What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2021-02-25 compared with 2020-03-26 · 926 added, 655 removed, 807 unchanged (66% of the section changed)

1 unchanged sentence

We are a clinical-stage immunology company focused on combining immunologic insights with cutting-edge technologies to treat and prevent serious infectious diseases.

Infectious diseases are one of the leading causes of death worldwide and cause hundreds of billions of dollars of economic burden each year.

We believe that now is the time to apply the recent and remarkable advances in immunology to combat infectious diseases.

Infectious diseases are one of the leading causes of death worldwide and can cause trillions of dollars of direct and indirect economic burden each year – as evidenced by the current coronavirus disease 2019, or COVID-19 pandemic.

We believe that now is the time to apply the recent and remarkable advances in immunology to combat current and prepare for potential future infectious diseases.

Our approach begins with identifying the limitations of the immune system in combating a particular pathogen, the vulnerabilities of that pathogen, and the reasons why previous approaches have failed.

We then bring to bear powerful technologies that we believe, individually or in combination, will lead to effective therapies.

Our current development pipeline consists of product candidates targeting COVID-19, hepatitis B virus, or HBV, influenza A virus, and human immunodeficiency virus, or HIV.

We have assembled four technology platforms, focused on antibodies, T cells, innate immunity, and small interfering ribonucleic acid, or siRNA, through internal development, collaborations, and acquisitions.

Our current development pipeline consists of product candidates targeting hepatitis B virus, or HBV, influenza A, severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, human immunodeficiency virus, or HIV, and tuberculosis, or TB.

VIR-2218, an HBV-targeting siRNA, has completed enrollment in an ongoing Phase 1/2 clinical trial.

Initial data have demonstrated substantial reduction of hepatitis B virus surface antigen, or HBsAg, and VIR-2218 has been generally well-tolerated.

We are next planning a Phase 2 trial combining VIR-2218 with pegylated interferon-alpha, or PEG-IFN - α, an approved immune modulatory agent.

Additionally, we have initiated a Phase 1/2 clinical trial for VIR-2482, a monoclonal antibody, or mAb, designed for the prevention of influenza A.

We have built an industry-leading team that has deep experience in immunology, infectious diseases and product development.

Given the global impact of infectious diseases, we are committed to developing cost-effective treatments that can be delivered at scale.

Our Technology Platforms

Our four current technology platforms are designed to stimulate and enhance the immune system by exploiting critical observations of natural immune processes.

We are using our platforms to advance product candidates for HBV, influenza A, SARS-CoV2, HIV and TB, as well as to generate additional product candidates for viral, bacterial, fungal and parasitic infections.

Antibody Platform :

We have established a robust method for capitalizing on unusually successful immune responses naturally occurring in people who are protected from, or have recovered from, infectious diseases.

This method uses specialized mAbs which have the potential to treat and prevent rapidly evolving and/or previously untreatable pathogens via direct pathogen neutralization and immune system stimulation.

We identify individuals who have recovered from an infection by the target pathogen, and then use a technology we refer to as High Throughput Isolation to screen hundreds of millions of B cells from those individuals for antibodies with specific properties.

We engineer these fully human antibodies that we discover to enhance their therapeutic potential.

For example, we have engineered our mAbs to potentially act as T cell vaccines, which may enable continued protection from a pathogen even after the mAb is no longer present.

T Cell Platform :

We are exploiting the unique immunology of human cytomegalovirus, or HCMV, a commonly occurring virus in humans, as a vaccine vector to potentially treat and prevent infection by pathogens refractory to current vaccine technologies.

This approach is based on fundamental observations made in non-human primates, or NHPs, with 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 that this platform may also have applicability beyond infectious diseases, to areas such as cancer.

Innate Immunity Platform :

Moving beyond more traditional approaches that are used to evoke adaptive immunity or that directly target pathogens, where the development of resistance can occur, we plan to target host proteins as a means of creating host-directed therapies with high barriers to resistance.

We believe that by leveraging the power of innate immunity, we can create medicines that break the “one-drug-for-one-bug” paradigm by producing “one-drug-for-multiple-bugs.” For example, we believe this platform can create a single product for respiratory viruses, such as respiratory syncytial virus, or RSV, and influenza.

This is enabled using clustered regularly interspaced short palindromic repeats , or CRISPR , -based genomics, computational biology and machine learning to identify key host factors necessary for each pathogen’s survival and the protective effects of the innate immune system.

We then identify product candidates that may be able to safely target host proteins to block pathogen replication or induce innate immunity to control infection.

siRNA Platform :

We are harnessing the power of siRNA to inhibit pathogen replication, eliminate key host factors necessary for pathogen survival and remove microbial immune countermeasures.

Our collaboration with Alnylam Pharmaceuticals, Inc., or Alnylam, includes VIR-2218 for HBV, the recently announced COVID-19 siRNA program, and up to four additional programs in infectious diseases.

This platform can leverage Alnylam’s proprietary N-acetylgalactosamine, or GalNAc, delivery technology, for product candidates targeting the liver, allowing for subcutaneous administration and extended tissue half-life, as well as Enhanced Stabilization Chemistry Plus, or ESC+, technology to enhance stability and minimize off-target activity, which potentially can result in an increased therapeutic index.

Our Development Pipeline

Our current product candidates are summarized in the chart below:

*VIR-1111 is a vaccine designed to establish proof of concept in Phase (Ph) 1 clinical trial to determine whether unique immune response observed in non-human primates can be replicated in humans;

*VIR-7831 IV formulation currently in Phase 3 COMET-ICE trial;

IM formulation currently in Phase 2 COMET-PEAK trial, and pending in Phase 3 COMET-TAIL and COMET-STAR trials.

**Vaccine designed to establish proof of concept in Phase (Ph) 1 clinical trial to determine whether unique immune response observed in non-human primates can be replicated in humans;

ultimately, any candidates we advance as a potential HIV vaccine will require modifications to VIR-1111 before further clinical development.

Investigational New Drug Application.

The substantial impact of viral outbreaks and the lack of global preparedness have been highlighted by the current coronavirus disease 2019, or COVID-19, pandemic.

As of March 24, 2020, there were over 420,000 recorded infections, almost 19,000 recorded deaths, and the virus had spread to 170 countries.

We have identified multiple antibodies that neutralize SARS-CoV-2, the virus that causes COVID-19, and believe that they may be applicable in four specific use cases:

Prevention of disease :

prophylaxis in health care workers or other individuals at high risk of becoming infected as well as prophylaxis for those at high risk of severe disease or death, such as the elderly with co-morbidities.

Prevention of progression to severe disease :

treatment of SARS-CoV-2 infected patients during the early phases of infection prior to onset of severe respiratory distress.

Treatment of severe disease :

treatment of SARS-CoV-2 infected patients with severe respiratory distress or other systemic illness.

Development of vaccines :

understanding the epitopes that lead to effective neutralization can aid in the development of effective vaccines.

In addition to addressing the COVID-19 pandemic, our long-term goal is to identify “pan-coronavirus” antibodies that can be effective against most or all coronavirus outbreaks.

Beyond antibodies, we are working with Alnylam to develop potential siRNA solutions and using our innate immunity platform that applies cutting-edge genomic technologies to explore ways to interrupt the disease process using small molecules.

SARS-CoV-2 mAbs :

We have confirmed the ability of our lead development candidate to neutralize the SARS-CoV-2 live virus in two separate laboratories.

The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as ‘SARS’), indicating that the epitope is highly conserved.

We believe the conservation of this epitope will make it more difficult for escape mutants to develop.

We are initially advancing two versions of our lead development candidate into clinical testing.

Both versions will be half-life engineered in order to potentially extend the time they remain in the body.

One will also be modified to potentially immunize against the virus at the same time it treats or prevents infection.

This property is known as a vaccinal effect, meaning the antibody may elicit continued immune protection against the virus even after it is no longer present in the body.

We plan to start a Phase 1/2 trial of these antibodies in the next 3-5 months.

To accelerate our progress in this critical area, we have signed a number of collaborations to aid in the development, manufacture, and potential commercialization of one or more antibodies.

As of February 2 4, 202 1 , there were over 1 12 .0 million recorded infections and almost 2.

5 million recorded deaths w orldwide from COVID-19.

Food and Drug Administration, or FDA, has granted Emergency Use Authorization , or EUA, to two vaccines for prophylaxis of COVID-19, to three monoclonal antibody , or mAb , regimens for treatment of mild-to-moderate COVID-19 and for convalescent plasm a, and has approved remdesivir for the treatment of hospitalized COVID-19 patients.

Corticosteroids and other drugs are also being used to treat hospitalized patients.

The ongoing safety and efficacy of these medicines, however, particularly as the virus mutates while it infects more people and comes under increased immune pressure, is uncertain.

We have moved rapidly to address this global health challenge, together with our collaboration partner GlaxoSmithKline plc .

Our focus is on treating and preventing severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2 (the virus that causes COVID-19), as well as potential future coronavirus outbreaks.

To do so, we are developing differentiated mAbs (VIR-7831 and VIR-7832), small molecules, and vaccines.

We anticipate that the initial registration populations for our mAb product candidates will include those in need of treatment for COVID-19, and potentially those who would benefit from prophylaxis of COVID-19.

VIR-7831 and VIR-7832 are SARS-CoV-2-neutralizing mAbs.

Both VIR-7831 and VIR-7832 are based on a parent antibody, S309, which was derived from samples previously gathered for research on pan-coronavirus-neutralizing mAbs.

Preclinical data suggest that VIR-7831 and VIR-7832 have the potential for ‘dual-action’, or the ability to block viral entry into healthy cells and an enhanced ability to clear infected cells.

Both mAbs also bind to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (the virus that causes SARS), indicating that the epitope is highly conserved, which may make it more difficult for viral resistance to develop.

Both mAbs have also been designed to achieve high concentration in the lungs for optimal penetration into airway tissues affected by SARS-CoV-2 and to have an extended half-life.

In addition, VIR-7832 has been designed to potentially enhance virus-specific T cell function, which could also help treat and/or prevent COVID-19 infection.

Our clinical program for VIR-7831 and VIR-7832 is comprised of the following trials:

In August 2020, we initiated the lead-in phase of our Phase 2/3 VIR-7831 trial named 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.

In October 2020, the trial continued into Phase 3 based on a positive evaluation of the safety and tolerability data from the Phase 2 lead-in.

Results for the primary endpoint of COMET-ICE are expected in the first quarter of 2021, and if positive, will be used to seek EUA from the FDA and ultimately approval through the submission of a biologics license application, or BLA.

In December 2020, we initiated a Phase 3 trial named Therapeutics for Inpatients with COVID-19, or TICO, of VIR-7831 for the treatment of hospitalized adults with COVID-19 as part of a new sub-trial of the National Institutes of Health’s, or NIH’s, Accelerating COVID-19 Therapeutic Interventions and Vaccines, or ACTIV, Program, specifically ACTIV-3.

An evaluation of the benefit/risk profile of VIR-7831 is expected in the first quarter of 2021 and will determine if VIR-7831 continues in the next part of the ACTIV-3 trial.

In January 2021, we initiated a Phase 2 combination trial of VIR-7831 and Eli Lilly and Company’s bamlanivimab (LY-CoV555) for the treatment of mild to moderate COVID-19 in low-risk adults as part of Eli Lilly and Company’s BLAZE-4 trial.

This trial will evaluate the impact of VIR-7831 plus bamlanivimab on viral clearance and clinical outcomes in participants with mild to moderate COVID-19.

Initial results for this arm of the BLAZE-4 trial are expected in the first half of 2021.

In February 2021, we initiated COMET-Patient SafEty, TolerAbility, PharmacoKinetics, or COMET-PEAK , a Phase 2 trial evaluating an intramuscular, or IM, formulation of VIR-7831 in low-risk adults with mild to moderate COVID-19.

