10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2021

Commission File Number 001-40703

Adagio Therapeutics, Inc.

(Exact name of Registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (781) 819-0080

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

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

Common Stock, $0.0001 par value per share ADGI The Nasdaq Global Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒

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

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

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

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

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

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

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

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

The Registrant was not a public company as of the last business day of its most recently completed second fiscal quarter and therefore cannot calculate the aggregate market value of the voting and non-voting common equity held by non-affiliates as of such date.

The number of shares of the Registrant’s Common Stock outstanding as of March 24, 2022 was 109,675,173.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s definitive proxy statement, to be filed pursuant to Regulation 14A under the Securities Exchange Act of 1934, for its 2022 Annual Meeting of Stockholders are incorporated by reference in Part III of this Form 10-K.

Table of Contents

Page

PART I

Item 1. Business 1

Item 1A. Risk Factors 43

Item 1B. Unresolved Staff Comments 103

Item 2. Properties 103

Item 3. Legal Proceedings 103

Item 4. Mine Safety Disclosures 103

PART II

Item 6. [Reserved] 105

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 122

Item 8. Financial Statements and Supplementary Data 122

Item 9A. Controls and Procedures 122

Item 9B. Other Information 123

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 123

PART III

Item 10. Directors, Executive Officers and Corporate Governance 124

Item 11. Executive Compensation 124

Item 14. Principal Accountant Fees and Services 124

PART IV

Item 15. Exhibit and Financial Statement Schedules 125

PART I

Item 1. Business.

Overview

We are a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of differentiated products for the prevention and treatment of infectious disease. We are developing our lead product candidate, adintrevimab, for the prevention and treatment of coronavirus disease 2019, or COVID-19, the disease caused by the virus SARS-CoV-2 and its variants. COVID-19 has caused the current global pandemic that remains a significant global health crisis and has resulted in millions of deaths and lasting health problems in many survivors. We believe that COVID-19 will become an endemic disease requiring a variety of effective, safe and convenient prevention and treatment options for years to come. We are leveraging our team’s collective expertise and platform to deliver adintrevimab to patients and to discover novel solutions to infectious diseases through internal research and collaborations.

Adintrevimab is designed to be a potent, long-acting and broadly neutralizing antibody for both the prevention and treatment of COVID-19. We believe several key attributes combine to differentiate adintrevimab, including breadth, potency, durability of protection, convenient intramuscular, or IM, administration, and potential for broad application across multiple indications, depending on the SARS-CoV-2 variant.

Data from our Phase 1 healthy volunteer study ADG20-1-001 confirmed the extended half-life of adintrevimab, which we believe may allow for durable protection against COVID-19, depending on the variant. In February 2022, we expanded the Phase 1 study to evaluate safety and pharmacokinetics at higher doses. As of March 27, 2022, there were no study drug related adverse events, serious adverse events, injection-site reactions or hypersensitivity reactions reported across all dose levels evaluated.

We are assessing adintrevimab in two separate Phase 2/3 clinical trials: our EVADE trial to evaluate adintrevimab for the prevention of COVID-19 and our STAMP trial to evaluate adintrevimab for the treatment of COVID-19. Our EVADE clinical trial is a global Phase 2/3 clinical trial evaluating adintrevimab as a prevention for COVID-19 in both the post-exposure and pre-exposure settings. Our STAMP trial is our global Phase 2/3 clinical trial evaluating adintrevimab as a treatment for COVID-19. Due to the emergence and global spread of the Omicron variant, against which adintrevimab has reduced in vitro neutralization potency compared to prior variants, enrollment in both EVADE and STAMP was paused on January 11, 2022, and preliminary efficacy and safety data were evaluated in pre-and post-Omicron populations.

In the primary analysis population, patients infected with or exposed to a non-Omicron variant, or the pre-Omicron group, adintrevimab met the primary objectives across all three indications, demonstrating statistically significant and clinically meaningful efficacy. In pre-exposure and post-exposure prophylaxis, adintrevimab was associated with 71% and 75% relative risk reductions compared to placebo, respectively, in the prevention of RT-PCR confirmed symptomatic COVID-19. In an exploratory analysis of patients exposed to the Omicron variant, or the post-Omicron group, in pre-exposure prophylaxis, adintrevimab was associated with a clinically meaningful reduction in the risk of developing RT-PCR confirmed symptomatic COVID-19 compared with placebo. In treatment, adintrevimab was associated with a 66% relative risk reduction compared to placebo in the incidence COVID-19 related hospitalization or all cause death through Day 29 in the pre-Omicron group. In patients treated within three days of symptom onset, adintrevimab was associated with a reduced risk of COVID-19 hospitalization or death from any cause through Day 29 by 77% compared to placebo. A preliminary analysis of available safety data in each trial revealed a safety profile similar to that of placebo for adintrevimab.

We are also evaluating additional broadly neutralizing antibodies targeting the receptor binding domain, or RBD, as well as other subdomains within the spike protein for COVID-19. In addition, we plan to leverage the robust antibody discovery and development capabilities that have enabled our expedited advancement of adintrevimab into clinical trials to develop therapeutic or preventative options for other infectious diseases, such as additional coronaviruses and influenza. In addition to building a portfolio of broadly neutralizing antibodies, we are leveraging our knowledge around broadly neutralizing antibody responses to inform the rational design of coronavirus vaccine antigens.

SARS-CoV-2 has given rise to a global pandemic that swept rapidly throughout the world in 2020. Of significant current concern is the continued emergence of a number of SARS-CoV-2 variants with increased transmissibility, pathogenicity, and/or the ability to evade neutralizing antibodies. In addition to the emergence of these variants, there are multiple factors that we believe contribute to the likelihood of COVID-19 becoming an endemic threat, including: (1) viral transmission before symptom onset; (2) uneven global rollout of vaccinations; (3) ongoing vaccine hesitancy; (4) limited duration of immunity conferred by both natural infection and vaccination; (5) limited vaccine efficacy against certain SARS-CoV-2 variants; (6)

uncertain impact of vaccines on transmission; and (7) variable implementation of virus mitigation behaviors, such as wearing masks and social distancing. We also believe that future pandemics similar to the COVID-19 pandemic are likely because, in many parts of the world, humans live in close proximity to animal species harboring coronaviruses that are capable of infecting humans.

Our vision is to discover, develop and commercialize differentiated products for the prevention and treatment of infectious diseases. To enable this vision, our current discovery efforts are focused on unique antibody-based product candidates that we optimize to improve breadth, potency, half-life, where applicable, and developability. Key elements that we believe differentiate our approach include: (1) recognition of the importance of and identification of broadly neutralizing antibodies; (2) industry-leading B cell mining, protein engineering and developability screening capabilities through our internal expertise and collaborations; and (3) reducing risk of clinical resistance.

Our Team

We were founded in June 2020 to develop a portfolio of anti-coronavirus antibodies discovered by Adimab, LLC, or Adimab, for both the prevention and treatment of COVID-19 and future emerging coronaviruses. Our founding scientists discovered adintrevimab, our lead product candidate, while working at Adimab, an industry leader in translating target hypotheses into therapeutically relevant antibodies. In order to maximize adintrevimab’s potential and to facilitate its development and commercialization with appropriate infectious disease and development expertise and resources, we were launched as a new biotechnology company. Since our founding, we have assembled a team of industry veterans with substantial experience in discovering, developing and commercializing novel treatments for infectious diseases, including extensive experience discovering and optimizing monoclonal antibodies, or mAbs. Our leadership team has more than 100 years of combined development and commercialization experience with small and large molecules in infectious disease, as well as decades of domain expertise in B-cell immunology of viral diseases. Many of our team members have held senior positions at companies such as Pfizer Inc., Cubist Pharmaceuticals, Inc., Adimab, Biogen Inc. and Ironwood Pharmaceuticals, Inc., among others.

Our Strategy

Our goal is to discover, develop and commercialize differentiated products for the prevention and treatment of infectious diseases. In order to achieve this goal, our strategy involves execution of the following key elements:

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Leverage our team’s collective expertise in development, manufacturing and commercialization to deliver adintrevimab and future product candidates to patients. Since our inception, we have assembled a team with deep and specific expertise in discovering, developing, manufacturing and commercializing novel treatments for infectious diseases, including extensive experience with developing mAb-based therapies. Based on our team’s collective successful track record, we believe we will be able to execute on the clinical, regulatory, manufacturing and commercialization plan for adintrevimab, as well as any future programs.

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Complete development and obtain regulatory authorization or approval for our lead product candidate, adintrevimab, for both the prevention and treatment of COVID-19. Our clinical development plan for adintrevimab includes two global clinical trials designed to demonstrate the efficacy and safety of adintrevimab for the prevention and treatment of COVID-19.Our Phase 2/3 global clinical trial, EVADE, evaluates adintrevimab in the prevention of symptomatic COVID-19 in two separate populations: (1) individuals with known exposure to a person with laboratory-confirmed SARS-CoV-2 infection, also known as post-exposure prophylaxis, and (2) individuals who are at increased risk for SARS-CoV-2 infection, also known as pre-exposure prophylaxis, including those at increased risk of poor vaccine response. Similarly, our Phase 2/3 global clinical trial, STAMP, evaluates adintrevimab for the treatment of mild to moderate COVID-19 in patients at high risk of disease progression. Due to the emergence and global spread of the Omicron variant, against which adintrevimab has reduced in vitro neutralization potency compared to prior variants and uncertainty around the ability of the 300 mg dose of adintrevimab to prevent and treat disease due to the Omicron variant, enrollment in both EVADE and STAMP was paused on January 11, 2022. Data generated prior to pausing trials has been evaluated and may provide a path to a potential Emergency Use Authorization, or EUA, and/or Biologics License Application, or BLA, and commercialization, if adintrevimab is authorized and/or approved. As variants with varying degrees of neutralization activity to adintrevimab or other antibodies emerge over time, a variant based approach, including pharmacokinetics and pharmacodynamics/PD modeling, may be needed to support dose modification based on the in vitro potency of adintrevimab against the predominant circulating variants at any given time. We plan to file for EUA in the second quarter of 2022 and to discuss a potential path to BLA with the FDA and marketing authorization with health authorities outside the United States.

