s programs, an exclusive option to be granted exclusive rights to develop and commercialize compounds and products arising from such Brii Bio programs in the United States for the Field of Use. The number of options that we may exercise for a Brii Bio program is limited to the corresponding number of options that Brii Bio exercises for a Vir program. All options granted to Brii Bio under the Brii Agreement that are not exercised will expire no later than seven years following the effective date, or two years earlier than such date if Brii Bio has not undergone an initial public offering within such shorter period. All options granted to us under the Brii Agreement that are not exercised will expire no later than two years following the expiration of all options granted to Brii Bio.

We are responsible, at our expense and discretion, for the conduct of all development activities under our programs prior to the exercise of Brii Bio’s options, and Brii Bio is responsible, at its expense and discretion, for all activities under its programs prior to the exercise of our options. Following the exercise of an option for a specified program by either us or Brii Bio, the exercising party is granted an exclusive, royalty-bearing license to develop, manufacture and commercialize products arising from the applicable program in the United States (where we are exercising the option) or the China Territory (where Brii Bio is exercising the option), and such party is thereafter responsible for all development and commercialization activities, at its expense, in the optioned territory. If Brii Bio exercises its option with respect to our development program being conducted under the Amended Alnylam Agreement, Brii Bio’s rights will be subject to the terms of such amended agreement.

Under the terms of the Brii Agreement, following our option exercise, we are obligated to use commercially reasonable efforts to develop at least one licensed product arising from each optioned Brii Bio program, and to commercialize each such product in the United States following regulatory approval, and following Brii Bio’s option exercise, Brii Bio is obligated to use commercially reasonable efforts to develop at least one licensed product arising from each optioned Vir program and to commercialize each such product in the China Territory following regulatory approval.

VIR US Equity

VIR · 10-K · period ended 2023-12-31

Item 1. Business.

VIR US Equity☆

VIR · 10-K · period ended 2023-12-31

Item 1. Business.

VIR US Equity