In the second quarter of 2021, we also plan to initiate two additional IM trials of VIR-7831:

COMET-Treatment of Acute COVID-19 with Intramuscular monocLonal antibody, or COMET-TAIL, a Phase 3 trial in adults at high risk of hospitalization or death, and COMET-Stop Transmission of Acute SARS-CoV-2, or COMET-STAR, for prophylaxis or prevention of symptomatic infection of COVID-19.

In addition, in the first quarter of 2021, we anticipate initiating a Phase 1b/2a trial of VIR-7832 for the treatment of adults with mild to moderate COVID-19 at high risk of hospitalization as part of the U.K.-based and National Health Service, or NHS, supported AGILE initiative.

The dose-escalation Phase 1b part of the trial will evaluate the safety and tolerability of single ascending doses of VIR-7832 for the treatment of mild to moderate COVID-19.

The Phase 2a portion will evaluate the safety and virologic activity of VIR-7832, as well as T cell responses to SARS-CoV-2 of VIR-7832 and VIR-7831.

In connection with the advancement of our COVID-19 mAbs, we and our collaboration partner, Glaxo Wellcome UK Limited and Beecham S.A.

( individually and collectively referred to as GSK), have established a strategic manufacturing network, which will enable the manufacture of approximately two million doses to patients the first year following potential EUA, and several fold that in the second year, depending on titer and yield.

See the section titled “Manufacturing” for a summary of our manufacturing activities and a description of the agreements with WuXi Biologics (Hong Kong) Limited, or WuXi Biologics, Biogen Inc., or Biogen, and Samsung Biologics Co., Ltd., or Samsung.

In addition, we are collaborating on potential commercialization with WuXi Biologics, for greater China and with GSK, for all other countries.

Approximately 290 million people globally are chronically infected with HBV and approximately 900,000 of them 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.

For a registrational trial to demonstrate a functional cure, the formal endpoint accepted by the U.S.

Food and Drug Administration, or the FDA, is undetectable HBsAg, defined as less than 0.05 international units per milliliter, or IU/ml, as well as HBV DNA less than the lower limit of quantification, in the blood six months after the end of therapy.

Currently, a year-long course of PEG-IFN-α, is the best available curative therapy.

For a registrational trial to demonstrate a functional cure, the formal endpoint accepted by the FDA is undetectable hepatitis B virus surface antigen, or HBsAg, defined as less than 0.05 international units per milliliter, or IU/ml, as well as HBV DNA less than the lower limit of quantification, in the blood six months after the end of therapy.

Currently, a year-long course of pegylated interferon-alpha, or PEG-IFN-α, is the best available curative therapy.

It has a low functional cure rate of approximately three to seven percent.

3 unchanged sentences

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.

While monotherapy with each of these agents may provide a functional cure in some patients, we believe combination therapy will be necessary for a functional cure in many patients.

We are planning trials that combine VIR-2218 with VIR-3434, which we believe have the potential to act in concert by removing potentially tolerogenic HBV proteins and stimulating new HBV specific T cells.

We are also initiating trials that combine VIR-2218 with PEG-IFN-α and are evaluating additional combinations with other immunotherapy agents and direct acting antiviral agents.

We anticipate that the initial registration population for these product candidates will be patients chronically infected with HBV on NRTIs.

VIR-2218 is an HBV-targeting siRNA that is currently in a Phase 1/2 clinical trial.

VIR-2218 is administered subcutaneously.

By targeting a conserved region of the HBV genome, it is designed to inhibit the production of all HBV proteins, including HBsAg.

Suppression of HBV proteins, particularly HBsAg, is hypothesized to remove the inhibition of T cell activity directed against HBV, allowing VIR-2218 to potentially result in a functional cure.

VIR-2218 was the first siRNA in the clinic to include ESC+ technology, which has the potential to enhance the therapeutic index.

As of December 11, 2019, 37 healthy volunteers have received VIR-2218 and 12 healthy volunteers have received placebo.

In addition, 24 patients with chronic HBV on NRTIs have received VIR-2218 and eight patients with chronic HBV on NRTIs have received placebo.

While monotherapy with VIR-2218 and VIR-3434 may provide a functional cure in some patients, we believe combination therapy will be necessary for a functional cure in many patients.

We plan to initiate a Phase 2 trial in the second half of 2021 that combines VIR-2218 and VIR-3434, which we believe have the potential to act in concert by inhibiting virion production, removing potentially tolerogenic HBV proteins, and stimulating new HBV specific T cells.

Additionally, in July 2020, we initiated a Phase 2 combination clinical trial of VIR-2218 with PEG-IFN-α, an approved immune modulatory agent, and anticipate initial clinical data in the second quarter of 2021 .

In January 2021, we announced a clinical trial collaboration with Gilead Sciences, Inc., or Gilead, to initiate a Phase 2 trial of VIR-2218 in combination with GS-9688 ( selgantolimod ), a TLR-8 agonist, and nivolumab, an approved PD-1 inhibitor , in 2021 in both treatment-experienced and treatment-naïve patients with HBV .

We also anticipate that Brii Biosciences Offshore Limited, or Brii Bio, will start a Phase 2 trial of VIR-2218 in combination with BRII-179, a n investigational T cell vaccine, in the first half of 2021.

We anticipate that the initial registration population for these product candidates will be patients chronically infected with HBV.

VIR-2218 is a subcutaneously administered HBV-targeting siRNA that is currently in a Phase 2 clinical trial.

By targeting a conserved region of the HBV genome, it is designed to inhibit the production of all HBV proteins:

X, polymerase, S, and core.

Suppression of HBV proteins, particularly HBsAg, is hypothesized to remove the inhibition of T cell and B cell activity directed against HBV, allowing VIR-2218 to potentially result in a functional cure.

VIR-2218 was the first siRNA in the clinic to include Alnylam Pharmaceuticals, Inc.’s, or Alnylam’s, Enhanced Stabilization Chemistry Plus, or ESC+, technology, which has the potential to enhance the therapeutic index.

In total, 37 healthy volunteers and 24 patients with chronic HBV on NRTIs have received VIR-2218.

The data suggest that VIR-2218 is generally well-tolerated in healthy volunteers given as a single dose up to 900 mg and in patients given as two doses of 20 mg, 50 mg, 100 mg or 200 mg each dose.

The data also demonstrate substantial, dose dependent reductions in HBsAg in patients at doses ranging from 20 mg to 200 mg, which are durable at the higher doses for at least 6 months.

VIR-2218 is the first asset in our collaboration with Alnylam to enter clinical trials.

We anticipate announcing additional details on this trial in the second quarter of 2020.

In addition, we anticipate starting a Phase 2 combination trial of VIR-2218 and PEG-IFN -α in the second half of 2020.

VIR-3434 is an HBV-neutralizing mAb that will be administered subcutaneously.

The data also demonstrate substantial, dose dependent reductions in HBsAg in patients at doses ranging from 20 mg to 200 mg, which are durable at the higher doses for at least nine months.

In July 2020, we initiated a Phase 2 combination clinical trial of VIR-2218 with PEG-IFN-α and anticipate initial clinical data in the second quarter of 2021.

VIR-3434 is a subcutaneously administered HBV-neutralizing mAb currently in a Phase 1 clinical trial.

By targeting a conserved region of HBsAg, it is designed to block entry of all 10 genotypes of HBV into liver cells called hepatocytes and reduce the level of virions and subviral particles in the blood.

We have also engineered VIR-3434 to have an extended half-life and to potentially function as a T cell vaccine against HBV in infected patients.

We have also engineered VIR-3434 to have an extended half-life and to potentially function as a therapeutic T cell vaccine for chronic HBV infection.

These modifications are intended to enhance its potential to result in an HBV functional cure.

VIR-3434 was planned to start a Phase 1 clinical trial in the first half of 2020 .

Due to the coronavirus disease 2019 (COVID-19) pandemic, however, we now anticipate this trial will start in the second half of 2020.

In January 2021, we announced initial data from the first blinded cohort of eight patients with chronic HBV on NRTIs, two of whom received placebo, and six of whom received a single dose of 6mg VIR-3434.

Six of the eight patients responded and achieved a mean reduction of 1.3 log 10 IU/mL in serum HBsAg by day eight, the day when nadir was achieved in most patients.

We anticipate additional clinical data from our Phase 1 trial in the second quarter of 2021.

We also expect to initiate a Phase 2 clinical trial of VIR-3434 in combination with VIR-2218 in the second half of 2021.

On average, each year the influenza virus infects 5% to 10% of the world’s population and results in an estimated 500,000 deaths.

In the 2017-2018 flu season, it is now estimated that 61,000 people died from influenza in the United States alone.

The efficacy of the annual flu vaccine has ranged from 10% to 60% over the past 15 years, with an average of 40%, overall, across all populations.

The efficacy in the elderly, defined as those 65 and older, has been found to be notably lower, in some flu seasons.

The limited success of influenza vaccines has been attributed to two primary factors.

First, flu vaccines have incomplete strain coverage and therefore often do not provide protection against all strains of influenza that circulate in a given season, despite being updated every year.

Second, flu vaccines are active immunizations that rely on a person’s own immune system to create protective influenza virus antibodies, and many individuals do not generate an effective immune response.

We are developing VIR-2482 as a universal prophylaxis for influenza A.

Influenza A has been estimated in the United States to cause 85% of influenza hospitalizations from 2005 to 2013 and has been the source of all known influenza pandemics.

VIR-2482 is designed to overcome the limitations of flu vaccines and lead to meaningfully higher levels of protection.

We anticipate that the initial registration population for VIR-2482 will be individuals at high risk of influenza A complications, such as the elderly with chronic lung disease.

VIR-2482 is an influenza A-neutralizing mAb.

In August 2019, we initiated dosing in a Phase 1/2 clinical trial for VIR-2482.

VIR-2482 is administered intramuscularly.

VIR-2482 targets a conserved region of the influenza A hemagglutinin protein and consequently has the potential to prevent illness by any strain of influenza A.

In the 2018-2019 flu season, it is estimated that 34,000 people died from influenza in the United States alone.

Influenza vaccines have historically had limited success, with an average efficacy of 40%.

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 VIR-2482 as a universal prophylactic for influenza A and have designed it to overcome both limitations of flu vaccines, which we believe will lead to meaningfully higher levels of protection against seasonal and pandemic strains of influenza A.

We anticipate that the initial registration population for VIR-2482 will include individuals at high risk of influenza A complications, such as the elderly with chronic lung disease or congestive heart failure.

In February 2021, we entered into a binding preliminary collaboration agreement with GSK, or the 2021 Preliminary Agreement, which included a program to research, develop and commercialize mAbs for the prevention, treatment or prophylaxis of the influenza virus.

In addition, after we complete and report Phase 2 trial outcomes for VIR-2482, GSK will have the exclusive option to obtain exclusive rights to co-develop and commercialize VIR-2482.

See the section titled “Our Collaboration, License and Grant Agreements—Collaboration Agreement with GSK” for a description of the 2021 Preliminary Agreement.

VIR-2482 is an intramuscularly administered influenza A-neutralizing mAb currently in a Phase 1/2 clinical trial.

In vitro, VIR-2482 has been shown to cover all major strains of influenza A that have arisen since the 1918 Spanish flu pandemic.

Since flu vaccines have incomplete strain coverage and limited efficacy, the broad coverage of VIR-2482 may allow it to achieve higher protection levels and for it to be used year after year.

In addition, because VIR-2482 is an antibody that can directly confer protection, it does not rely on a person to create his or her own antibodies.

Thus, we believe VIR-2482 has the potential to be effective even in a person with a compromised immune system.

VIR-2482 has been half-life engineered so that a single dose has the potential to last the entire flu season, which is typically five to six months long.

Due to the COVID-19 pandemic, we now anticipate starting the Phase 2 clinical trial in the northern hemisphere in the fourth quarter of 2020, rather than in the southern hemisphere in the second quarter of 2020, as previously planned.

Data from the first flu season (now in the northern hemisphere) of the Phase 1/2 clinical trial are anticipated to be available in the first half of 2021, and from the second flu season (now in the southern hemisphere) are anticipated to be available in the second half of 2021.