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Successfully commercialize adintrevimab, if authorized or approved. We believe adintrevimab will have several attractive attributes, including (1) broad application across multiple patient types, including pre- and post-exposure prophylaxis and treatment; (2) convenient IM dosing for use in the outpatient setting; (3) differentiated durability to protect the vulnerable, depending on the variant; (4) rapid onset of protection in the setting of post-exposure prophylaxis compared to vaccines; (5) standard refrigeration requirements to facilitate long term storage and distribution; and (6) long shelf life. Our plan for the commercialization of adintrevimab involves direct sales to governments, including relevant health agencies and national health systems, and in the United States, health insurers, integrated delivery networks and large employers. We intend to establish our own commercial organization in the United States, where we believe a focused commercial infrastructure will be able to successfully commercialize adintrevimab under a regulatory authorization and/or approval, and we are considering commercial options in Europe and beyond. In certain markets, such as Latin America, Asia-Pacific, including China, and Middle Eastern and African countries, we intend to commercialize adintrevimab through partnerships. For example, in July 2021, we entered into a license agreement with Biocon to combat COVID-19 in Southern Asia.

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Ensure supply of drug product for adintrevimab and future clinical product candidates. We have partnered with WuXi Biologics (Hong Kong) Limited, or WuXi, for advintrevimab clinical and commercial drug substance and drug product supply, and we have manufactured an initial supply of adintrevimab at commercial process scale. We believe we have secured sufficient capacity for our initial supply needs, in the event that adintrevimab is authorized under EUA. We continue to evaluate access to worldwide capacity at both WuXi and other contract development and manufacturing organizations, or CDMOs, to ensure we can meet expected future demand for advintrevimab. For future clinical product candidates, we plan to continue to use contract facilities for the development and good manufacturing practices, or GMP, manufacture of our products. CDMOs, including WuXi, will be evaluated for relevant capabilities, program suitability, and ability to meet desired timelines for candidate development. We expect to continue to use multiple contract CDMOs and laboratories to develop our pipeline candidates.

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Advance differentiated product candidates to address infectious diseases through internal research, in-licensing and leveraging collaborations. We have built a portfolio of broadly neutralizing SARS-CoV-2 antibodies as our lead disease area of focus. We have exclusive access to Adimab’s unique B cell mining and protein engineering capabilities for coronavirus and influenza antibody discovery. We are currently leveraging this partnership and building internal capabilities to further expand our portfolio with additional uniquely differentiated anti-viral antibodies targeting COVID-19, as well as other infectious diseases. In addition, we have employed unique protein engineering strategies to significantly enhance adintrevimab activity against the Omicron variant and its sublineages. We are also collaborating with academic institutions on the discovery of vaccine immunogens that elicit broadly neutralizing antibodies to coronaviruses. Finally, we continue to evaluate product candidates for infectious diseases with high unmet medical need through in-licensing opportunities in addition to utilizing our team’s expertise and differentiated design capabilities.

Background on Coronaviruses

Coronaviruses comprise a large family of viruses that are grouped into four genera: alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus. Over the past 20 years, three pathogenic novel betacoronaviruses have spilled over into the human population from animal reservoirs to cause outbreaks of deadly pneumonia, including COVID-19, SARS and MERS. In many parts of the world, humans live in close proximity to animal species harboring sarbecoviruses, a lineage of betacoronaviruses that are capable of using human angiotensin-converting enzyme 2, or hACE2, receptors, and enabling infection in humans. In particular, bats are known to host such viruses, and large bat populations exist alongside humans in certain regions across the world, including eastern Europe, East Africa and southern China. Furthermore, bats are capable of carrying multiple sarbecoviruses, allowing for genetic recombination and the emergence of viral variants with higher propensity for transmission to humans. Current estimates suggest that between 6% and 23% of bats harbor viruses with such transmission potential. Not surprisingly, humans living in close proximity to bat populations have been infected by SARS-like coronaviruses. For example, approximately 0.5% to 3% of the rural population in southern China have antibody responses to these viruses, demonstrating past infection. This highlights the zoonotic nature of the sarbecovirus lineage, which includes both SARS-CoV-1 and SARS-CoV-2. Continued human intrusion into previously undeveloped habitats and increased exposure to these viral reservoirs are likely to result in more frequent occurrences of viral spillover, with potentially catastrophic consequences.

COVID-19, the disease caused by SARS-CoV-2 and its variants, has given rise to a global pandemic that swept rapidly throughout the world in 2020 and continues to cause infection and disease due to waning immunity and the continued emergence of resistant SAR-CoV-2 variants. The genome of SARS-CoV-2 encodes a spike, or S, protein, which is the surface

protein common to all members of the coronavirus family and mediates attachment and entry into host cells. The S protein is the only known target for neutralizing antibodies, and neutralizing antibodies to this protein are associated with protection from infection and disease. For this reason, the S protein is the primary target for currently available vaccines and therapeutic mAbs. Because the vast majority of potent neutralizing antibodies recognize epitopes overlapping the human ACE2 binding site on the RBD, most clinical-stage and EUA authorized SARS-CoV-2 antibodies target this antigenic region.

COVID-19 remains a significant global health crisis and case numbers continue to rise. According to estimates as of March 25, 2022 from the Johns Hopkins University, there have been approximately 478 million cases of laboratory-confirmed COVID-19 and 6.1 million COVID-19-related deaths worldwide, with approximately 80 million laboratory-confirmed cases of COVID-19 and more than 975,000 COVID-19-related deaths in the United States. Disease modeling conducted by several different organizations have further suggested that these estimates significantly undercount the true number of infections and deaths related to COVID-19.

Of significant current concern is the emergence of a number of SARS-CoV-2 variants with increased transmissibility, pathogenicity, and/or the ability to evade neutralizing antibodies. Variants of concern, or VOCs, include Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1); Delta (B.1.617.2) and Omicron (B.1.1.529/BA.1). Since their initial detection, some of these variants have spread rapidly worldwide, with confirmed cases in the United States, Canada and several European countries, indicating increased transmissibility relative to ancestral strains of SARS-CoV-2. As of March 19, 2022, the U.S. Centers for Disease Control and Prevention projected that the Omicron variant and its sub-lineages account for >99% of new COVID-19 cases in the United States. Importantly, several of the amino acid substitutions within the Omicron RBD are associated with escape from common classes of neutralizing antibodies, thereby endowing Omicron with significantly increased resistance to serum neutralizing antibodies induced following natural infection and vaccination with ancestral strains of the virus. Correspondingly, two doses of currently available vaccines have been shown to confer little to no protection against symptomatic disease caused by Omicron at >25 weeks post-vaccination. Homologous and heterologous BNT162b2 or mRNA-1273 booster immunization increases the level of protective efficacy to 60-70%, but this protection has been shown to wane over time. Due to its immune evasive properties, the emergence of the Omicron variant has been accompanied by a significant increase in SARS-CoV-2 breakthrough infections globally. Importantly, recent studies have shown that almost all clinical-stage and EUA authorized mAbs display significantly reduced or completely abolished activity against Omicron (BA.1) and/or its sublineages (BA1.1 and BA.2). Thus, there is an urgent need to develop next-generation mAbs that recognize current and future SARS-CoV-2 VOCs.

SARS-CoV-2 Variants Continue to Emerge Causing New Waves of Infections

In addition to the emergence of these variants, there are multiple factors that we believe contribute to the likelihood of COVID-19 becoming an endemic threat, including: (1) viral transmission before symptom onset; (2) uneven global rollout of vaccinations; (3) ongoing vaccine hesitancy; (4) limited duration of immunity conferred by both natural infection and vaccination; (5) limited vaccine efficacy against certain SARS-CoV-2 variants; (6) uncertain impact of vaccines on transmission; and (7) variable implementation of virus mitigation behaviors, such as wearing masks and social distancing.

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

In response to the ongoing pandemic, multiple agents have been discovered, developed and authorized at an unprecedented speed to address COVID-19.

Vaccines for Prevention of COVID-19

Several vaccines have been approved for the prevention of COVID-19 both in the United States and abroad. These include mRNA-based vaccines, such as Moderna’s mRNA-1273 and Pfizer/BioNTech’s BNT162b2, and adenovirus-based vaccines, such as AstraZeneca’s AZD1222, and Janssen’s JNJ-78436735. While available COVID-19 vaccines have demonstrated meaningful efficacy in preventing symptomatic disease caused the original SARS-CoV-2 strain and early ancestral variants (e.g. D614G and Alpha), we believe additional solutions for the prevention of COVID-19 are required given considerable uncertainty around the future ability of vaccines to protect against disease and transmission, due to multiple factors, including:

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Limited efficacy against certain viral variants. While COVID-19 vaccines have demonstrated meaningful efficacy in preventing infection by the original strain of COVID-19, emerging evidence shows significantly lower levels of protection against certain variants. Multiple clinical and real-world studies have demonstrated reduced vaccine effectiveness against the Beta (B.1.351), Delta, and Omicron variants. For example, studies have shown that two doses of currently available vaccines confer little to no protection against symptomatic disease caused by the Omicron variant and its sub-lineages.

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

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Unpredictable level of protection in immunocompromised individuals. Since vaccines leverage an individual’s existing immune system to generate protection, vaccines may have little to no effectiveness against infection and disease in those who have compromised immune systems. Studies show that a subset of these individuals mount poor antibody responses to currently available mRNA vaccines, demonstrating the unmet medical need for effective preventative options for immunocompromised populations.

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

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Vaccine hesitancy. Numerous surveys attribute vaccine hesitancy to a constellation of perceived safety, side effect and quality concerns. As of mid-March 2022, according to the CDC, only 65% of the total U.S. population was fully vaccinated and only 45% had received at least one booster. Globally, vaccine adoption and hesitancy are consistent with the U.S. figures. According to Our World in Data, as of mid-March 2022, 57% of the world population had been fully vaccinated.