Each year there are approximately 1.8 million new cases of HIV and approximately 1.0 million HIV-related deaths globally.

We believe that VIR-2482 has the potential to provide superior protection to flu vaccines and be able to be used year after year because it has broad strain coverage as opposed to the limited strain coverage generated by vaccines.

We also believe that it provides passive immunity rather than relying on a person to generate active immunity via a functional immune response, an ability that is known to decline with age.

VIR-2482 has been engineered to increase lung tissue bioavailability and to extend its half-life so that a single intramuscular dose has the potential to last the entire flu season, which is typically five to six months long.

VIR-2482 is estimated to have a half-life of 58 days based on preliminary data.

VIR-2482 has been generally well-tolerated in the approximately 100 healthy volunteers dosed in the Phase 1 portion of the clinical trial.

Initiation of the Phase 2 trial for VIR-2482, which was delayed due to the impact of COVID-19, is now planned for the fourth quarter of 2021 with proof-of-concept results anticipated in the first half of 2022.

Each year there are approximately 1.7 million new cases of HIV and approximately 700,000 HIV-related deaths globally.

Current prevention approaches such as behavioral modification and pharmacological intervention have had only a modest effect on HIV transmission globally, leaving a high unmet medical need for a safe and effective vaccine for the billions of individuals who are or may become sexually active.

Previous attempts at an HIV vaccine were designed to boost the natural immune response to HIV.

We believe a different type of immune response is needed.

VIR-1111 is a proof of concept HIV vaccine designed to elicit a type of immune response that is different from other vaccines.

We are developing VIR-1111 as a proof of concept HIV vaccine designed to elicit a type of immune response that is different from other vaccines.

In December 2020, we initiated a Phase 1 trial for VIR-1111.

We anticipate the initial registration population for our eventual HIV vaccine will be individuals at high risk of contracting HIV.

VIR-1111 is an HIV T cell vaccine based on HCMV and was planned to start a Phase 1 clinical trial in the first half of 2020.

Due to the COVID-19 pandemic, however, we now anticipate this trial will start in the second half of 2020.

VIR-1111 will be administered by subcutaneous injection.

VIR-1111 is a subcutaneously administered HIV T cell vaccine based on human cytomegalovirus, or HCMV, currently in a Phase 1 clinical trial.

VIR-1111 has been designed 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.

An HLA-E restricted immune response has been shown to be associated with protection of NHPs from simian immunodeficiency virus, or SIV, the NHP equivalent of HIV.

VIR-1111 is a vaccine designed to establish proof of concept in a Phase 1 clinical trial to determine whether the unique immune response observed in NHPs can be replicated in humans.

Ultimately any candidates we advance as a potential HIV vaccine will require modifications to VIR-1111 before further clinical development.

Globally, nearly two billion people are latently infected with TB, and each year there are approximately 10 million new active cases of TB and approximately 1.6 million TB-related deaths.

There is a high unmet medical need for a safe and effective vaccine that prevents active pulmonary TB in adolescents and adults, as they represent the key sources of TB transmission and are the primary contributors to overall disease burden.

The bacterium that causes TB can evade the immune response, which often leads to persistent infection.

We believe that a different type of immune response is needed.

VIR-2020 is a vaccine designed to provide a type of immune response that is different from other vaccines and lead to meaningful levels

of protection from active TB.

We anticipate that the initial registration population for VIR-2020 will be people at high risk of developing active TB, such as those who have latent TB infection.

VIR-2020 is a TB T cell vaccine based on HCMV for which we plan to submit an IND in 2023 and thereafter commence a Phase 1 clinical trial.

VIR-2020 will be administered by subcutaneous injection.

VIR-2020 is designed to stimulate T cells that reside in the lung and to recognize TB epitopes that are different from those recognized by prior TB vaccines.

In preclinical studies, a T cell vaccine based on rhesus cytomegalovirus, or RhCMV, has been shown to provide protection of NHPs from TB.

Our Corporate Information

We were incorporated under the laws of the State of Delaware on April 7, 2016.

Our principal executive offices are located at 499 Illinois Street, Suite 500, San Francisco, California 94158, and our telephone number is (415) 906-4324.

Our corporate website address is www.vir.bio.

Information contained on, or accessible through, our website shall not be deemed incorporated into and is not a part of this report, and the inclusion of our website address in this report is an inactive textual reference only.

We have an industry-leading management team, board of directors and scientific advisors with significant experience in immunology and infectious diseases and progressing product candidates from early stage research to clinical trials, regulatory approval and ultimately commercialization.

An HLA-E restricted immune response has been shown to be associated with protection of non-human primates, or NHPs, from simian immunodeficiency virus, or SIV, the NHP equivalent of HIV.

VIR-1111 is a vaccine designed solely to establish proof of concept in a Phase 1 clinical trial to determine whether the unique immune response observed in NHPs can be replicated in humans.

We anticipate initial clinical data for VIR-1111 in the second half of 2021.

Our Technology Platforms

Our four current technology platforms are designed to stimulate and enhance 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.

Antibody Platform :

We have established a robust method for capitalizing on unusually successful immune responses naturally occurring in people who are protected from, or have recovered from, infectious diseases.

We identify rare antibodies from survivors that have the potential to treat and prevent rapidly evolving and/or previously untreatable pathogens via direct pathogen neutralization and immune system stimulation.

The fully-human antibodies that we discover may also be modified to enhance their therapeutic potential.

We have applied these methods to identify mAbs for a range of pathogens including SARS-CoV-2, HBV, influenza A and influenza B virus, Ebola, respiratory syncytial virus, or RSV, and malaria, and bacterial pathogens, including clostridium difficile, Staphylococcus aureus , Klebsiella pneumoniae , and Acinetobacter spp .

An example of the power of this platform is the anti-Ebola virus mAb Ebanga (ansuvimab-zykl, formerly known as mAb114), which was approved by the FDA on December 21, 2020 and marketed by Ridgeback Biotherapeutics LP.

T Cell Platform :

We are exploiting the unique immunology of HCMV, a commonly occurring virus in humans, as a vaccine vector to potentially treat and prevent infection by pathogens refractory to current vaccine technologies.

This approach is based on fundamental observations made in NHPs, with rhesus cytomegalovirus, or RhCMV.

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 that this platform may also have applicability beyond infectious diseases, to areas such as cancer.

Innate Immunity Platform :

This is enabled using clustered regularly interspaced short palindromic repeats, or CRISPR, -based genomics, computational biology and machine learning to identify key host factors necessary for each pathogen’s survival and the protective effects of the innate immune system.

We then identify product candidates that may be able to safely target host proteins to block pathogen replication or induce innate immunity to control infection.

We believe that this platform may also have applicability beyond infectious diseases.

siRNA Platform :

We are harnessing the power of siRNA to inhibit pathogen replication, eliminate key host factors necessary for pathogen survival and remove microbial immune countermeasures.

Our collaboration with Alnylam includes VIR-2218 for HBV and up to four additional programs for infectious diseases.

This platform can leverage Alnylam’s proprietary N- acetylgalactosamine , or GalNAc , delivery technology, for product candidates targeting the liver, allowing for subcutaneous administration and extended tissue half-life, as well as ESC+ technology to enhance stability and minimize off-target activity, which potentially can result in an increased therapeutic index.

We have an industry-leading management team and board of directors with significant experience in immunology and infectious diseases and progressing product candidates from early stage research to clinical trials, regulatory approval and ultimately commercialization.

Our Chief Executive Officer, George Scangos, Ph.D., has spent over 30 years developing treatments in infectious disease, neuroscience and oncology, among other fields, and was previously the Chief Executive Officer of Biogen Inc., or Biogen, the Chief Executive Officer of Exelixis, Inc.

2 unchanged sentences

Louis, Missouri.

Our Senior Vice President and Senior Research Fellow, Antonio Lanzavecchia, M.D., is a Member of the National Academy of Sciences, was a co-founder of Humabs Biomed SA, or Humabs, which we acquired in 2017, and is the Director of the Institute for Research in Biomedicine in Bellinzona, Switzerland.

Our Chief Medical Officer, Phil Pang, M.D., Ph.D., was previously Chief Medical Officer of Riboscience LLC, and before that was the Harvoni ® project lead at Gilead Sciences, Inc., or Gilead, where he led the team responsible for worldwide regulatory approval.

Our Senior Vice President and Senior Research Fellow, Antonio Lanzavecchia, M.D., is a Member of the National Academy of Sciences, was a co-founder of Humabs Biomed SA, or Humabs, which we acquired in 2017, and was the Director of the Institute for Research in Biomedicine in Bellinzona, Switzerland.

Our Chief Medical Officer, Phil Pang, M.D., Ph.D., was previously Chief Medical Officer of Riboscience LLC, and before that was the Harvoni ® project lead at Gilead, where he led the team responsible for worldwide regulatory approval.

Our Chief Technology Officer, Michael Kamarck, Ph.D., was previously Senior Vice President of Global Vaccines and Biologics Manufacturing at Merck & Co., Inc., President of Merck BioVentures and President of Technical Operations and Product Supply across all of the businesses of Wyeth Pharmaceuticals, Inc.

5 unchanged sentences

Our board of directors is composed of a leader from academia, Nobel laureate Phillip Sharp, Ph.D.;

from the biopharmaceutical industry, Robert Perez, Saira Ramasastry and our Chairman Vicki Sato, Ph.D.;

and from the life science investment community, Kristina Burow, Robert More, Robert Nelsen (a co-founder) and Dipchand (Deep) Nishar.

Our scientific advisors include members of the National Academies of Sciences, Engineering, and Medicine, Jeffrey Bluestone, Ph.D., Francis Chisari, Ph.D., Lawrence Corey, M.D.

(a co-founder), Mark Davis, Ph.D., Jeffrey Ravetch, M.D., Ph.D.

and Charles Rice, Ph.D., the director of the HIV program at the Bill & Melinda Gates Foundation, Emilio Emini, Ph.D., a long-time biopharmaceutical industry executive, Thomas Daniel, M.D., and professors of immunology, virology, infectious disease, oncology, and other fields, Klaus Frueh, Ph.D.

(a co-founder), Suzanna Naggie, M.D., Louis Picker, M.D.

(a co-founder) and George Poste, D.V.M., Ph.D.

from the biopharmaceutical industry, Jeffrey Hatfield, Robert Perez, Saira Ramasastry, Elliott Sigal, M.D., Ph.D., and our Chairman Vicki Sato, Ph.D.;

from the life science investment community, Robert More, Robert Nelsen (a co-founder) and Dipchand (Deep) Nishar;

and from government, Janet Napolitano.

We are a clinical-stage immunology company focused on combining immunologic insights with cutting-edge technologies to treat and prevent serious infectious diseases.

1 unchanged sentence

Rapidly advancing our pipeline .

We have completed enrollment of a Phase 1/2 clinical trial for VIR-2218 and commenced a Phase 1/2 clinical trial for VIR-2482.

We anticipate moving multiple preclinical candidates into the clinic in the next 12-18 months and initiating combination trials where applicable.

Currently underway are two Phase 3 clinical trials, four Phase 2 clinical trials, and three Phase 1 clinical trials across four distinct therapeutic areas.

We anticipate moving additional preclinical candidates into the clinic and initiating additional later-stage combination trials where applicable in the next 12-18 months.

Expanding our pipeline using our current technology platforms .

We are leveraging our four current technology platforms to discover and develop novel product candidates for HBV, influenza A, SARS-CoV-2, HIV and TB, as well as additional viral, bacterial, fungal and parasitic infections, and potentially cancers.

Acquiring new technology platforms and assets .

We are leveraging our four current technology platforms to discover and develop novel product candidates for COVID-19, HBV, influenza A virus, HIV and TB, as well as additional viral, bacterial, fungal and parasitic infections, and potentially cancers.

Acquiring or accessing new technology platforms and assets .

We continually evaluate external technology platforms and assets that may help us develop therapies to treat and prevent serious infectious diseases.

Scaling our capabilities .

We are investing in our people, processes and systems across all functions of our company to ensure that we are able to take full advantage of our multiple technology platforms and multiple product candidates.

We are investing in our people, processes and systems across all functions of our company to ensure that we are able to take full advantage of our multiple product candidates and multiple technology platforms.

Enabling global access to our future medicines .

We have established relationships with organizations seeking to make a global impact like the Bill & Melinda Gates Foundation and the NIH to further enable and facilitate access to our future medicines and to support our clinical development efforts.

We have established relationships with organizations seeking to make a global impact like the Bill & Melinda Gates Foundation, the NIH, and the NHS to further enable and facilitate access to our future medicines and to support our clinical development efforts.

We will continue to pursue additional relationships like these moving forward.

Technology Platforms

Platforms for the Creation of Transformative Medicines for Infectious Diseases

We have purposefully assembled a portfolio of technology platforms that we believe will, individually or in combination, allow us to enhance immunity in innovative ways and to exploit the vulnerabilities of pathogens.

Our current platforms are focused on antibodies, T cells, the innate immune response and siRNAs targeting pathogen and host gene expression.

We have assembled these platforms through internal development, collaborations and acquisitions.

We are using these platforms, and continue to evaluate others, to advance multiple new product candidates for HBV, influenza A, SARS-CoV-2, HIV and TB, as well as additional viral, bacterial, fungal and parasitic infections.

We follow the science to select the modality, or combination of modalities, that gives us the highest chance of success for a specific infection 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 are using specialized mAbs to treat or prevent rapidly evolving and/or previously untreatable pathogens.

These mAbs act in a variety of ways, including direct pathogen neutralization and immune system stimulation.

We combine high-throughput, rapid isolation of rare, highly potent, broad-spectrum and fully human antibodies with targeted engineering to enhance their therapeutic potential.

We expect that these specialized mAbs can be administered to transfer protective immunity to all at-risk individuals.

We expect the following benefits from our antibody platform:

Effective regardless of an individual’s ability to generate his or her own immune response

Diminished likelihood of self-reactivity because they are selected in humans

Broad coverage of most or all strains of a pathogen, or even multiple pathogens

High affinity binding to conserved pathogen antigens, resulting in a high barrier to resistance

Longer half-life than naturally occurring antibodies

Potential to induce a vaccinal effect, i.e., to elicit continued protection even after the mAb is no longer present

Three of our product candidates, VIR-3434 , VIR-2482, and our SARS-CoV-2 mAbs were generated using our antibody platform.

We use a proprietary antibody screening technology that allows us to characterize the antibodies produced from hundreds of millions of B cells derived from survivors of an infection to identify those rare antibodies that have the rare characteristics needed to create an effective medicine.

Rare characteristics include, for example, the ability to bind to a highly conserved antigen within a pathogen and the ability to neutralize multiple different pathogens.

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 weeks.

Following isolation, we clone the antibody genes and express the resulting fully human antibody for further studies, engineering and development.

We have applied these methods to identify mAbs for a range of pathogens including Ebola, HBV, influenza A and influenza B virus, SARS-CoV-2, RSV, malaria and a range of bacterial pathogens, including Staphylococcus aureus , Klebsiella pneumoniae , and Acinetobacter spp .

An example of the power of this platform is the anti-Ebola virus mAb114, which is now in a Phase 2/3 clinical trial in Africa as part of the efforts to quell the current virulent Ebola outbreak.

This mAb was identified by our scientists using the technologies described above in collaboration with the NIH and others.

mAb114 has been shown to cure severe Ebola virus-induced illness in infected NHPs and has successfully completed Phase 1 clinical trials in healthy volunteers.

It is being developed by Ridgeback Biotherapeutics LP and the NIH.

Precision Antibody Engineering to Create the Best Medicines

Our strategy is to optimize both the Fab and Fc domains of a mAb to generate the best medicine to treat or prevent infection.

Having isolated a rare, fully human antibody via High Throughput Isolation, we then engineer as desired both parts of the mAb, the Fab and Fc domains, to enhance efficacy, potency and manufacturability.

The Fab portion binds to the protective antigen on the pathogen.

The Fc portion binds to effector proteins and cells in the body to engage the immune system in killing and clearing the infection.

Fab engineering is performed to further increase mAb potency and breadth of coverage.

mAb potency and breadth are based on the epitope bound, 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.

There are many approaches to creating multi-specific antibodies, and we are exploring a number of them, including some that naturally occur in people.

We believe that naturally occurring multi-specific antibodies can be leveraged to create new and potent therapeutics and to enhance antibody prophylaxis of disease, and have the potential for higher manufacturing yields and better pharmacokinetics in patients, as compared to artificial multi-specific formats currently being developed.

Fc engineering selects and optimizes the specific ways in which mAbs engage Fc receptors, or FcRs, which in turn govern “effector functions” such as the half-life of the antibody and the way that the immune system is recruited by the mAb to fight infection.

Effector functions can be enhanced or reduced via Fc mutations that alter the binding affinity of the Fc domain of an mAb to the various FcRs, based on a detailed understanding of the role of individual FcRs in half-life and immunity.

Examples of immunity that can be altered in this way include the recruitment of serum proteins to infected areas, phagocytosis and destruction of viruses and viral particles, the killing of virus infected cells through a process known as antibody-dependent cell cytotoxicity, or ADCC, and the presentation of antigens to elicit B and T cell immunity.

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 immunize an infected individual against future infections.

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 different parts of the Fc portion of the mAb.

By engineering the Fc region, we can select which FcRs interact with the antibody-antigen complex to generate activated DCs that we believe can effectively induce T cell immunity.

Design and mechanism of vaccinal antibodies intended to induce enhanced immunity through induction of T cells .

The Fc portion of mAbs interacts with FcRs on DCs to trigger uptake of antigen and induction of T cells.

Engineering of the Fc portion of the mAb is predicted to increase the induction of T cells by these DCs.

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 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 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.

80% of the mice 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 T-cell response.

We plan to do first-in-human testing of this concept in chronic HBV infection using VIR-3434.

If this technology performs as expected, we believe that this platform may have applicability to multiple infections.

T Cell Platform

T cells can prevent or control infection and cancer.

T cells are diverse in how they sense pathogens and cancer cells, the tissues that they protect and the effector functions that they use to control infection or cancer.

Our approach is to use HCMV as a vaccine vector to potentially treat and prevent infection by pathogens refractory to current vaccine technologies because HCMV 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.

Experiments in NHPs demonstrate the ability of vaccine vectors based on the closely related RhCMV to protect against SIV, a close relative of HIV, and TB, two of the most challenging infections for which to create effective vaccines.

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.

We expect the following benefits from our T cell platform:

Highly potent and long-lived T cell responses throughout the body

Induction of high numbers of specialized T cells, known as effector memory cells, that allow control of disease in the first few days after infection

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

Generation of universal T cells that may be active in most or all people despite high genetic variability between people in immune response genes

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

Opportunity to use the same vaccine to protect against multiple pathogens

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

VIR-1111 and VIR-2020 were generated using our T cell platform.

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 combatting infections such as HIV and TB that have proven intractable, to date, for other vaccine technologies.

Immune programming is best understood in the context of the normal processes that elicit T cell immunity.

T cells that fight infection and cancer are elicited by DCs, as well as other types of cells.

The elicited T cells detect small peptide fragments from antigens on the surface of DCs and other antigen presenting cells, which have been captured in grooves found within specialized proteins encoded by major histocompatibility complex, or MHC, genes.

The unique immunology of HCMV depends on the virus’s ability to regulate the normal immune processes of antigen presentation by MHC genes.

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.

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 MHC genes to present foreign antigens to T cells.

Some immune response MHC genes are highly variable between individuals, while others are less variable between individuals as illustrated below.

The immune response MHC genes that are highly variable between individuals are responsible for most T cell responses.

These MHC molecules enable T cells to recognize foreign proteins through the use of a highly specialized T cell receptor, or TCR, on the T cell surface.

An important consequence of the inter-individual variation in some immune response MHC genes is that a TCR that recognizes an antigenic peptide associated with one person’s MHC molecules could attack even normal tissues of a person with different MHC genes.

As a result, identifying universal TCRs and universal T cell antigens that work in all people has been very challenging.

Our T cell platform may enable us to create vaccines or other types of medicines that are near universal in their effects on human immunity.

The programmed T cell responses elicited by engineered HCMV vectors are predicted to use immune response MHC genes that vary minimally between people, instead of the highly variable immune response MHC genes targeted by other types of vaccines.

As demonstrated by the graphic below, TCRs recognizing antigenic peptides together with MHC-E may be functional in all individuals, potentially allowing for the generation of universal TCR-based medicines, such as off-the-shelf cancer cell therapy.

The peptides presented by MHC-E may be immunogenic in all individuals, potentially allowing for the generation of universal infectious disease and cancer vaccines.

Comparison of standard T cell responses to MHC-E responses .

Peptides that are bound to MHC-I, -II or -E proteins are expressed on cell surfaces where they are recognized by T cell receptors on T cells (TCRs).

This interaction results in the expansion of T cells that can recognize diverse antigen peptides (top row) and that carry out functions that protect the host.

Since MHC-I and MHC-II molecules are highly variable between people, peptide presentation to TCRs has a high degree of individual specificity, as illustrated by the different colors of each peptide in the top row.

In contrast to MHC-I and MHC-II, MHC-E proteins (bottom row) are conserved in the human population.

Specifically programmed RhCMV vectors can elicit strong T cell responses that target MHC molecules which vary minimally between NHPs.

One such protein is MHC-E.

The fundamental discovery, by some of our founders, that enables this part of our T cell platform is that RhCMV responses can be programmed to generate abundant MHC-E-restricted T cells.

We believe that using our T cell programming approach will allow us to select vaccine antigens and to identify TCRs that work across the human population.

An example of a use of such a TCR would be creating a biological product that specifically recognizes infected cells in all individuals.

Programming T Cell Responses to Create HIV and TB Vaccines

Two of the most challenging infections for vaccine development are HIV and TB.

Preclinical studies have demonstrated that programmed RhCMV vectors can be used to vaccinate against either SIV or TB in NHPs.

For example, as shown in the figure below, in an NHP study, an MHC-E programmed RhCMV vaccine effectively protected more than half of NHPs from infection when challenged with a highly virulent form of SIV, under conditions in which all animals in the control group became infected.

SIV vaccines programmed in other ways were not protective, demonstrating the potential value of having a programmable T cell vaccine platform.

Primary data for the protective effects of RhCMV-derived T cell vaccines on SIV infection .

Rhesus monkeys were vaccinated with an RhCMV vaccine that elicits CD8 T cells recognizing SIV peptides presented by MHC-E and MHC-II or a control before challenge with SIV by rectal or vaginal routes.

SIV genome copies were measured in peripheral blood (vertical axis) at intervals after challenge (horizontal axis).

SIV infection was cleared in approximately 51% of intrarectal challenged animals and approximately 60% of intravaginal challenged animals while infection was progressive in all unvaccinated controls.

Protection has also been observed against TB in preclinical studies of NHPs after immunization with either of two different RhCMV vaccines.

One of the protective vaccines was programmed to elicit MHC-II and MHC-E responses, while the other was programmed to elicit a response depending on MHC-I genes.

This shows the potential significance of being able to specifically program a T cell vaccine to target 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 support our plans to use our T cell platform to vaccinate against HIV and TB.

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

If proof of concept for the potential efficacy of our T cell vaccine platform is obtained in currently planned clinical trials, we plan to apply this T cell platform for treating additional types of infections, as well as potentially even cancers.

Innate Immunity Platform

Innate immunity protects us during the early stages of infection until antibodies and T cells can be generated by the immune system.

Importantly, innate immunity is not pathogen-specific.

We believe that we can target innate immunity to create medicines that break the “one-drug-for-one-bug” paradigm by producing “one-drug-for-multiple-bugs.” We term this concept “host-directed therapy” because the medicine would target a host protein instead of pathogen proteins, which are the target of standard antibiotics and antivirals.