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Availability and adoption in children. While children generally do not develop the severe consequences of COVID-19 seen in adults, studies have shown that they are still capable of transmitting SARS-CoV-2. Although an EUA was granted for use of the Pfizer/BioNTech vaccine in children ages five through eleven years, vaccine hesitancy by parents remains a potential obstacle to widespread adoption in school-aged children. Survey data collected in February 2022 by the Kaiser Family Foundation indicated that 41% of parents do not plan to or are waiting to see if they will vaccinate their children under 5-years old when vaccines first become available to them. This same survey indicated the percentage is 21% for children aged 5 to 11.

mAbs for Prevention or Treatment of COVID-19

Some SARS-CoV-2 mAb therapies have been granted an EUA in the United States for the prevention of symptomatic COVID-19. Bamlanivimab/etesevimab and casirivimab/imdevimab were granted an EUA for post-exposure prophylaxis for individuals at high risk for progression to severe COVID-19 who are not fully vaccinated or not expected to mount an adequate immune response to vaccines. Tixagevimab/cilgavimab is the only mAb product that has been granted an EUA for pre-exposure prophylaxis and is limited to use in individuals who have moderate to severe immune compromise and may not mount an adequate immune response to vaccines or from whom vaccination is not recommended due to a history of severe adverse reaction to a COVID-19 vaccine. This product has also recently been recommended for authorization in EU member states by the European Medicines Agency.

Similarly, some SARS-CoV-2 mAb therapies, either as a monotherapy or a combination cocktail, have been granted an EUA in the United States or full marketing authorization in EU member states for the treatment of mild to moderate COVID-19 in patients at high risk of disease progression. Products granted an EUA include bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab and bebtelovimab; casirivimab/imdevimab, sotrovimab and regdanvimab have been granted marketing authorization in the EU.

Despite this progress in the availability of mAbs for the prevention and treatment of COVID-19, the clinical utility of some of these products has varied over time due to the emergence of SARS-CoV-2 variants demonstrating partial or full resistance to neutralization. The longevity of currently available mAbs for the prevention and treatment of COVID-19 is unknown due to the ongoing risk of the emergence of additional SARS-CoV-2 variants. For this reason, a broad range of mAb products are still needed for prevention and treatment of COVID-19 as waves of SARS-COV-2 variants continue to emerge over time.

Limitations of Currently Available mAbs

The COVID-19 pandemic has been characterized by waves of SARS-CoV-2 variants with increased transmissibility, pathogenicity, and/or the ability to evade neutralizing antibodies. Different variants have shown partial or full resistance to neutralization by certain currently available mAbs, leading to temporary pauses or permanent discontinuation of certain products and the need to alter dosing regimens for other products. For example, the FDA previously revoked the EUA for bamlanivimab as a single agent, and distribution of a second agent, bamlanvimab/etesevimab, was paused in the United States on June 25, 2021 due to lack of activity against the Gamma (P.1) and Beta (B.1.351) variants. Distribution of bamlanivimab/etesevimab subsequently resumed with the emergence of the Delta variant, against which this product retained in vitro neutralizing activity. The FDA subsequently halted the use of bamlanvimab/etesevimab and casirivimab/imdevimab in all U.S. regions on January 24, 2022 and halted the use of sotrovimab in certain U.S. regions on March 25, 2022 due to decreased in vitro neutralization activity against all or a subset of the Omicron variant lineage, leaving bebtelovimab as the only mAb product available for treatment in all U.S. regions as of March 26, 2022. Bebtelovimab is only recommended for use if none of the preferred therapies for high risk, non-hospitalized patients are available, feasible to deliver or clinically appropriate. On February 24, 2022, the FDA revised the EUA for tixagevimab/cilgavimab to increase the initial dose in response to reduced neutralization activity against some lineages of the Omicron variant. In addition, the use of currently available mAbs for the treatment of COVID-19 has been limited by the inconvenience of their intravenous, or IV, administration, which requires specialized facilities that are properly equipped to accommodate IV infusions in actively infected patients and may lead to a delay in administration. In Europe, IV administration in outpatient settings by community nurses or general practitioners remains very limited due to lack of appropriate infrastructure and sites of care. Additional factors that have limited use of mAbs include lack of awareness and education on appropriate use as well as perceived or genuine difficulty accessing treatment.

Antivirals for Treatment of COVID-19

Some antiviral products have been granted approval or EUA in the United States or marketing authorization in EU member states for the treatment of mild to moderate COVID-19 in patients at high risk of disease progression. Remdesevir, delivered as 3 days of intravenous therapy, is approved for this use in the United States and oral nirmatrelvir/ritonavir and molnupiravir have been granted an EUA. Remdesevir has been granted conditional marking authorization and nirmatrelvir/ritonavir has been granted full marketing authorization in the EU. Molnupiravir is currently not authorized for use in the European Union; the EMA’s Committee for Medicinal Products for Human Use issued advice on the use of this agent for the treatment of COVID-19 to support national authorities, who may decide on possible early use of this medicine prior to marketing authorization.

Limitations of Currently Available Antivirals for the Treatment of COVID-19

Adoption of oral antivirals may be impacted by high pill burden, drug-drug interactions, limitations of use in certain populations and concerns about resistance. Adherence to the high pill burden of currently available oral agent’s dosing regimens may be difficult for some patients. In addition, drug-drug interactions may complicate dosing, particularly for nirmatrelvir/ ritonavir, and this agent is also not recommended for use in patients for severe renal or hepatic impairment. Molnupiravir is currently recommended as a last-line agent due to low efficacy and is not recommended for use in pregnancy or patients less than 18 years of age. Use of remdesevir for outpatient treatment may be limited by the inconvenience of its multi-day IV dosing regimen. In addition, resistance is also a concern for all antivirals, as evidenced in HIV and hepatitis C.

Our Approach to The Development of Antibody-based Solutions for Coronaviruses and Other Infectious Diseases

Our vision is to discover, develop and commercialize differentiated products for the prevention and treatment of infectious diseases. To enable this vision, our current discovery efforts are focused on unique antibody-based product candidates that we optimize to improve breadth, potency, half-life, where applicable, and developability. We believe that mAb therapies with the following characteristics will have the potential to address the limitations of certain currently available mAbs used for the prevention or treatment of infectious diseases:

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High potency and broad neutralizing activity against circulating viral variants and future outbreaks caused by antigenically related viruses;

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Multiple mechanisms of action, including direct virus neutralization and elimination of infected host cells;

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Convenient outpatient administration as IM or subcutaneous administration; and

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Ability to provide both rapid and durable protection against disease.

To develop mAb therapies with these characteristics, we optimize both the antigen-binding fragment, or Fab, and constant fragment, or Fc, regions of candidate molecules to improve breadth, potency, half-life and developability. The Fab region binds to the viral antigen and is a key determinant of specificity and potency. The Fc portion binds to host cell receptors to activate the innate immune system to eliminate infected host cells and is a key determinant of serum half-life. Key elements that we believe differentiate our approach include:

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Recognition of the importance of and identification of broadly neutralizing antibodies: From the outset for our COVID-19 program, we chose to focus on mAbs capable of broadly neutralizing not only SARS-CoV-2 and its variants, but also the entire viral class of sarbecoviruses that target the hACE2 receptor. Our rationale was driven by the recognition that COVID-19 is a continuation of previous human coronavirus outbreaks, including SARS and MERS, and the likelihood that future variants will continue to emerge and cause outbreaks in the human population. We are employing similar strategies for other antigenically variable viruses, such as influenza.

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Industry-leading B cell mining, protein engineering and developability screening capabilities through internal expertise and our partnership with Adimab: We leverage deep B cell mining capabilities to isolate broadly neutralizing antibodies from human donors and other in vivo sources. We then utilize protein engineering capabilities to improve the potency, breadth, biophysical properties, developability and half-life of the antibody candidates we advance into preclinical development. Where applicable, we specifically engineer our antibodies to extend their half-lives without affecting Fc-mediated innate immune effector activity. We also have the ability to engineer antibodies using alternative molecular formats, such as single domains or bispecifics, to further enhance functional activity.

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Reducing risk of clinical resistance: We are developing antibodies that target conserved residues on viral spike proteins, which are often important for viral fitness and therefore less likely to mutate. In addition, the residues that our antibodies recognize are not readily targeted by antibodies induced by natural infection, thus limiting immune pressure on these sites. Targeting of conserved sites that are subject to limited immune selection pressure reduces but does not fully eliminate the risk of circulating resistance. For these reasons, broadly neutralizing anti-coronavirus antibodies, including adintrevimab, have maintained neutralizing activity in vitro against most circulating SARS-CoV-2 variants described to date. In contrast, many SARS-CoV-2-specific antibodies, which bind to variable epitopes that are readily targeted by endogenous neutralizing antibodies, have shown reduced activity against several variants of concern.

Adintrevimab: An Example of B cell Mining and Protein Engineering Capabilities

We have employed this platform to discover adintrevimab. As the first step in the identification of advintrevimab, a blood sample was obtained from a survivor of the 2003 SARS outbreak who had never been exposed to SARS-CoV-2. The B cells were sorted based on reactivity to SARS-CoV-2, enabling us to isolate and identify 200 antibodies that bound to the SARS-CoV-2 S protein. Three of these antibodies were affinity engineered using the Adimab protein engineering platform. Affinity maturation allowed us to increase SARS-CoV-2 S protein binding affinity and neutralization potency by as much as 500- and 77-fold, respectively, as shown in the graphic below. Based on this enhanced profile, we selected ADG2, the progeny with the most improved binding affinity and neutralization potency, for further study. Additional preclinical studies indicated that ADG2 also exhibited highly potent activity against a panel of divergent SARS-like viruses, including SARS-CoV-1, WIV1 and SHC014, whereas the other clinical-stage antibodies demonstrated either limited potency or were non-neutralizing, or N.N., at the highest concentration tested, as shown in the graphic below. We further engineered ADG2 with an Fc region modification

designed to extend the half-life to enable the potential for a single-dose administration to provide durable protection against symptomatic COVID-19 which resulted in our lead product candidate, adintrevimab.

Protein Engineering Substantially Improved Binding to and Neutralization of SARS-CoV-2

To determine whether ADG2 displayed broad neutralization, we evaluated its activity against additional members of the sarbecovirus lineage. Clade 1 of this lineage is of particular concern as it includes members that can infect human cells using the hACE2 receptor. We compared the activity of ADG2 with other currently available or clinical-stage mAbs against a subset of Clade 1 sarbecoviruses in authentic virus neutralization assays using transfected HeLa cells that express the hACE2 receptor and non-human primate Vero cells. ADG2 demonstrated high potency, defined as an IC50 value of 0.01 mcg/mL or less, against SARS-CoV-2 in the two different assays, whereas the potency of certain other antibodies was observed to vary. Importantly, ADG2 exhibited highly potent activity against the other Clade 1 viruses tested, including SARS-CoV-1, WIV1 and SHC014, whereas the other antibodies demonstrated either limited potency or were non-neutralizing, or N.N., at the highest concentration tested, as shown in the graphic below.

ADG2 Shows Broad Neutralization Activity Across Diverse SARS-Related Coronaviruses

Subsequent work indicated that advintrevimab neutralized the Omicron BA.1 variant with reduced potency relative to previous SARS-CoV-2 VOCs (Alpha, Beta, Delta, and Gamma). We therefore employed our protein engineering platform to enhance advintrevimab activity against BA.1 while retaining activity against other SARS-CoV-2 VOCs. Within two months, we generated affinity matured versions of advintrevimab with over 100-fold improved binding affinity and up to 40-fold enhanced neutralization against BA.1 while maintaining activity against other VOCs and SARS-CoV. Thus, our unique B cell mining and protein engineering capabilities allow us to identify unique, functionally active clones that can be engineered and re-engineered for enhanced neutralization potency and breadth of recognition.

Protein Engineering Substantially Improved Binding and Neutralizing Activity of ADG20 (adintrevimab) Against Omicron/BA.1

Re-engineered ADG20 (adintrevimab) Progeny Maintain Binding and Neutralizing Activity Against Other SARS-CoV-2 Variants of Concern

Adintrevimab: Our Near-Term Solution for the Prevention and Treatment of COVID-19

Adintrevimab, our lead product candidate, is designed to be a potent, broadly neutralizing antibody for both the prevention and treatment of COVID-19, including disease caused by most variants, as either a single or combination agent. Unlike most other antibody-based therapies specifically targeting SARS-CoV-2, adintrevimab has demonstrated in non-clinical studies an ability to neutralize SARS-CoV-2, including most variants of concern, as well as a broad range of sarbecoviruses with neutralization IC50s ranging from 0.004-1.1 mcg/mL in live-virus neutralization assays. In addition, adintrevimab has the

potential to be conveniently administered as an IM injection. We believe these and other attributes of adintrevimab differentiate it from some antibodies that are either available under EUA or in development to address COVID-19.

Our clinical development plan for adintrevimab includes a Phase 1 healthy volunteer single ascending-dose escalation study to establish safety, pharmacokinetics, and serum virus neutralizing antibody titers of adintrevimab and two global clinical trials designed to demonstrate the safety and efficacy of adintrevimab for the prevention and treatment of COVID-19, respectively. Our Phase 2/3 global clinical trial, EVADE, evaluates adintrevimab in the prevention of symptomatic COVID-19 in two separate populations: (1) individuals with known exposure to a person with laboratory-confirmed SARS-CoV-2 infection, also known as post-exposure prophylaxis, and (2) individuals who are at increased risk for SARS-CoV-2 infection, also known as pre-exposure prophylaxis, including those at increased risk of poor vaccine response. Similarly, we are evaluating adintrevimab for the treatment of mild to moderate COVID-19 in patients at high risk of disease progression, in our Phase 2/3 STAMP trial.

Key Advantages of Adintrevimab

We believe adintrevimab will have the following key advantages:

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Broadly neutralizing activity across sarbecoviruses. From the outset, we selected and engineered the mAb that became adintrevimab specifically for its potential ability to broadly neutralize not only SARS-CoV-2 and the majority of SARS-CoV-2 variants of concern, but also additional members of the sarbecovirus lineage.

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Broad application across multiple patient indications. Adintrevimab has the potential to address pre- and post-exposure prophylaxis in addition to treatment of COVID-19, allowing governments and providers the flexibility to potentially use adintrevimab in the populations where it is most needed.

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Rapid onset of protection. As a mAb, adintrevimab has the potential to confer rapid protection post-dose against COVID-19 in the post-exposure setting.

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Differentiated durability. Adintrevimab has the potential to provide durable protection by virtue of its potency and half-life extension. Physiologically-based pharmacokinetic modeling has suggested that a single-dose 300 mg IM injection of adintrevimab will result in serum neutralizing titers that we believe may provide durable protection, depending on the variant. Duration of protection is especially important in the immunocompromised population who may remain unprotected by vaccines.

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Convenient, IM administration for use in the outpatient setting. Intravenous administration of currently available COVID-19 mAbs requires specialized facilities that are properly equipped to accommodate IV dosing in actively infected patients, which may lead to a delay in administration. In contrast, the low viscosity, high concentration formulation and potency of adintrevimab, allow it to be delivered as a convenient, IM injection in traditional outpatient settings.

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Potential for affordability. An antibody therapy that is administered by IM injection with potential durable protection, depending on the variant, has the potential to offer payors, providers and patients an affordable option to prevent and treat COVID-19. Initiatives by the Centers for Medicare & Medicaid Services to decrease out-of-pocket costs to patients and increase reimbursement for COVID-19 antibody therapies to providers underscore the importance of ensuring affordable access to COVID-19 antibodies. We believe adintrevimab’s potential for affordability may allow for greater pricing flexibility to encourage broader access to adintrevimab and appropriate use by government and private payors, physicians and patients.

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Standard refrigeration requirements to facilitate worldwide distribution and storage. Adintrevimab may be conveniently stored and distributed under standard refrigerated conditions prior to administration. We anticipate that adintrevimab will be stable in sterile liquid form under refrigerated storage conditions and continue to confirm the long-term stability of adintrevimab.

Mechanism of Action

Adintrevimab has the potential to impact viral replication and subsequent disease through multiple mechanisms of action, including direct neutralization of free virus and elimination of infected host cells through Fc-mediated innate immune effector activity. The majority of SARS-CoV-2-specific neutralizing antibodies target the RBD of the spike protein. Neutralizing anti-RBD antibodies that are commonly elicited by natural SARS-CoV-2 infection and vaccination (so-called “public” antibodies) have been categorized into three classes (class 1, 2, and 3) based on their convergent sequence features and binding epitopes. Public antibodies target amino acid residues that are variable among SARS-like coronaviruses, suggesting that they are less

likely to be important for viral fitness and are therefore more susceptible to mutation. Amino acid mutations that are present in multiple variants of concern, including those at positions E484, L452 and K417, confer resistance to many class 1 and class 2 antibodies, suggesting that these mutations emerged due to immune selection pressure by these types of antibodies. Because many clinical-stage and EUA authorized SARS-CoV-2 antibodies were identified from COVID-19 survivors and belong to one of these three public antibody classes, several of these mAbs display reduced activity against multiple SARS-CoV-2 variants of concern.

Adintrevimab recognizes an RBD epitope that is distinct from those targeted by public class 1-3 antibodies. The amino acid residues that adintrevimab engages are conserved among most bat SARS-like coronaviruses, which provides it with broadly neutralizing capabilities and suggests that these residues may be important to viral fitness, and thus less likely to mutate in the context of an infection. In addition, the binding site engaged by adintrevimab is not readily targeted by endogenous public antibodies, which limits immune pressure at these residues. A comparison of adintrevimab binding to the RBD of the SARS-CoV-2 S protein with that of Class 1-3 antibodies is illustrated in the molecular model presented below. Although adintrevimab displays reduced activity against the Omicron (BA.1) variant and lacks activity against the BA.2 sublineage relative to earlier variants of concern, the potency of neutralization shown in vitro against BA.1 is similar to or higher than that of most EUA approved SARS-CoV-2-specific antibodies that bind variable epitopes. Furthermore, unlike many other SARS-CoV-2-specific antibodies, adintrevimab has been shown in vitro to bind and neutralize the majority of SARS-CoV-2 variants of concern and variants of interest that have emerged to date. Thus, although Omicron variant and its sub-lineages have demonstrated that universal SARS-CoV-2 variant neutralization may not be feasible with anti-RBD antibody monotherapies, antibodies that show broad-spectrum activity against divergent sarbecoviruses are more likely to retain activity against emerging SARS-CoV-2 variants than antibodies with narrow activity.

Adintrevimab Targets a Unique Site on the RBD of the SARS-CoV-2 S Protein

In addition to neutralizing activity, adintrevimab displays Fc-mediated innate immune effector activity in vitro, including antibody-dependent cellular cytotoxicity, or ADCC, antibody-dependent cellular phagocytosis, or ADCP, and antibody-dependent complement deposition, or ADCD. We believe this mechanism of action may help to clear infected host cells in vivo and contribute to the control of SARS-CoV-2 infection.

Preclinical Data

Adintrevimab has been evaluated in a series of in vitro and in vivo studies to demonstrate its potency and breadth as well as safety and efficacy in various animal models. In vitro binding studies have demonstrated that adintrevimab binds with high affinity to a diverse set of RBD subdomain 1, or RBD SD1, molecules from naturally circulating SARS-CoV-2 variants and related sarbecoviruses. Additional binding studies have indicated that the Fc modifications of adintrevimab confer enhanced affinity to non-human primate and human neonatal Fc receptors, or FcRn, at low pH, which has translated into a prolonged serum half-life in non-human primates due to enhanced recycling via FcRn. In in vitro studies, adintrevimab has demonstrated neutralizing activity against SARS-CoV-2 and most emerging variants that have been associated with lower efficacy rates of certain vaccines and are resistant or partially resistant to a subset of currently available or clinical-stage mAbs. In in vivo models, adintrevimab demonstrated an ability to prevent and treat SARS-CoV-2 infection and associated disease as well as a prolonged serum half-life. Prophylactic administration of ADG2 or adintrevimab provided protection against SARS-CoV-2 infection in three different animal models, and treatment with ADG2 reduced disease burden in animals infected with SARS-CoV-2.