We can also identify proteins that are critical for a high priority infection, such as HBV, for which host-directed therapy might be part of a functional cure or complete cure.

This platform may also identify targets relevant to diseases outside of infection.

Our scientists have developed and applied cutting-edge CRISPR-based genetic technologies to identify host genes that regulate innate immunity and/or pathogen replication.

We have built internal capacity to systematically extend such studies to multiple pathogens and multiple aspects of innate immunity.

We have joined the Broad Institute’s Functional Genomics Consortium, which provides us access to cutting-edge CRISPR reagents and computational services for whole-genome and custom-designed genetic screens.

Design of steps in our innate immunity platform .

We are systematically mapping the genes that regulate pathogen control across a diverse set of pathogens.

To accomplish this, advanced gene editing technology (CRISPR) is used to create cell libraries in which individual genes are either knocked out or activated.

By exposing these cell libraries to pathogens of interest, under different screening conditions, we can systematically create genomic maps that identify genes that could lead to pathogen control.

By computationally comparing these genomic maps, genes or pathways that are common to multiple pathogens can be identified and could lead to the development of products that could treat more than a single pathogen.

Human rhinovirus = HRV.

We expect the following benefits from our innate immunity platform:

Enhancement of the potency of innate immunity, allowing for control of multiple unrelated pathogens

High barrier to resistance since the targeted host protein is not likely to mutate

Identification of key host targets in areas outside of infectious disease

Our innate immunity platform envisions three steps leading to new medicines, as illustrated in the figure above.

CRISPR Screens to Map the Genomic Landscape of Infection and Innate Immunity

Multiple types of proteins participate in innate immunity and infection, as they may be required for entry, replication, gene expression, pathogenicity and/or innate immune control of an infectious agent.

To identify such proteins, we screen CRISPR-derived cell libraries after infection, treatment with cytokines that trigger innate immunity, or both, and then select cells with desired properties.

Using next-generation sequencing, we identify genes responsible for the desired property.

By combining these data across screens and across pathogens, our team has created, and is continuously expanding, a proprietary database of the genomic landscape of infection and innate immunity.

CRISPR screen for genes involved in RSV replication .

A CRISPR cell library was prepared in cells in which RSV can replicate.

After a period of infection with an RSV strain expressing a fluorescent protein which serves as a surrogate for viral replication, cells were separated using flow cytometry into populations in which RSV replication was decreased or increased.

Deep sequencing of the population exhibiting decreased replication compared to control revealed candidate genes required for efficient replication.

Computational analysis represented on the right panel revealed that some of these genes fall into nodes that function in specific cellular processes.

These nodes are represented as dots interconnected with a dense network of lines.

As an example, to identify genes required for RSV growth, we performed a screen in which a CRISPR-generated cell library was infected with RSV, as shown in the figure above.

We then purified and sequenced populations exhibiting low or high RSV growth.

Sequencing of the RSV low population revealed genes potentially required for RSV infection.

When analyzed computationally, these genes fell into sets involved in specific cellular processes.

These genes are potential targets for product candidates.

We performed a similar screen with the influenza A virus and HRV and found that certain genes are shared between RSV, influenza A and HRV.

Targeting such proteins might result in a pan-respiratory virus product candidate capable of treating RSV, influenza A and HRV.

The result from this step of the innate immune platform is a continuously updated database of the genomic landscape of pathogen replication and innate immunity.

We have already performed multiple screens, and additional screens and target validation studies are in progress.

Computational Analysis for Identification of Product Targets

Results from CRISPR screens provide the critical data that helps identify host targets necessary for a given pathogen.

When creating a single drug for multiple pathogens, host targets in common among multiple pathogens are identified.

After having identified the critical set of host targets necessary for a pathogen or pathogens, the specific target for a new medicine is selected by computationally integrating diverse data sets that account for tissue gene expression, human genetic variation, redundancies in cellular pathways and protein-protein interaction networks, among other factors.

Product Discovery

Once a specific target has been chosen, the modality used to disrupt the function of the target is then selected.

Potential modalities may include small molecules, antibodies or siRNAs.

Standard drug discovery efforts are then applied to identify a lead product candidate.

Alternatively, machine learning and database mining can be used to identify pre-existing chemical matter that is already known to inhibit an identified host target.

This chemical matter can then be verified as having anti-pathogen activity, and serve as a lead compound.

There are two potential outcomes from Step 3:

one-drug-for-one-bug and one-drug-for-multiple-bugs.

siRNA Platform

Gene expression can be altered by two main types of synthetic oligonucleotides:

(i) antisense oligonucleotides;

and (ii) siRNAs.

We believe that our current approach leveraging siRNAs may have safety and potency advantages over antisense oligonucleotides.

The first FDA-approved siRNA in the United States was ONPATTRO (patisiran), which was developed by our collaborator, Alnylam.

Mechanism of siRNA action to regulate gene expression .

Intracellular double stranded RNA, or dsRNA, is processed by the “dicer” complex to produce siRNAs that become integrated into a multi-subunit protein complex, the RNA-induced silencing complex, or RISC, which guides the siRNAs to the target messenger RNA, or mRNA, sequence.

The siRNA duplex unwinds, and the antisense strand remains bound to RISC and directs site-specific cleavage of the target complementary mRNA sequence, resulting in mRNA degradation and reduced expression of the target protein.

(A)n = polyadenylation.

siRNAs act via an RNA interference, or RNAi, mechanism involving sequence-specific knockdown of target RNAs.

Our bodies create their own so-called endogenous siRNAs, which act via the RNAi mechanism.

This RNAi mechanism can be exploited by chemically synthesizing synthetic siRNAs that are introduced as medicines to knock down target RNAs that express pathogen or host proteins of interest.

Pursuant to our collaboration and license agreement with Alnylam, we have an option to license Alnylam’s siRNA technology for use in up to four other infectious disease targets in addition to the HBV target now in the clinic and the recently announced COVID-19 siRNA program.

See the section titled “Business—Our Collaboration, License and Grant Agreements” for a description of the collaboration and license agreement.

We expect the following benefits from our siRNA platform and siRNAs generally:

Cutting-edge siRNA design, through collaboration with Alnylam

Direct anti-pathogen activity and potential for immunomodulation

Diminished off-target siRNA effects via use of next generation ESC+ technology as a differentiator compared to other siRNA approaches, which has the potential to increase the therapeutic index

Efficient targeting of siRNAs to the liver using GalNAc technology

Extended effects of siRNA may last for weeks to months in humans

One of our product candidates, VIR-2218, was generated using our siRNA platform.

We have elected to develop modified siRNAs initially for infectious diseases of the liver because these product candidates can be administered subcutaneously, are highly stable in the blood stream and are efficiently delivered into hepatocytes via GalNAc sugar modification.

Once in a liver cell, the siRNA can act to reduce pathogen or host gene expression.

Such siRNAs can be further modified to reduce off-target activity, and potentially increase the therapeutic index.

Since October 2017, we have collaborated with Alnylam to leverage this validated technology, with the goal of eliminating key host factors necessary for pathogen survival and removing microbial immune countermeasures.

We believe that HBV persists in part due to the expression of viral proteins such as HBsAg, which potentially inhibit antibody, T cell, and innate immune responses.

This prevents the immune response from clearing HBV.

By inhibiting the expression of these viral proteins, we envision enhancing immune function in persistently infected individuals.

Furthermore, we believe that combining siRNA therapy with products derived from our other platforms, including antibodies, T cells and innate immune modulators, may allow us to rapidly advance a functional cure for HBV.

siRNA Delivery Mechanism

Since unmodified synthetic siRNAs can be unstable in the blood stream, methods to stabilize synthetic siRNAs have been pioneered by Alnylam including using their ESC technology.

An approach that has been used successfully to deliver siRNA to liver cells is to conjugate siRNAs to a specific sugar known as a GalNAc, whose receptor is exclusively expressed at high levels on hepatocytes, allowing for uptake of large quantities of siRNA into hepatocytes.

Importantly, a GalNAc-conjugated siRNA can be delivered to the liver by subcutaneous injection, making administration relatively simple.

Potentially Enhancing the Therapeutic Index by Diminishing Off-Target Activity of siRNAs

A distinguishing characteristic of VIR-2218 siRNA, and of future siRNAs that we may develop with Alnylam, is the application of a new approach to diminish off-target effects of RNAi.

siRNAs may cause unwanted alterations to non-target host RNAs, a process known as off-target activity, which can result in short- or long-term toxicity.

To reduce off-target activity, which is thought to be due in part to microRNA, or miRNA, activity, it is necessary to preserve the RNAi activity of an siRNA while simultaneously decreasing its miRNA activity, as shown in the figure below.

Alnylam scientists have pioneered placement of a modified nucleotide called a glycol nucleic acid, or GNA, into the part of the siRNA that generates miRNA-like activity.

GNA modification has been shown to reduce miRNA activity, while preserving the RNAi activity of siRNA.

The combination of GNA modification and other chemical modifications that enhance siRNA stability is called ESC+ technology.

In animal models, reducing off-target miRNA activity can result in an increased therapeutic index of approximately five-fold.

A higher therapeutic index has the potential to allow for higher siRNA doses and/or a longer duration of therapy, while maintaining a favorable safety profile.

VIR-2218 was the first siRNA to enter the clinic with ESC+ technology.

On-Target and Off-Target Activity of siRNA .

siRNAs can have off-target activity when siRNA binds to mRNA with a partial sequence match, leading to translation repression or mRNA destabilization of unrelated messages (right side).

This contrasts with the intended on-target activity of an siRNA, which binds to an mRNA through a match to the entire sequence, leading to mRNA cleavage (left side).

mRNA = messenger ribonucleic acid;

RISC = ribonucleic acid-induced silencing complex.

Development Programs

Our current development pipeline consists of product candidates that address unmet needs caused by HBV, influenza A, SARS-CoV-2, HIV and TB.

*VIR-1111 is a vaccine designed to establish proof of concept in Phase (Ph) 1 clinical trial to determine whether unique immune response observed in non-human primates can be replicated in humans;

Our current development pipeline consists of product candidates that address unmet needs caused by COVID-19, HBV, influenza A virus, and HIV.

*VIR-7831 IV formulation currently in Phase 3 COMET-ICE trial;

IM formulation currently in Phase 2 COMET-PEAK trial, and pending in Phase 3 COMET-TAIL and COMET-STAR trials.

**Vaccine designed to establish proof of concept in Phase (Ph) 1 clinical trial to determine whether unique immune response observed in non-human primates can be replicated in humans;

ultimately, any candidates we advance as a potential HIV vaccine will require modifications to VIR-1111 before further clinical development.

Treatment and Prophylaxis for COVID-19

We are developing VIR-7831 and VIR-7832 treatment and prophylaxis of COVID-19.

Both VIR-7831 and VIR-7832 are based on a parent antibody, S309, which was derived from samples previously gathered for research on pan-coronavirus-neutralizing mAbs.

Preclinical data suggest that VIR-7831 and VIR-7832 have the potential for ‘dual-action’, or the ability to block viral entry into healthy cells and an enhanced ability to clear infected cells.

Both mAbs have also been designed to achieve high concentration in the lungs to ensure optimal penetration into airway tissues affected by SARS-CoV-2 and to have an extended half-life.

In addition, VIR-7832 has been designed to potentially enhance virus-specific T cell function, which could help treat and/or prevent COVID-19 infection.

VIR-7831 is currently in a Phase 3 clinical trial for the treatment of ambulatory patients at high risk of hospitalization or death from COVID-19.

Results for the primary endpoint of the trial are expected in the first quarter of 2021 , and if positive, will be used to seek EUA from the FDA and ultimately approval through the submission of a BLA .

VIR-7831 is also currently in a Phase 3 trial for the treatment of hospitalized adults with mild to moderate COVID-19, a Phase 2 combination trial of VIR-7831 and bamla n ivimab ( L Y -CoV555) for the treatment of mild to moderate COVID-19, and in the second quarter of 2021, we p lan to initiate a Phase 3 trial of VIR-7831 trial for prophylaxis or prevention of symptomatic infection of COVID-19.