In Vitro Studies of Adintrevimab Demonstrated Potency and Broad Neutralization of SARS-CoV-2 Against the Majority of Known Variants

In an in vitro analysis conducted by an independent laboratory using authentic SARS-CoV-2 assays, we evaluated the potency and neutralizing activity of adintrevimab against the Victoria virus strain, which is similar to the original Wuhan-Hu-1 virus strain, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron (B.1.529 or BA.1) and two Omicron sub-lineages (BA.1.1 and BA.2) variants. Adintrevimab demonstrated potent viral neutralization activity (defined as an IC50 of 0.01 mcg/ml or less) against the original Victoria virus as well as the Alpha, Beta, Gamma, and Delta variants. In contrast, a subset of SARS-CoV-2-specific antibodies displayed substantial loss of neutralization activity against a subset of these variants, with IC50 values exceeding 1 mcg/mL. Adintrevimab also displayed neutralizing activity against the Omicron BA.1 and BA1.1 lineages, albeit with reduced potency (IC50 ~ 1 mcg/ml) relative to earlier SARS-CoV-2 strains but lacked detectable activity against the BA.2 lineage. Similarly, the majority of other clinical-stage or EUA authorized mAbs demonstrated significantly reduced or completely abolished activity against Omicron and its sublineages, thus highlighting the remarkable immune evasive properties of this particular variant of concern.

Adintrevimab Displays Neutralizing Activity Against Most SARS-CoV-2 Variants of Concern

The neutralization potency and breadth of adintrevimab was also evaluated by an independent U.S. government laboratory against a panel of 64 SARS-CoV-2 pseudovirus variants. We utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases to generate this data. Variants tested included spike proteins encoding the full sets of mutations observed in emerging variants of concern and variants of interest. As shown in the graphic below, adintrevimab displayed neutralization activity across most variants tested to date.

Adintrevimab Displayed Neutralization Activity Against Most SARS-CoV-2 Variants

Clinical Development

As shown in the graphic below, we believe that intervention with an antiviral neutralizing antibody before exposure to SARS-CoV-2, post-exposure but prior to the onset of symptoms or early in the course of symptomatic disease when viral replication is high but before the onset of significant immune pathology is likely to provide the greatest benefit to patients. This belief is supported by clinical experience with SARS-CoV-2 mAbs as well as prior experience with the use of neutralizing antibodies for the prevention and treatment of other respiratory virus infections such as influenza and respiratory syncytial virus, or RSV. For these reasons, our clinical development strategy is focused on prevention and early treatment of COVID-19 with the goal of preventing severe disease and its sequelae.

Adintrevimab: In Development for Prevention and Treatment of COVID-19

As shown below, our clinical development plan foradintrevimab includes a series of clinical trials to demonstrate the potential of adintrevimab for both the prevention and treatment of COVID-19 in adults and adolescents. We initiated our clinical program with a Phase 1 healthy volunteer single ascending-dose escalation study to establish safety, pharmacokinetics, and serum virus neutralizing antibody titers ofadintrevimab over a period of 12 months. This study also provided preliminary safety and pharmacokinetic data at the 300 mg IM dose to support progression to Phase 2/3 trials. Our Phase 2/3 global clinical trial, EVADE, evaluates adintrevimab in the prevention of symptomatic COVID-19 in two separate populations: (1) individuals with known exposure to a person with laboratory-confirmed SARS-CoV-2 infection, also known as post-exposure prophylaxis, and (2) individuals who are at increased risk for SARS-CoV-2 infection, also known as pre-exposure prophylaxis, including those at increased risk of poor vaccine response. Our Phase 2/3 global clinical trial, STAMP, evaluates adintrevimab in the treatment of mild to moderate COVID-19 in patients at high risk of disease progression. Follow-up in all three trials is ongoing and preliminary results are presented below across all populations studied.

Our Clinical Development Program for Adintrevimab

First-in-Human Phase 1 Dose Escalation Clinical Trial

In February 2021, we initiated a Phase 1 single ascending-dose escalation clinical trial (ADG20-1-001), which is designed to evaluate the safety, tolerability and pharmacokinetic properties of adintrevimab, along with serum virus neutralizing antibody titers. We completed enrollment of 30 healthy volunteers across three cohorts in March of 2021, with ten participants per cohort randomized 8 to 2 to adintrevimab or placebo, respectively. Each participant received a single dose of either 300 mg IM, 500 mg IV or 600 mg IM of adintrevimab or placebo.Data from a six-month evaluation timepoint confirmed the extended half-life of adintrevimab, which approached 100 days based on the 300 mg IM dose cohort and we believe may allow for durable protection, depending on the SARS-CoV-2 variant. As of March 28, 2022, there were no study drug related adverse events, serious adverse events, injection-site reactions or hypersensitivity reactions reported through 12 month follow-up across the majority of participants in all three initial cohorts. Due to the reduction in neutralizing activity of adintrevimab against the Omicron variant and the potential for higher doses to overcome this shift in potency as well as address potential future SARS-CoV-2 variants, the Phase 1 study was amended in February 2022 to evaluate safety and pharmacokinetics of higher doses of adintrevimab. Preliminary safety data through two weeks post dosing suggest a favorable safety profile at the 1200 mg dose administered IM or IV with no study drug related adverse events, serious adverse events, injection-site reactions or hypersensitivity reactions reported. A population pharmacokinetic model based on the Phase 1 healthy volunteer data from the initial dose cohorts supported the extended half-life of adintrevimab and showed high bioavailabity (92%) following IM administration.

Preliminary Pharmacokinetic Profile of a Single 300 mg IM Dose of Adintrevimab at 6 Months

Serum virus neutralizing antibody titers are believed to be a key correlate of protection against COVID-19. In an exploratory analysis using an authentic virus neutralization assay, we compared serum virus neutralizing antibody titers on days 2, 7 and 21, and months 3 and 6 following a single 300 mg IM dose of adintrevimab to titers achieved 7 to 31 days, corresponding to peak titers, following administration of two doses of the AZD1222 or mRNA-1273 vaccine. As illustrated in the graphic below, by day 2 or the day following administration of a single 300 mg IM dose of adintrevimab, measured serum neutralizing antibody titers against the D614G strain were similar to peak serum neutralizing antibody titers induced by the mRNA-1273 COVID-19 vaccine and significantly exceeded peak titers generated by the AZD1222 vaccine. By day 7, serum neutralizing antibody titers for adintrevimab were significantly higher than peak titers generated by either vaccine and at month 6, neutralizing antibody titers were similar to the level of peak serum neutralizing antibody titers induced by the mRNA-1273 COVID-19 vaccine. These data further support the potential for a single 300 mg IM injection of adintrevimab to provide durable protection against COVID-19,depending on the SARS-CoV-2 variant.

Preliminary Serum Virus Neutralizing Titers After of a Single 300 mg IM Dose of Adintrevimab at 6 Months

aVaccine timepoint: 7 to 31 days post 2nd dose; badintrevimab recipients only; c Excludes samples taken following SARS-CoV-2 vaccination. Samples above upper limit of quantification (ULOQ) imputed to ULOQ. LOD=limit of detection; *P£ 0.05;**P£ 0.01; ****P£ 0.0001 (2-tailed Mann-Whitney U test; nominal p values shown).

Combined Phase 2/3 EVADE Trial of Adintrevimab for the Prevention of COVID-19

Our combined Phase 2/3 EVADE clinical trial of adintrevimab evaluates the safety and efficacy of adintrevimab in the prevention of symptomatic COVID-19 in two independent trial populations: (1) individuals with known exposure to a person with laboratory-confirmed SARS-CoV-2 infection, which we refer to as post-exposure prophylaxis, and (2) individuals who are at increased risk for SARS-CoV-2 infection, which we refer to as pre-exposure prophylaxis. The eligible trial populations also include individuals at risk of generating poor vaccine response, such as those who are immunocompromised. Our EVADE trial is designed as a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of a single IM dose of adintrevimab in preventing COVID-19, with an original target enrollment of approximately 6,400 individuals across both populations in the United States and other countries. We initiated enrollment in our EVADE trial in April 2021 and expanded enrollment to adolescents in the Phase 3 portion of both populations after iDMC review of safety data from the first 200 adult participants across both populations in the Phase 2 portion of the trial on August 24, 2021. We subsequently paused enrollment on January 11, 2022, due to the emergence and global spread of the Omicron variant, against which adintrevimab has reduced in vitro neutralization potency and, at the time, the 300 mg dose was thought to be unlikely to provide durable protection against COVID-19 due to the Omicron variant. At the time of the enrollment pause, a total of 487 participants were enrolled in the post-exposure cohort and 2,101 participants were enrolled in the pre-exposure cohort. The primary endpoint for these cohorts is the proportion of participants with laboratory-confirmed symptomatic COVID-19 through Day 28 and 3 months, respectively. The primary efficacy endpoint for pre-exposure prophylaxis was adjusted to 3 months, compared to the original planned follow-up period of 6 months, to allow assessment of efficacy against the Delta variant prior to widespread emergence of Omicron. All participants will be followed in both cohorts through 14 months for safety. Some of our clinical trial sites are located in Ukraine and we are monitoring the current conflict in this region to evaluate any potential impact to the trial.

Of the 487 participants randomized in the post-exposure cohort, 348 were included in the primary efficacy population, which included all randomized participants without evidence of current SARS-CoV-2 infection and who were randomized prior to November 30, 2021. In the primary efficacy analysis, adintrevimab was associated with a statistically significant lower incidence of SARS-CoV-2 RT-PCR positive symptomatic COVID-19 through Day 28 compared with placebo (3/173, 1.7%

vs. 12/175, 6.9%, respectively). The standardized risk difference was -4.9% (95% CI: -8.8, -1.0; p=0.0135), demonstrating a 75% relative risk reduction in favor of adintrevimab through 28 days or the emergence of Omicron, whichever was earlier. There were two (1.1%) COVID-19 related hospitalizations in the placebo group compared to none in the adintrevimab group. Of the 2,101 participants enrolled in the pre-exposure cohort, 1,433 were included in the primary efficacy population, which included all randomized participants without evidence of current or prior SARS-CoV-2 infection and who were randomized prior to November 30, 2021. In the primary efficacy analysis, adintrevimab was associated with a statistically significant lower incidence of SARS-CoV-2 RT-PCR positive symptomatic COVID-19 compared with placebo through Month 3 or the emergence of Omicron (12/730, 1.6% vs. 40/703, 5.7%). The standardized risk difference was -4.0% (95% CI –6.0, -2.1; p < 0.0001), demonstrating a 71% relative risk reduction in favor of adintrevimab through 3 months or the emergence of Omicron, whichever was earlier. There were 5 (0.7%) COVID-19 related hospitalizations in the placebo group compared to none in the adintrevimab group.