In the first quarter of 2021, we anticipate initiating a Phase 1b/2a trial of VIR-7832 for the treatment of mild to moderate COVID-19.

Disease Overview and Limitations of Current Standard of Care

As of February 24, 2021, there were over 112.0 million recorded infections and almost 2.5 million recorded deaths worldwide from COVID-19.

T he FDA has granted EUA to two vaccines for prophylaxis of COVID-19, to three mAb regimens for treatment of mild-to-moderate COVID-19, and for convalescent plasma, and has approved remdesivir for the treatment of hospitalized COVID-19 patients.

Corticosteroids and other drugs are also being used the treat hospitalized patients.

Although it is anticipated that additional vaccines and potentially other medicines in development may become available during 2021, initial supplies will likely be limited and it will take time for widespread distribution programs to be rolled out globally to mitigate the pandemic.

Despite the high efficacy of the initial vaccine candidates, there are still populations in whom vaccine immunogenicity may potentially be suboptimal, such as the elderly with comorbidities, immunocompromised persons, or those who may not be able to tolerate vaccines.

Importantly, the durability of current vaccines and other medicines in the setting of the continued emergence of SARS-CoV-2 mutations is uncertain.

A highly effective SARS-CoV-2 mAb with the ability to block viral entry into healthy cells and clear infected cells, with lung bioavailability, with long half-life, and a high barrier to resistance that can be used to treat and/or prevent COVID-19, could have an impact on reducing disease-associated morbidity and mortality in ambulatory and hospitalized settings, as well as reducing virus transmission and decreasing the infection burden globally.

An increased distribution to mucosal tissue is expected to result in higher and more sustained levels of VIR-7831 in the respiratory mucosa, which is a potential advantage for treatment and prophylaxis.

Furthermore, mAbs are expected to confer rapid clinical benefit and protection following dosing as opposed to a vaccine which may require longer duration to attain a complete immunogenic response.

Our clinical program for VIR-7831 and VIR-7832 is comprised of the following trials:

VIR-7831 for COVID-19

Molecular Characteristics.

VIR-7831 is an investigational fully human IgG1 neutralizing anti-SARS-CoV-2 monoclonal antibody that has Fc modifications that are designed to improve bioavailability in the respiratory mucosa and increase half-life, and incorporates Xencor’s Xtend TM technology.

VIR-7831 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.

VIR-7831 potently neutralizes live SARS-CoV-2 in vitro, reduces viral replication and symptoms in the hamster model in vivo, and binds to a highly conserved epitope that is shared with SARS-CoV-1, thus potentially leading to a wide breadth of sarbecovirus coverage and a higher barrier to resistance.

Vir and GSK are collaborating on the development of VIR-7831 for the treatment and prophylaxis of COVID 19.

Phase 2/3 Trials of VIR-7831.

VIR-7831 is currently being assessed as a treatment in adults with mild to moderate COVID-19 who are at high risk of hospitalization or death.

This trial is a Phase 3, randomized, double-blind, multi-center, placebo-controlled trial of VIR-7831 with planned interim analyses to allow early stopping for futility, efficacy, or safety.

The trial includes a lead-in phase to evaluate the safety and tolerability of VIR-7831, followed by an expansion phase with 1:1 randomization of VIR-7831 and placebo in approximately 1,340 participants.

Results for the primary clinical endpoint of reduction of hospitalization and/or death are expected in the first quarter of 2021.

ACTIV-3/TICO:

VIR-7831 is also being assessed in an ongoing trial to decrease time to sustained recovery in hospitalized adults with COVID-19.

This is a Phase 3, multicenter, adaptive, randomized, blinded controlled platform trial evaluating the safety and efficacy of therapeutics for hospitalized patients with COVID-19.

An evaluation of the safety and efficacy using pulmonary and extrapulmonary ordinal outcomes comparing VIR-7831 against control (i.e.

placebo plus standard of care) in Part 1 (150 patients on VIR-7831) is expected in the first quarter of 2021 and will determine if VIR-7831 continues into Part 2 of the trial (350 patients on VIR-7831).

In Part 1, five days after dosing, participants’ clinical status is assessed, based on the need for supplemental oxygen, mechanical ventilation, or other supportive care.

If the VIR-7831 treatment arm appears to have a positive benefit-risk profile, the trial will move into Part 2 and enroll additional participants, including those who are more severely ill (i.e., adults with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs).

These patients will be followed for 90 days to analyze their response to treatment.

The primary efficacy endpoint is the sustained recovery for 14 days after release from the hospital and/or reduction in death.

This trial is part of a sub-trial of the NIH ACTIV-3 platform.

VIR-7831 is also being assessed in Eli Lilly and Company’s ongoing BLAZE-4 trial, which is a Phase 2, randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety and efficacy of mono and combination therapy with mAbs in low-risk adults with mild to moderate COVID-19.

An arm of this trial will evaluate the impact of the combination of VIR-7831 plus Eli Lilly and Company’s bamlanivimab (LY-CoV555) on viral clearance and clinical outcomes in participants with mild and moderate COVID-19.

Initial results for this arm of the BLAZE-4 trial are expected in the first half of 2021.

VIR-7831 is also currently being evaluated in a Phase 2, multicenter, randomized, double-blind, two-part, parallel group trial designed to compare 1) the safety, tolerability and pharmacokinetics of second-generation VIR-7831 manufactured material to first-generation VIR-7831 manufactured material intravenously, and 2) the viral kinetics and safety of intravenous, or IV, administration compared to IM administration of VIR-7831 in low-risk adults with mild to moderate COVID-19.

The low, 500 mg dose of VIR-7831 lends itself to an IM administration, which could facilitate broader access to monoclonal antibody therapy in settings where IV administration is not feasible.

This is a planned Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating an IM route of administration of VIR-7831 in adults at high risk of hospitalization or death.

The primary clinical endpoint is the reduction of hospitalization and/or death, and the trial is expected to start in the second quarter of 2021.

This is a planned Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of VIR-7831 as prophylaxis for COVID-19.

Adult participants at risk of becoming infected by COVID-19 will receive one dose of VIR-7831 by IM administration.

The primary clinical endpoint of this trial is the prevention of symptomatic infection.

This trial is expected to start in the second quarter of 2021.

VIR-7832 for COVID-19

Molecular Characteristics.

VIR-7832 is identical to VIR-7831, except that VIR-7832 contains additional modifications in the Fc domain that is designed to further enhance its effector function, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, abrogate C1q binding, as well as elicit enhanced T cell and antibody responses.

VIR-7832 incorporates Xencor’s Xtend TM and other Fc technologies.

These additional modifications may increase potency and induce a “vaccinal” effect (the induction of antigen-specific T cell responses) in patients with COVID-19.

Phase 1b/2a Trial of VIR-7832.

The Phase 1b portion of this trial is a double-blinded, randomized, first-in-human dose-escalation trial for VIR-7832 in which adults with mild to moderate COVID-19 infection will be randomized to VIR-7832 or placebo in a 3:1 ratio.

The primary objective of Phase 1b is to determine the safety and tolerability of single ascending doses of VIR-7832 for the treatment of mild to moderate COVID-19.

Once a suitable dose is identified, VIR-7832 will progress to Phase 2a in which VIR-7832, VIR-7831 and placebo will be randomized in a 2:2:1 ratio in participants with mild to moderate COVID-19.

The primary objective of the double-blinded, placebo-controlled, randomized Phase 2a will be to investigate the safety and virologic activity of VIR-7832 in patients with mild to moderate COVID-19 infection.

Immunologic parameters, such as T-cell responses to SARS-CoV-2, will also be examined.

The trial is a collaboration between Vir and GSK and is being conducted as part of the U.K.-based NHS supported AGILE initiative.

Functional Cure for HBV

2 unchanged sentences

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.

While monotherapy with each of these agents may provide a functional cure in some patients, we believe combination therapy will be necessary for a functional cure in many patients.

We are therefore also planning trials that combine VIR-2218 with VIR-3434, which we believe have the potential to act in concert by removing potentially tolerogenic HBV proteins and stimulating new HBV specific T cells.

We are also initiating trials that combine VIR-2218 with PEG-IFN- α and are evaluating additional combinations with other immunotherapy agents and direct acting antiviral agents.

We have completed enrollment of a Phase 1/2 clinical trial of VIR-2218, an HBV-targeting siRNA.

In this ongoing trial, which enrolled total of 81 subjects, initial data demonstrate substantial reductions in HBsAg in patients at doses ranging from 20 mg to 200 mg.

Based on our data, VIR-2218 has been generally well tolerated in healthy volunteers given as a single dose up to 900 mg and in patients given as two doses of 20 mg, 50 mg, 100 mg or 200 mg each dose.

As of December 11, 2019, 37 healthy volunteers have received VIR-2218 and 12 healthy volunteers have received placebo.

In addition, 24 patients with chronic HBV on NRTIs have received VIR-2218 and eight patients with chronic HBV on NRTIs have received placebo.

We anticipate announcing additional details on our Phase 1/2 clinical trial of VIR-2218 in the second quarter 2020.

In addition, we anticipate starting a Phase 2 combination trial of VIR-2218 and PEG-IFN-α in the second half of 2020.

VIR-3434, an HBV-neutralizing mAb, was planned to start a Phase 1 clinical trial in the first half of 2020.

Due to the COVID-19 pandemic, however, we now anticipate this trial will start in the second half of 2020.

While monotherapy with VIR-2218 and VIR-3434 may provide a functional cure in some patients, we believe combination therapy will be necessary for a functional cure in many patients.

We plan to initiate a Phase 2 trial in the second half of 2021 that combines VIR-2218 and VIR-3434.

We believe that this combination has the potential to inhibit virion production, removing potentially tolerogenic HBV proteins, and stimulating new HBV specific T cells.

In January 2021, we announced a clinical trial collaboration with Gilead to initiate a Phase 2 trial of VIR-2218 in combination with GS-9688 (selgantolimod), a TLR-8 agonist, and nivolumab, an approved PD-1 inhibitor in 2021 in both treatment-experienced and treatment-naïve patients with HBV.

We also anticipate that Brii Bio will start a Phase 2 trial of VIR-2218 in combination with BRII-179, an investigational T cell vaccine, in the first half of 2021.

VIR-2218, an HBV-targeting siRNA, is currently in a Phase 2 clinical trial .

In Parts A to C of the trial, 37 healthy volunteers and 24 patients with chronic HBV on NRTIs received VIR-2218.

The data suggest that VIR-2218 is generally well-tolerated in healthy volunteers given as a single dose up to 900 mg and in patients given as two doses of 20 mg, 50 mg, 100 mg or 200 mg each dose.

The data also demonstrate substantial, dose dependent reductions in HBsAg in patients at doses ranging from 20 mg to 200 mg, which are durable at the higher doses for at least nine months.

Parts D-F are evaluating additional doses of VIR-2218, with and without PEG-IFN-α.

VIR-3434, an HBV-neutralizing mAb, is currently in a Phase 1 clinical trial.

In January 2021, we announced initial data from the first blinded cohort of eight patients with chronic HBV infection on NRTIs, two of whom received placebo, and six of whom received a single dose of 6mg VIR-3434, which showed six of eight patients responded and achieved a mean reduction of 1.3 log 10 IU/mL in serum HBsAg by day eight, the day when nadir was achieved in most patients.

We anticipate additional clinical data from our Phase 1 trial in the second quarter of 2021.

Disease Overview and Limitations of Current Standard of Care

23 unchanged sentences

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.

For a registrational trial to demonstrate a functional cure, the formal endpoint accepted by the U.S.

For a registrational trial to demonstrate a functional cure, the formal endpoint accepted by the FDA, is undetectable HBsAg, defined as less than 0.05 international units per milliliter, or 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.

1 unchanged sentence

Molecular Characteristics.

VIR-2218 is a single siRNA targeting a conserved sequence of HBV that allows for predicted activity against 99.7% of the strains of HBV, including all 10 HBV genotypes.

VIR-2218 is an investigational, single siRNA targeting a conserved sequence of HBV that allows for predicted activity against 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, VIR-2218 is able to degrade each transcript, and consequently decrease the expression of all proteins produced by the virus:

X, polymerase, S, and core.

VIR-2218 is thus potentially a broad-spectrum, potent antiviral.

8 unchanged sentences

We believe that VIR-2218 is the only HBV-targeting siRNA currently in development that includes ESC+ technology.

We believe this technology may be able to enhance the potential safety and efficacy of VIR-2218.

We believe this technology may be able to enhance the potential safety of VIR-2218.

Phase 1/2 Trial of VIR-2218.

VIR-2218-1001 is an adaptive clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of VIR-2218.

The current trial design of VIR-2218-1001, as of December 2019, is shown below.

The current trial design of VIR-2218-1001 is shown below.

We initiated dosing of the Part A portion of the trial for VIR-2218 in November 2018.

Status of VIR-2218-1001 trial in healthy volunteers and patients with chronic HBV infection .

17 unchanged sentences

VIR-2218-1001 is an ongoing clinical trial.

As of December 11, 2019, 49 healthy volunteers have enrolled in Part A of the trial.

49 healthy volunteers enrolled in Part A of the trial.

Each Part A completed cohort includes six subjects receiving VIR-2218 and two subjects receiving placebo.

1 unchanged sentence

In the 400 mg cohort, a replacement subject was enrolled due to a subject who voluntarily withdrew from the trial.

The 900 mg cohort is designed to assess the maximum tolerated dose of VIR-2218.

The 900 mg cohort was designed to assess the maximum tolerated dose of VIR-2218.

In Part B of the trial, 24 patients with chronic HBV who are HBeAg negative have been enrolled.

Each Part B completed cohort includes three patients receiving VIR-2218 and one patient receiving placebo.

All cohorts have completed dosing and are in follow-up.

All cohorts have completed dosing and have completed follow-up.

In Part C of the trial, eight patients with chronic HBV who are HBeAg positive have been enrolled.

Each completed cohort includes three patients receiving VIR-2218 and one patient receiving placebo.

All cohorts have completed dosing and are in follow-up.

All cohorts have completed dosing and have completed follow-up.

Clinical Data.

1 unchanged sentence

No clinically significant alanine transaminase or 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, have been observed in a subset of subjects.

Two serious adverse events, or SAEs, have been reported, both in Part B.

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 serious adverse events, or SAEs, have been reported, all in Part B.

The first, a Grade 2 headache, resolved with intravenous fluids and non-opioid pain medications.

1 unchanged sentence

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 VIR-2218.

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 VIR-2218.

Three Grade 3 adverse events of upper-respiratory tract infection, chest pain and low phosphate levels in the blood have also been reported.

1 unchanged sentence

The biologic activity of VIR-2218 was assessed by declines in HBsAg.

The activity of VIR-2218 through Week 16 in the 200 mg cohorts of Part B, HBeAg negative, and Part C, HBeAg positive, is shown in the graph below.

The activity of VIR-2218 through Week 36 for each dose level is shown in the graph below.

For Parts B and C, the average baseline HBsAg levels were 3.3 log 10 IU/mL and 3.9 log 10 IU/mL, respectively.

1 unchanged sentence

The declines observed in HBsAg at Week 16 ranged from 0.97 log 10 to 2.2 log 10 , or an approximately nine to 160-fold reduction, after two 200 mg doses of VIR-2218 given four weeks apart.

The average HBsAg level at Week 16 was 314 IU/mL, with half of patients achieving HBsAg values < 100 IU/mL and 5/6 achieving HBsAg values < 1000 IU/mL.

The ability of VIR-2218 to result in substantial declines in HBsAg after only two doses suggests that VIR-2218 has the potential to play an important role in the functional cure of chronic HBV.

We plan to conduct clinical trials evaluating additional dosing regimens of VIR-2218 alone, as well as given in combination with the potential vaccinal mAb VIR-3434 , PEG-IFN-α, and other immunomodulatory agents.

The average 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.

At Week 36, the average reduction in patients receiving 200 mg dose level was 1 log, demonstrating a durable HBsAg response.

The ability of VIR-2218 to result in substantial and durable declines in HBsAg after only two doses suggests that VIR-2218 has the potential to play an important role in the functional cure of chronic HBV.

We have initiated and plan to initiate additional clinical trials evaluating VIR-2218 in combination with other immunomodulatory agents.

Change from Baseline in HBsAg following administration of VIR-2218 .

The solid blue line represents the average activity of VIR-2218 in HBeAg negative and positive patients at the 200 mg dose level, excluding placebo patients.

The activity of VIR-2218 in individual patients is shown in grey lines, with solid lines representing HBeAg negative patients and dotted lines representing HBeAg positive patients.

Each line represents the average decline from baseline in HBsAg for VIR-2218 for each dosing level or pooled placebo in Parts B and C.

VIR-3434 for HBV

Molecular Characteristics and Preclinical Data .

VIR-3434 is a mAb targeting a conserved region on HBsAg that allows it to neutralize strains from all 10 HBV genotypes.

VIR-3434 is an investigational mAb targeting a conserved region on HBsAg that allows it to neutralize strains from all 10 HBV genotypes.

VIR-3434 specifically targets the antigenic loop, or AGL, on HBsAg.

The AGL helps the virus bind to hepatocytes and subsequently infect these liver cells.

By binding to the AGL, VIR-3434 prevents viral entry, which prevents spread of HBV to uninfected hepatocytes.

By binding to the AGL, VIR-3434 prevents viral entry, which prevents the spread of HBV to uninfected hepatocytes.

VIR-3434, through a process called opsonization, also helps remove HBV virions and SVPs from the blood.

6 unchanged sentences

First, due to specialized mutations in the Fc domain of VIR-3434, it has the potential to act as a T cell vaccine.

VIR-3434 has been engineered with mutations that enhance binding to the FcR IIa activating receptor and diminish binding to the FcR IIb inhibitory receptor.

VIR-3434 , which incorporates Xencor’s Xtend TM and other Fc technologies , has been engineered with mutations that enhance binding to the FcR IIa activating receptor and diminish binding to the FcR IIb inhibitory receptor.

As such, VIR-3434 is designed to capture virions and SVPs, deliver such virions and SVPs to DCs, and instruct these DCs to mature and stimulate T cells that can eliminate HBV infected hepatocytes.

6 unchanged sentences

VIR-2218 and VIR-3434, which was modified to have a mouse mAb backbone for this experiment, administered alone or together result in reduced HBsAg in a mouse model .

Planned Phase 1 Trial of VIR-3434.

VIR-3434-1002 is an adaptive clinical trial designed evaluate the safety, tolerability, pharmacokinetics and antiviral activity of VIR-3434.

Phase 1 Trial of VIR-3434.

VIR-3434-1002 is an adaptive clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of VIR-3434.

The current trial design of VIR-3434-1002 is shown below.

VIR-3434 was planned to start a Phase 1 clinical trial in the first half of 2020.

Due to the COVID-19 pandemic, however, we now anticipate this trial will start in the second half of 2020.

We anticipate that this trial will have three parts.

We initiated dosing of the Phase 1 trial in May 2020.

The Phase 1 clinical trial has three parts.

Part A is a single ascending dose design in healthy volunteers.

Parts B and C are single ascending dose designs in patients with chronic HBV on NRTIs.

Patients in Part B will have HBsAg levels less than 1,000 IU/ml.

It is possible that patients with such lower HBsAg levels will have a more profound response to VIR-3434 than patients with higher HBsAg levels.

Patients in Part B will have HBsAg levels less than 1,000 IU/ml for the 6 mg cohort, or less than 3,000 IU/mL for the other cohorts.

It is possible that patients with lower HBsAg levels will have a more profound response to VIR-3434 than patients with higher HBsAg levels.

Patients with HBsAg levels greater than or equal to 3,000 IU/ml may be evaluated in an optional Part C.

3 unchanged sentences

Optional Part C not shown.

*Part B 6 mg cohort conducted in patients with HBsAg levels less than 1,000 IU/ml.

The primary endpoints across all parts of the trial are safety and tolerability.

The key secondary endpoint in Parts B and C is the maximum reduction of serum HBsAg from baseline.

Clinical Data.

To date, all Part A cohorts have completed dosing up to 3000 mg administered intravenously.

The trial’s Safety Review Committee, or SRC, has reviewed blinded safety data for at least two weeks post dose from all Part A cohorts.

Based on this data, VIR-3434 was generally well tolerated in healthy volunteers with no clinical safety concerns.

The majority of AEs were Grade 1, and no Grade ≥ 3 AEs or SAEs were reported.

No clinically significant effects on laboratory or electrocardiogram parameters were observed.

All dose levels were associated with an acceptable safety and tolerability profile, as determined through a blinded review of data by the SRC.

In January 2021, we announced initial data from Part B in patients with chronic HBV on NRTIs receiving 6mg VIR-3434 or placebo.

Data from the first blinded cohort of eight patients, two of whom received placebo and six of whom received a single dose of 6 mg of VIR-3434, showed that six of eight patients responded and in those who responded, a mean reduction of 1.3 log 10 IU/mL in serum HBsAg by day eight was achieved, the day when nadir was achieved in most patients.

The ability of a single dose of 6mg of VIR-3434 to markedly lower HBsAg demonstrate VIR-3434 has the potential to play an important role in the functional cure of HBV.

We anticipate additional clinical data from our Phase 1 trial in the second quarter of 2021.

Other HBV Combinations and New Product Candidates

In addition to the planned combination trial of VIR-2218 and VIR-3434, we are planning clinical trials that will combine our product candidates with other immunomodulatory agents.

We plan to commence a Phase 2 combination trial with PEG-IFN-α in the second half of 2020.

Phase 2 Trial of VIR-2218 in combination with PEG-IFN-α.

VIR-2218-1001 Parts D to F is a clinical trial evaluating the safety, tolerability, pharmacokinetics and antiviral activity of VIR-2218 alone and in combination with PEG-IFN-α in patients with chronic HBV infection on NRTIs .

We initiated the dosing of the trial in July 2020.

VIR-2218-1001 Parts D to F will evaluate multiple doses of VIR-2218, either 50mg or 200mg, alone or in combination with PEG-IFN-α starting on Day 1 or at Week 12.

The trial cohorts are shown below.

We anticipate initial clinical data in the second quarter of 2021.

VIR-2218-1001 Parts D to F are evaluating multiple doses of VIR-2218 alone or in combination with PEG-IFN-α in patients with chronic hepatitis B virus infection .

Additionally, In January 2021, we announced a clinical trial collaboration with Gilead to initiate a Phase 2 trial of VIR-2218 in combination with GS-9688 (selgantolimod), a TLR-8 agonist, and nivolumab, an approved PD-1 inhibitor in 2021 in both treatment-experienced and treatment-naïve patients with HBV.

The primary outcome of the trial will be the proportion of patients achieving a functional cure, defined as an off-therapy loss of HBsAg and HBV DNA from the serum.

Trial costs will be shared equally by the parties, and we will supply VIR-2218 and Gilead will supply selgantolimod.

We and Gilead will retain full rights to our respective product candidates and will discuss the potential path forward for any future combination trials based on the outcome of the Phase 2 trial.

We also anticipate that Brii Bio will start a Phase 2 trial of VIR-2218 in combination with BRII-179, an investigational a T cell vaccine, in the first half of 2021.

Furthermore, in parallel with the above development programs, research efforts are underway to use our innate immunity platform to identify and disrupt the host proteins necessary for HBV cccDNA formation and stability, which we believe could result in a complete cure.

3 unchanged sentences

We are developing VIR-2482 as universal prophylaxis for influenza A.

VIR-2482 is a mAb that targets a conserved region of the influenza A hemagglutinin protein and consequently has the potential to be prevent illness by any strain of influenza A.

VIR-2482 is a mAb that targets a conserved region of the influenza A hemagglutinin protein and consequently has the potential to prevent illness from any strain of influenza A, including seasonal and pandemic strains.