We also conducted an exploratory analysis of participants enrolled after November 30, 2021 and who were at risk of exposure to Omicron through the data cut-off date of March 2, 2022. In the small number of participants in the post-exposure prophylaxis population randomized post-Omicron, adintrevimab was not associated with a benefit in the reduction of RT-PCR-confirmed symptomatic COVID-19 through Day 28. In a pre-specified exploratory analysis of the pre-exposure prophylaxis cohort, which included 402 participants (196 and 206 in the adintrevimab and placebo groups, respectively) randomized after November 30, 2021 and followed after the emergence of Omicron (BA.1), a clinically meaningful reduction in the risk of developing RT-PCR confirmed symptomatic COVID-19 was observed with adintrevimab, as compared to placebo. Adintrevimab was associated with a relative risk reduction of 59% and 47% with a median follow-up duration of 56 and 77 days, respectively (nominal p <0.05).

A preliminary analysis of available safety data across both cohorts through March 2, 2022 with a median follow-up duration of 140 days for the pre-exposure cohort and 126 days for the post-exposure cohort in 1,239 adintrevimab treated participants revealed a similar safety profile to that of placebo. The incidence of adverse events, including serious adverse events, was similar between the adintrevimab and placebo groups. No study drug related serious adverse events, including no study drug related adverse events leading to death, were reported. The most frequently reported adverse events were solicited injection site reactions, the majority of which were mild or moderate in severity and occurred with similar frequency in both groups. One mild hypersensitivity reaction of mild urticaria was reported in an adintrevimab treated participant.

Combined Phase 2/3 STAMP Trial of Adintrevimab for the Treatment of COVID-19

Our STAMP combined Phase 2/3 clinical trial evaluates adintrevimab for the treatment of COVID-19 in ambulatory adult patients with mild to moderate disease who are at high risk of disease progression. Our STAMP trial is designed as a double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy of a single IM dose of adintrevimab compared to placebo in preventing COVID-19-related hospitalization or all-cause death through Day 29, with an original target enrollment of approximately 1,100 patients, all of whom were to be enrolled outside of the United States. We initiated enrollment in our STAMP trial in July 2021and expanded enrollment to adolescents after iDMC review of safety and preliminary efficacy data from the Phase 2 portion of the trials on December 21, 2021. We subsequently paused enrollment on January 11, 2022 due to the emergence and global spread of the Omicron variant, against which adintrevimab has reduced in vitro neutralization potency and was thought to be unlikely to provide benefit for disease due to this variant. At the time of the enrollment pause, a total of 399 participants were randomized in the trial. The primary objectives of this clinical trial are to assess the safety and efficacy of adintrevimab compared to placebo in the prevention of COVID-19-related hospitalization or death through Day 29. All participants will be followed through 14 months for safety. Some of our clinical trial sites are in Ukraine and we are monitoring the current conflict in this region to evaluate any potential impact on the trial.

Of the 399 participants randomized in the trial, 336 were included in the primary efficacy population, which was defined as all randomized participants with COVID-19 due to non-Omicron SARS-CoV-2 variants, as determined by whole genome sequencing or epidemiology. In the primary analysis of efficacy, adintrevimab met statistical significance and was associated with a lower incidence of COVID-19 related hospitalization or all cause death through Day 29 compared with placebo (8/169, 4.7% vs. 23/167, 13.8%). The standardized risk difference was -8.6 % (95% CI: -14.65,

-2.57; p=0.0052), demonstrating a 66% relative risk reduction in favor of adintrevimab. There was 1 (0.6%) death in the adintrevimab group, compared with 6 (3.6%) deaths in the placebo group through Day 29. In patients treated within three days of symptom onset, adintrevimab was associated with a reduced risk of COVID-19 hospitalization or death from any cause through Day 29 by 77% compared to placebo, 3.3% (3/91) in the adintrevimab group compared to 14.1% (12/85) in the placebo group. An exploratory analysis of efficacy was conducted in the small number (N=63; 29 in the adintrevimab group and 34 in the placebo group) of participants with COVID-19 due to the Omicron SARS-CoV-2 variant. There were two events of COVID-19 related hospitalization and no deaths through day 29; both events of hospitalization occurred in the placebo group. The sample size was too small to draw any conclusion regarding the efficacy of adintrevimab for the treatment of COVID-19 due to the Omicron variant.

An analysis of available safety data through February 2, 2022 with a median duration of follow-up of 73 days in the 192 participants in the adintrevimab group revealed no safety concerns for adintrevimab. The incidence of adverse events, including serious adverse events, was lower in the adintrevimab group compared to the placebo group. No study drug related serious adverse events, including no study drug related adverse events leading to death, were reported. The most frequently reported adverse events were solicited injection site reactions, all of which were mild or moderate in severity and occurred with similar frequency in both groups.

Regulatory Strategy

Based on the available data from EVADE and STAMP, we plan to request an EUA in the second quarter of 2022 for the use of adintrevimab in pre-and post-exposure prophylaxis as well as in the treatment of mild to moderate COVID-19 in high-risk individuals. We also plan to discuss the path to a biologics license application, or BLA, for adintrevimab with the FDA in the second quarter of 2022 and to determine the path to marketing authorization with regulatory authorities outside the United States.

Pediatric Clinical Development Plan

Similar to our strategy for the adult and adolescent populations, we anticipate generating data to support the use of adintrevimab for both the prevention and treatment of COVID-19 in the pediatric population. We currently have an aligned clinical plan with the FDA to evaluate adintrevimab as a preventative and treatment option in the pediatric population, with a trial in individuals between two and eleven years of age. The pediatric study plan may need to be modified following BLA discussions with the FDA. We believe adintrevimab has the potential to provide a treatment option for children at high risk of severe disease and be a viable prevention option for high risk children, such as those with moderate to severe immunocompromise who generate suboptimal vaccine responses.

Commercial Opportunity

Market Opportunity

Emergency Use Authorization (EUA) Environment

In an EUA environment where the federal government signs an Advance Purchase Agreement, or APA, with a manufacturer for a specific number of doses at a fixed price, product distribution is overseen by federal and state governments and product is ordered by institutions, prescribed by physicians and administered in a variety of settings. Product is free to the institutions and patients, but patients can be billed for administration costs. Currently, all oral antivirals and monoclonal antibodies are made available under APAs. Only Gilead's intravenous antiviral, remdesivir, which received full FDA approval for treatment of non-hospitalized patients (12 years of age or older) at high risk for COVID-19 disease progression in January 2022, is available under a standard purchase model where hospitals, clinics, and other institutions purchase product through distributors.

In an EUA environment where the federal government does not sign an APA, the manufacturer sells product directly to wholesalers and/or distributors who ship the product to various sites of care, and provider institutions and clinics can bill health plans for product. GlaxoSmithKline and Vir Biotechnology’s sotrovimab was granted an EUA in May 2021 but did not receive an APA until November 2021. In an EUA, a manufacturer cannot make any claims about the safety and efficacy of its drug; with a full marketing authorization/BLA, a manufacturer can make these claims as long as they are consistent with the product’s label.

If we are successful with our request for emergency use authorization of adintrevimab in the U.S., we intend to seek an APA and to sell product directly to wholesalers and/or distributors while our request for an APA is pending.

Addressable Patient Populations

Pre-Exposure Prophylaxis (PrEP)

In an EUA environment, the Healthcare Provider and Patient Fact Sheets specify the patient populations eligible to receive COVID-19 treatment and prevention, and utilization of PrEP products is bound by these specifications. If we are successful with our request for EUA of adintrevimab for pre-exposure prophylaxis, we estimate that the total addressable PrEP market for adintrevimab in the U.S. is approximately 7-8 million immunocompromised patients.

For example, the tixagevimab/cilgavimab February 2022 Fact Sheet states, in part, that tixagevimab/cilgavimab may only be used in adults and pediatric individuals (12 years of age and older weighing at least 40 kg):

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Who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2; and

Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination; or

For whom vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).

CDC Guidelines suggest prioritizing the following patient populations due to limited drug supply:

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Patients who are within 1 year of receiving B-cell depleting therapies (e.g., rituximab, ocrelizumab, ofatumumab, alemtuzumab);

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Patients receiving Bruton tyrosine kinase inhibitors;

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Chimeric antigen receptor T cell recipients;

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Post-hematopoietic cell transplant recipients who have chronic graft versus host disease or who are taking immunosuppressive medications for another indication;

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Patients with hematologic malignancies who are on active therapy;

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Lung transplant recipients;

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Patients who are within 1 year of receiving a solid-organ transplant (other than lung transplant);

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Solid-organ transplant recipients with recent treatment for acute rejection with T or B cell depleting agents;

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Patients with severe combined immunodeficiencies; and

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Patients with untreated HIV who have a CD4 T lymphocyte cell count <50 cells/mm3.

If we are successful with our request for emergency use authorization of adintrevimab for pre-exposure prophylaxis, Adagio estimates that the total addressable PrEP market for adintrevimab in the U.S. is approximately 7-8 million immunocompromised patients.

We have conducted several waves of market research with physicians that have reflected that there are gaps in pre-exposure prophylactic alternatives in a variety of U.S. populations. Specifically, Adagio recently commissioned a consulting firm to conduct epidemiological analyses supplemented with physician interviews to quantify the size of the adult immunocompromised population in the United States. Their analysis suggested that there are an additional 10-12 million adults in the U.S. with impaired immune responses attributable to conditions such as uncontrolled Type 2 diabetes and autoimmune disorders such as severe multiple sclerosis, psoriasis, rheumatoid arthritis, and irritable bowel disease, bringing the total potential addressable immunocompromised population in the U.S. closer to 20 million patients. Extrapolated to European Union countries (whose population is approximately 1.5x that of the United States), there are an additional 30 million immunocompromised adults that could be candidates for PrEP therapy in the EU.

Additional populations identified include:

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Of the 200 million “fully-vaccinated” adults, the 20% who will “definitely not” not seek a booster (200 million adults x .20 = 40 million adults);

•

Of the 200 million “fully-vaccinated” adults, the 1-2% who experienced side effects so severe they would not seek a booster (200 million adults x .015 = 3 million adults);

•

The 20% of the unvaccinated adult population (15% of the U.S. population) who refuse to get vaccinated but who have indicated interest in neutralizing monoclonal antibody therapy (258 million adults x .15 x .20 = 7.7 million adults); and

•

Of the 48 million children < 12 years old, the approximately 1% who are immunocompromised and/or have health conditions that predispose them to negative outcomes with COVID-19 (48 million children < 12 x .01 = 480,000).

Treatment

In an EUA environment, the Healthcare Provider and Patient Fact Sheets specify the patient populations eligible to receive COVID-19 treatments. These Fact Sheets are largely driven by the CDC’s Guidelines, which are updated frequently.

Specifically, the CDC COVID-19 Treatment Guidelines prioritize the following risk groups for anti-SARS-CoV-2 therapy based on 4 key elements: age, vaccination status, immune status, and clinical risk factors. The groups are listed by tier in descending order of priority:

Tier 1

•

Immunocompromised individuals not expected to mount an adequate immune response to COVID-19 vaccination or SARS-CoV-2 infection due to their underlying conditions, regardless of vaccine status (see Immunocompromising Conditions below); or

•

Unvaccinated individuals at the highest risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years with additional risk factors)

Tier 2

•

Unvaccinated individuals at risk of severe disease not included in Tier 1 (anyone aged ≥65 years or anyone aged <65 years with clinical risk factors)

Tier 3

•

Vaccinated individuals at high risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years with clinical risk factors)

Tier 4

•

Vaccinated individuals at risk of severe disease (anyone aged ≥65 years or anyone aged <65 with clinical risk factors)

In 2020, the CDC estimated that 45% of the U.S. adult population, or 115 million individuals, have one or more comorbidities associated with increased risk for complications from SARS-CoV-2 infections.

We have conducted several waves of market research with physicians that have reflected that there are gaps in COVID-19 treatment alternatives in a variety of U.S. patient populations, including:

•

Infected patients concerned about “Long COVID” seeking to rapidly drive down their viral load; and

•

Infected patients for whom quarantining is not an option due to impending travel, work obligations, or other reasons.

Post-Exposure Prophylaxis (PEP)

In an EUA environment, the Healthcare Provider and Patient Fact Sheets specify the patient populations eligible to receive COVID-19 post-exposure prophylaxis. For example, at the time casirivimab/imdevimab was available for distribution, its Healthcare Provider Fact Sheet stated it was authorized for use in:

•

Adult and pediatric individuals (12 years of age and older weighing at least 40 kg) for post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are

Not fully vaccinated; or

Who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications); and

▪

Have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC); or

▪

Who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).

Since exposures are directly related to infections, the size of the PEP population is difficult to quantify at any given time. As a guide, the March 2022 casirivimab/imdevimab Physician Letter references the consideration of use in the following U.S. PEP populations:

•

8 million individuals in long-term care facilities

•

2 million incarcerated individuals

•

7 million immunocompromised adults

•

115 million adults who are at high risk for progression to severe COVID-19

We have conducted several waves of market research with physicians that have reflected that there are gaps in post-exposure prophylactic alternatives in a variety of U.S. patient populations, including:

•

Exposed patients concerned about “Long COVID” seeking to rapidly drive down their viral load in case they have COVID; and

•

Exposed patients for whom quarantining is not an option due to impending travel, work obligations, or other reasons.

Pediatrics

Although children are at lower risk of developing severe COVID-19 compared to adults, a subset of children experience poor outcomes, including severe acute disease, such as the multisystem inflammatory syndrome, or MIS-C, and long-term sequelae of disease, also known as long COVID. Safe and effective therapies are needed to prevent severe disease and hospitalization in high-risk children as well as complications of COVID-19 such as MIS-C and long COVID. Similarly, although there is a paucity of data regarding the immune response to COVID-19 vaccines in children with moderate to severe immunocompromise, a subset of these children may have suboptimal immune responses to vaccines similar to adults with certain forms of immunocompromise and thus have the potential to benefit from a passive immune approach. Currently, the CDC recommends that children ages 5 to 11 with moderate to severe immunocompromise receive a 3 dose primary series of the Pfizer-BioNTech vaccine and that pre-teens and adolescents with moderate to severe immunocompromise receive a total of 4 doses of a mRNA COVID-19 vaccine.

Adintrevimab Attributes vs. Competitive mAbs

We believe adintrevimab has a unique combination of attributes that positions adintrevimab to be a potentially differentiated mAb for both the prevention and treatment of COVID-19. There are no head-to-head trials between adintrevimab and any product, and therefore no safety or efficacy comparisons can be made.

Reducing Risk of Clinical Resistance. Many SARS-CoV-2 variants of concern and variants of interest likely emerged in response to immune pressure exerted on variable amino acid residues such as K417 and E484, which are targeted by public antibodies commonly induced by natural infection and vaccination. Because most of the mAbs currently in development were isolated from COVID-19 survivors and belong to one of the three classes of public RBD-directed antibodies, many of the clinical-stage mAbs show significant loss of potency against multiple variants of concern. For example, casirivimab, bamlanivimab, etesevimab and regandivimab all show significant loss of in vitro neutralizing potency against the Beta (B1.351), Gamma (P.1), Iota (B.1.526), Epsilon (B.1.429), and Omicron (B.1.529) variants, which contain mutations at the key amino acid residues recognized by these antibodies. In contrast, the adintrevimab epitope is not readily targeted by endogenous antibodies, thereby potentially increasing the barrier to circulating viral escape. In support of this notion, adintrevimab demonstrates potent neutralizing activity against many SARS-CoV-2 variants that escape recognition by certain clinical-stage or EUA authorized mAbs, including the Alpha (B.1.1.7), Beta (B1.351), Gamma (P.1) and Delta (B.1.617.2) variants of concern. Adintrevimab also displays neutralizing activity against the Omicron BA.1 sub-variant, albeit with reduced potency relative to earlier variants, and no activity against the BA.2 sub-variant.

Half-Life Extension. Adintrevimab was engineered from its parent antibody, ADG2, with a modification in the Fc region that results in enhanced binding to FcRn at low pH levels. Enhanced binding to FcRn receptors at low pH levels improves FcRn-mediated antibody recycling, leading to an extended serum half-life in humans. The prolonged half-life for adintrevimab is supported by preliminary pharmacokinetic data from the Phase 1 healthy volunteer study. Adintrevimab has the potential to provide durable protection by virtue of its potency and half-life extension, depending on the variant.

Effector Function. Antibodies with Fc-mediated immune effector function summon immune cells and other immune mediators to the site of infection to help destroy infected cells and clear the infection. Preclinical in vivo studies for other SARS-CoV-2 mAbs also suggest that Fc effector functions help to modulate protective immune responses. Notably, tixagevimab/cilgavimab includes Fc modifications that reduce innate immune effector functions. In contrast, adintrevimab was engineered to retain Fc-mediated innate immune effector activity, including ADCC and ADCP.

Potency. Adintrevimab displays highly potent neutralizing activity (defined as in vitro IC50 approximately equal to 0.01 mcg/mL or less) against the majority of variants of concern andvariants of interest,including Alpha (B.1.1.7), Beta (B1.351), Gamma (P.1) and Delta (B.1.617.2). Adintrevimab also demonstrates neutralizing activity against the Omicron BA.1 and BA.1.1 variants with in vitro IC50s of approximately 1.0 mcg/mL. Adintrevimab did not show detectable neutralizing activity against the BA.2 variant in authentic virus neutralization assays. Importantly, when combining the overall neutralization breadth, including additional SARS-like viruses, and potency profile, adintrevimab is potentially differentiated from almost all clinical-stage and EUA authorized SARS-CoV-2-specific antibodies.

Convenient Dosing Regimen. Intravenous administration of currently available COVID-19 mAbs requires specialized facilities that are properly equipped to accommodate IV dosing in actively infected patients, which may lead to a delay in administration. Given the potency, low viscosity and high concentration formulation of adintrevimab, we are developing adintrevimab as an IM injection for both the prevention and treatment of COVID-19.

Breadth. Adintrevimab has demonstrated broad neutralizing activity against most SARS-CoV-2 variants and other SARS-like viruses that infect human cells through the same hACE2 receptor pathway as SARS-CoV-2. To our knowledge, the only other mAb in late-stage clinical development that has demonstrated activity against additional SARS-like viruses is sotrovimab, but with lower potency against most variants compared to adintrevimab.

Adintrevimab Attributes vs. Antivirals

We believe adintrevimab has the potential to address certain limitations of currently available COVID antivirals for the treatment of COVID-19, including inconvenient administration and potential for lack of compliance, drug-drug interactions and restrictions of use in certain patient populations. Oral and IV antivirals require patients to take doses over several days, whereas adintrevimab has the potential to provide clinical benefit with a single dose. Oral antivirals require the patient to receive, fill and pay for the prescription via a retail or specialty pharmacy, whereas adintrevimab is expected to be administered in a physician’s office or urgent care setting, minimizing delays in administration of therapy. As a mAb, adintrevimab has low potential for drug-drug interactions and pharmacokinetics are not anticipated to be impacted by patient factors such as renal or hepatic impairment. There are no head-to-head trials between adintrevimab and any product, and therefore no safety or efficacy comparisons can be made.

Go-to-Market Strategy

We believe the commercialization of adintrevimab, if authorized or approved, will involve direct sales to governments, including relevant health agencies and national health systems, and in the United States, health insurers, integrated delivery networks and large employers. We intend to establish our own commercial organization in the United States, where we believe a focused commercial infrastructure will be able to successfully commercialize adintrevimab under a regulatory authorization and/or approval, and we are considering commercial options in Europe and beyond. We have begun discussions with some of these entities and will continue to do so as we progress adintrevimab through a potential EUA and commercialization. In certain markets, such as Latin America, Asia-Pacific, including China, and Middle Eastern and African countries, we intend to commercialize adintrevimab through partnerships.