In vitro, VIR-2482 has been shown to cover all major strains of influenza A that have arisen since the 1918 Spanish flu pandemic.

3 unchanged sentences

VIR-2482 has been half-life engineered so that a single dose has the potential to last the entire flu season, which is typically five to six months long.

In August 2019, we initiated dosing in the Phase 1/2 clinical trial for VIR-2482.

VIR-2482 is currently in a Phase 1/2 clinical trial.

Initiation of Phase 2 clinical trial for VIR-2482, which was delayed due to the impact of COVID-19, is now expected in the fourth quarter of 2021 with proof-of-concept results anticipated in the first half of 2022.

In February 2021, we entered into the 2021 Preliminary Agreement with GSK, which included a program to research, develop and commercialize mAbs for the prevention, treatment or prophylaxis of the influenza virus.

In addition, after we complete and report Phase 2 trial outcomes for VIR-2482, GSK will have the exclusive option to obtain exclusive rights to co-develop and commercialize VIR-2482.

See the section titled “Our Collaboration, License and Grant Agreements—Collaboration Agreement with GSK” for a description of the 2021 Preliminary Agreement.

Disease Overview and Limitations of Current Standard of Care

On average, each year the influenza virus infects 5% to 10% of the world’s population and results in an estimated 500,000 deaths.

The efficacy of the flu vaccine has ranged from 10% to 60% over the past 15 years, with an average of 40%, overall, across all populations.

The efficacy in the elderly, defined as those 65 and older, has been found to be notably lower, in some flu seasons.

In the 2017-2018 flu season, despite the availability of the flu vaccine, approximately 48 million people were diagnosed with influenza, one million people were hospitalized, and 61,000 people died from influenza in the United States alone.

Thus, more Americans died of influenza in the 2017-2018 flu season than from breast or prostate cancer in all of 2018.

The efficacy of the seasonal flu vaccine has ranged from 10% to 60% over the past 15 years, with an average of 40%, overall, across all populations.

seasonal flu vaccine efficacy in the elderly, defined as those 65 and older, has been found to be notably lower, in some flu seasons.

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 United States alone.

Thus, more Americans died of influenza in the 2018-2019 flu season than from prostate cancer in all of 2019.

The large majority of these influenza-related deaths occurred in the elderly and/or those who had either pre-existing lung and/or heart disease.

12 unchanged sentences

Clinical and technology advances in flu vaccines, such as cell-based manufacturing and higher dose administration, do not address these two fundamental limitations.

Clinical and technological advances in flu vaccines, such as cell-based manufacturing and higher dose administration, do not address these two fundamental limitations.

VIR-2482 for Influenza A

Molecular Characteristics and Preclinical Data.

VIR-2482 is a mAb targeting a functionally conserved epitope on the influenza A hemagglutinin protein located within the stem region.

VIR-2482 is an investigational mAb targeting a functionally conserved epitope on the influenza A hemagglutinin protein located within the stem region.

We believe that all strains of influenza, past and future, have and likely will contain this conserved epitope within the stem region.

3 unchanged sentences

Thus, we believe VIR-2482 has the potential to be effective irrespective of the status of a person’s immune system.

Notably, in a recent clinical epidemiology study, it was observed that the presence of rare, stem-binding influenza antibodies correlated with protection from influenza infection.

Notably, in a 2019 clinical epidemiology study, it was observed that the presence of rare, stem-binding influenza antibodies correlated with protection from influenza infection.

VIR-2482 targets a highly conserved region of the influenza virus and exhibits potency against the last century of influenza viruses .

8 unchanged sentences

These strains were selected to cover the antigenic variation of the seasonal H1N1 and H3N2 strains back to 1938 and 1968, respectively, and strains from other subtypes that infected humans in past pandemics or that caused sporadic animal-derived outbreaks.

We engineered the parent form of VIR-2482 to extend its half-life to create VIR-2482.

We engineered the parent form of VIR-2482 to extend its half-life to create VIR-2482 , which incorporates Xencor’s Xtend TM technology .

This half-life extension potentially allows for a single injection of VIR-2482 given at the start of the influenza season to maintain a protective concentration in the respiratory tract for the duration of the influenza season.

1 unchanged sentence

VIR-2482-3001 is a clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of VIR-2482.

The current design of VIR-2482-3001 is shown below.

In August 2019, we initiated dosing in the Phase 1/2 clinical trial for VIR-2482.

The current trial design of VIR-2482-3001 is shown below.

We initiated dosing of the Phase 1/2 clinical trial for VIR-2482 in August 2019.

This trial is designed to include up to 2,860 healthy volunteers across the Phase 1 and Phase 2 portions.

Initiation of Phase 2 clinical trial for VIR-2482, which was delayed due to the impact of COVID-19, is now planned for the fourth quarter of 2021 with proof-of-concept results anticipated in the first half of 2022.

VIR-2482-3001 clinical trial design in healthy adult volunteers .

Flu = influenza.

The Phase 1 portion of this trial, a single ascending dose trial in healthy adult volunteers, has completed enrollment of all four dose cohorts (60mg, 300 mg, 1200 mg, and 1800 mg) and the subjects remain in follow-up.

1 unchanged sentence

Healthy volunteers in the Phase 1 portion may receive a second dose, one year later, to evaluate for the possibility of anti-drug antibodies.

The primary endpoints of the Phase 1 and Phase 2 portions of this trial are safety and tolerability.

The primary endpoint of the Phase 1 portion is evaluation of safety and tolerability.

The primary efficacy endpoint of the Phase 2 portion is laboratory-confirmed influenza A illness with key secondary endpoints of severity and duration of illness due to influenza A, as well as quantification of influenza A viral load at the time of presentation with influenza illness.

3 unchanged sentences

An HLA-E restricted immune response has been shown to be associated with protection of NHPs from SIV.

VIR-1111 was planned to start a Phase 1 clinical trial in the first half of 2020.

Due to the coronavirus COVID-19 pandemic, however, we now anticipate this trial will start in the second half of 2020.

VIR-1111 is a proof of concept vaccine, because, at minimum, changes to the vaccine antigen from HIV will be required before subsequent phases of clinical development.

In December 2020, we initiated a Phase 1 trial for VIR-1111.

VIR-1111 is a proof of concept vaccine, because, at minimum, changes to the vaccine antigen from HIV will be required before starting subsequent phases of clinical development.

The need to alter the antigen within VIR-1111 or other aspects of the vaccine design to allow for further clinical development will require additional Phase 1 work with the altered product candidate.

1 unchanged sentence

Disease Overview and Limitations of the Current Standard of Care

Each year there are approximately 1.8 million new cases of HIV and approximately 1.0 million HIV-related deaths globally.

Each year there are approximately 1.7 million new cases of HIV and 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, over 35 million people have died from HIV-related illnesses globally.

According to the World Health Organization, almost 33 million people have died from HIV-related illnesses globally.

Highly effective HIV treatments are now available, but these medicines only suppress HIV and are not curative.

27 unchanged sentences

If protection effectiveness is found to be less than 100%, such data may allow us to predict who will be protected as well as to generate next-generation vaccines.

Planned Phase 1 Trial of VIR-1111.

VIR-1111-2001 is an ascending dose clinical trial designed to evaluate the safety, tolerability and immunogenicity of VIR-1111 in CMV-positive healthy volunteers.

The immunogenicity evaluation includes assessment of the breadth and nature of the T cell response to the vaccine.

VIR-1111 was planned to start a Phase 1 clinical trial in the first half of 2020.

Due to the COVID-19 pandemic, however, we now anticipate this trial will start in the second half of 2020.

Phase 1 Trial of VIR-1111.

VIR-1111-2001 is a multiple ascending dose clinical trial designed to evaluate the safety, tolerability, reactogenicity and immunogenicity of VIR-1111 in CMV-positive healthy adult volunteers.

The immunogenicity evaluation includes an assessment of the breadth and nature of the T cell response to the vaccine.

The current trial design of VIR-1111-2001 is shown below.

We initiated a Phase 1 clinical trial for VIR-1111 in December 2020 .

The manufacture and early clinical development of VIR-1111 is funded by the Bill & Melinda Gates Foundation.

Modifications to VIR-1111 will be required before subsequent phases of clinical development, as VIR-1111 is a proof of concept vaccine and will not in its current format result in a commercial product.

Vaccine for TB Prophylaxis

We are developing VIR-2020 as a vaccine to prevent active TB, including preventing latent infection from progressing to active pulmonary disease, which is a key source of ongoing transmission of TB.

VIR-2020, a T cell vaccine based on HCMV, is designed to stimulate T cells that reside in the lung and recognize TB epitopes different from those recognized by prior TB vaccines.

In an NHP model, T cell vaccines based on RhCMV were shown to provide protection against TB.

We plan to submit an IND for VIR-2020 in 2023 and thereafter commence a Phase 1 clinical trial.

Disease Overview and Limitations of the Current Standard of Care

TB is the leading cause of death from a single infectious agent globally.

Each year there are approximately 10 million new cases of TB and approximately 1.6 million deaths.

Approximately 1.7 billion people are estimated to have an asymptomatic form of TB known as latent TB.

These approximately 1.7 billion people with latent TB worldwide are at risk of progressing to active disease.

Treatment for active TB requires multiple medications, taken for a minimum of six months.

Treatment is unsuccessful approximately 20% of the time for drug susceptible cases and 45% of the time for multidrug-resistant cases.

The World Health Organization estimates that the current global economic burden of TB amounts to approximately $12 billion annually.

We believe the most effective means of curbing this worldwide TB epidemic would be a safe and effective vaccine that prevents active pulmonary TB.

Currently, the only vaccine recommended for preventing TB is the Bacillus Calmette–Guérin, or BCG, vaccine, which was introduced over 80 years ago.

Although BCG is partially efficacious at protecting infants and young children from disseminated disease, it is poorly protective against pulmonary disease in adolescents and adults, who represent the key sources of TB transmission and are the primary contributors to the overall disease burden.

We believe that a key reason why an effective TB vaccine does not exist is because TB is not easily cleared by boosting our immune system’s natural response to infection.

VIR-2020 for TB

Molecular Characteristics and Preclinical Data.

VIR-2020, a T cell vaccine based on HCMV, is designed to stimulate T cells that reside in the lung and recognize TB epitopes which are different from those recognized by prior TB vaccines.

In NHPs, vaccines based on RhCMV were shown to protect against TB.

To our knowledge, this was the first demonstration of complete prevention of active TB in a substantial portion of NHPs by a peripherally administered vaccine after challenge with a highly pathogenic strain of Mycobacterium tuberculosis , the causative agent of TB.

As shown previously in the NHP-SIV model, the TB vaccine was observed to elicit T cells that recognize three to four times the number of epitopes compared to other vaccine platforms.

Similarly, preliminary data suggest that determining which NHPs will be protected from TB after vaccination can be predicted using transcriptomic signatures.

Planned Phase 1 Trial of VIR-2020 .

VIR-2020-4001 is a clinical trial designed to evaluate the safety, tolerability and immunogenicity of VIR-2020 in CMV-negative and CMV-positive healthy volunteers.

The immunogenicity evaluation will include assessment of the breadth and nature of the T cell response to the vaccine.

The design of this trial is under development.

We plan to submit an IND for VIR-2020 in 2023.

The manufacture and early clinical development of VIR-2020 is funded by the Bill & Melinda Gates Foundation.

VIR-1111-2001 is a multiple ascending dose escalation trial in CMV seropositive, HIV uninfected healthy adult volunteers.

Arrows indicate trial progression.

CMV = cytomegalovirus, HIV = human immunodeficiency virus, SC = subcutaneous, ffu = focus forming units

Technology Platforms

Platforms for the Creation of Transformative Medicines for Infectious Diseases

We have purposefully assembled a portfolio of technology platforms that we believe will, individually or in combination, allow us to stimulate and enhance the immune system in innovative ways and to exploit the vulnerabilities of pathogens.

Our current platforms are focused on antibodies, T cells, the innate immune response and siRNAs.

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.