Additional Product Candidates Beyond Adintrevimab

As illustrated in the graphic above, we are developing additional product candidates that target conserved epitopes both within and outside of the RBD for the prevention and treatment of COVID-19 and have initiated discovery programs focused

on preventative agents for additional coronaviruses as well as seasonal and pandemic influenza, which are discussed in greater detail below. We have discontinued development of ADG10 due its less favorable neutralization profile compared to adintrevimab.

Additional Programs in Discovery

We envision additional product development opportunities emerging from our coronavirus discovery efforts for the prevention and treatment of COVID-19. We believe the discovery of additional broadly neutralizing antibodies that target new viral epitopes both within and outside the RBD will ensure long-lasting product activity for COVID-19 as new variants of SARS-CoV-2 arise as well as for future outbreaks of disease that may emerge from additional SARS-like viruses with pandemic potential.

We believe that the robust antibody discovery, engineering, and development capabilities that have enabled our expedited advancement of adintrevimab into clinical trials may also be used to develop preventative or therapeutic options for other infectious diseases, such as seasonal and pandemic influenza. Broadly neutralizing antibodies with extended half-life have the potential to be used directly for the prevention of infection and disease. We have formulated a strategy to discover and engineer potent, broadly neutralizing antibodies targeting certain regions of the influenza virus surface protein, with the goal of generating product candidates with the potential to provide protection against both seasonal and pandemic influenza.

In addition, the epitopes targeted by broadly neutralizing antibodies can be used as templates for the rational design of vaccine immunogens that elicit similar types of antibodies. In collaboration with an academic partner, we have initiated work on the design of coronavirus vaccine antigens that focus the antibody response on highly conserved epitopes defined by adintrevimab and other broadly neutralizing antibodies discovered by us and others.

Manufacturing Strategy

We do not currently own or operate any manufacturing facilities and have invested significant resources to develop a commercial scale manufacturing process for adintrevimab in partnership with our contract manufacturer partner, WuXi, with whom we have been working since our inception. With WuXi, we have manufactured drug substance supply at commercial scale in the planned commercial launch facility. Adintrevimab drug substance is produced using an industry standard mAb manufacturing process including a recombinant Chinese Hamster Ovary, or CHO, commercial cell line, fed-batch suspension cell culture and a chromatography column-based purification process. We have also manufactured drug product supply at commercial scale in the planned commercial launch facility at WuXi. The drug product manufacture uses an industry standard sterile liquid drug product manufacturing process and formulation that enables IM delivery of adintrevimab.

We have established long-term master services agreements with WuXi, pursuant to which we purchase adintrevimab drug substance and drug product for both clinical and commercial supply. The master services agreements are also applicable to any future clinical candidates identified for development, should we elect to use WuXi for development and supply of those candidates. We may stop placing orders under the master services agreements at any time, provided that we fulfill our obligations to make payment for, or pay cancellation-related costs related to, all committed purchases. Either party may also terminate the master services agreements with respect to an uncured breach by the other party in accordance with the terms of the agreements. The agreements include confidentiality and intellectual property provisions to protect our proprietary rights related to our product candidates.

We have also established a cell line license agreement with WuXi that allows for the transfer and use of the commercial cell line currently used in the manufacture of adintrevimab drug substance at WuXi. This license enables cell line and manufacturing process transfer to additional contract manufacturers. We are obligated to pay WuXi royalties in the range of 0.3% to 0.5% based on our net sales of any products covered by the cell line license agreement, unless we use WuXi to manufacture all of our commercial supplies, and we may buy out our royalty obligations by making a one-time payment of $15.0 million to WuXi at our option. Royalties are due on a licensed product-by-licensed product basis commencing on the date of the first commercial sale of the applicable product and continue for so long as we commercialize licensed products or until we exercise our option to buy out the royalty obligations.

We expect to continue to devote significant resources to the manufacture of adintrevimab, and we do not expect any meaningful impediments to executing our current supply plan to provide under EUA or for commercial use. However, within the context of the global pandemic, sufficient capacity for commercial scale manufacturing has been constrained on a worldwide basis. While any reduction or halt in the supply of adintrevimab drug substance or drug product could limit our ability to supply product until a replacement contract manufacturer is found and qualified, we believe that we have sufficient

supply of adintrevimab to support our clinical trial needs and to fulfill our initial supply needs upon receipt of an EUA or BLA approval, if granted. We will also continue to apply mitigation strategies to ensure minimal disruption to our manufacturing supply due to global raw material supply chain shortages. We continue to identify additional drug substance and drug product contract manufacturers to ensure that we will have sufficient capacity and redundancy within our supply chain to avoid product shortages or product delays in the future, This continued surveillance of drug substance and drug product contract manufacturer capabilities applies to our adintrevimab program as well as to our clinical pipeline candidates.

Our Relationship with Adimab

We were founded in June 2020 by Adimab to focus initially on the development of antibodies for both the prevention and treatment of COVID-19. Adimab is a leading provider of antibody discovery, engineering and optimization services and has established an extensive presence in the drug discovery industry.

We are party to an assignment and license agreement with Adimab under which Adimab assigned to us its rights to all existing coronavirus antibodies controlled by it and their derivatives, including adintrevimab. See “—Licensing, Collaborations and Partnerships—Assignment and License Agreement with Adimab.” In addition, in May 2021, we entered into a funded discovery agreement with Adimab focused on discovery efforts for new antibodies that may be effective against other coronaviruses and influenza, both of which have the potential to cause pandemics. In the event that Adimab discovers an antibody that is expected to meet certain product profiles developed by Adagio, Adagio will have the exclusive option to require Adimab to assign us its rights in any such antibody and to grant us certain licenses. See “—Licensing, Collaborations and Partnerships—Collaboration Agreement with Adimab.”

Licensing, Collaborations and Partnerships

Adimab Assignment Agreement

In July 2020, we entered into an assignment and license agreement with Adimab, or the Adimab Assignment Agreement, with respect to discovery and optimization of coronavirus-specific antibodies, including COVID-19 and SARS. Under the Adimab Assignment Agreement, Adimab assigned to us its rights to all existing coronavirus antibodies controlled by it and their derivatives, patents claiming such antibodies, know-how related to such antibodies, and biological and chemical materials specifically related to such antibodies. Adimab also granted us a non-exclusive, worldwide, royalty-bearing, sublicensable license to certain of its antibody discovery and optimization platform technology to research, develop, make, use, and sell coronavirus antibodies and products containing or comprising coronavirus antibodies, provided that we may not use such licensed rights to discover or optimize antibodies. Adimab cannot grant any third party any license or right under any patent claiming our coronavirus antibodies and cannot deliver our coronavirus antibodies to third parties; however, we have limited recourse in the event of accidental disclosures.

We are obligated to use commercially reasonable efforts to achieve specified development and regulatory milestones for products in certain major markets and to commercialize a product in any country in which we obtain marketing approval. We are obligated to pay Adimab quarterly for its services performed under the agreement at a specified full-time equivalent rate.

In July 2020, in consideration for the rights assigned and license conveyed under the Adimab Assignment Agreement, we issued 5,000,000 shares of our Series A preferred stock, then having a fair value of $40.0 million, to Adimab. In addition, under the Adimab Assignment Agreement, we are obligated to pay Adimab up to $24.6 million upon the achievement of specified development and regulatory milestones for the first two products that comprise or contain coronavirus antibodies assigned to us, antibodies discovered or optimized under the Adimab Assignment Agreement, or any derivative of such antibody, or the Products. Through December 31, 2021, we had made aggregate milestone payments of $7.5 million to Adimab under the Adimab Assignment Agreement. We are also obligated to pay Adimab royalties of a mid single-digit percentage based on annual aggregate worldwide net sales of any Products, subject to reductions for third-party licenses, biosimilar competition, compulsory licensing and a royalty floor. The royalty term expires for each Product on a country-by-country basis beginning upon the first commercial sale of each Product and ending on the later of (i) 12 years after the first commercial sale of such Product in such country and (ii) the expiration of the last valid claim of any patent in such country that was assigned to us under the Adimab Assignment Agreement or that claims priority to any such patent. If we commercialize any products as a diagnostic device (other than a companion diagnostic device) or as a research reagent, we must negotiate reasonable financial terms for such products.

The Adimab Assignment Agreement will expire, unless earlier terminated, on the expiration of the last-to-expire royalty term. We have the right to terminate the Adimab Assignment Agreement at any time upon advance written notice to Adimab. In addition, subject to certain conditions, either we or Adimab may terminate the Adimab Assignment Agreement if the other

party commits a material breach of the agreement and fails to cure such breach within a specified cure period after written notice is provided, except that after the initiation of the first clinical trial of a Product, Adimab may only terminate the agreement if we materially breach, and do not cure, our diligence obligation or a payment obligation. Upon expiration of the Adimab Assignment Agreement, the license becomes royalty-free, irrevocable and perpetual. Upon termination of the Adimab Assignment Agreement, all licenses and rights granted by either party will terminate and, in the case of our termination for convenience or Adimab’s termination for our material breach, we are required to assign to Adimab all right, title and interest to the patents assigned by Adimab to us or that claim priority to such patents.

Through December 31, 2021, we had made aggregate payments of $9.0 million to Adimab under the Adimab Assignment Agreement, inclusive of the milestone payments.

Adimab Collaboration Agreement

In May 2021, we entered into a collaboration agreement with Adimab, or the Adimab Collaboration Agreement, for the discovery and optimization of proprietary antibodies as potential therapeutic product candidates. Under the Adimab Collaboration Agreement, we and Adimab will collaborate on research programs for a specified number of targets selected by us within a specified time period. If Adimab is unable to generate antibodies directed against a target selected by us, then we may replace such target. Under the Adimab Collaboration Agreement, Adimab granted us a worldwide, non-exclusive license to certain of Adimab’s platform patents and technology and antibody patents to perform our responsibilities during the ongoing research period and for a specified evaluation period thereafter, or the Evaluation Term. We granted Adimab a non-exclusive, non-sublicensable license to certain of our patents and intellectual property solely to perform Adimab’s responsibilities under the research plans. Under the agreement, we have an exclusive option on a program-by-program basis to obtain licenses and assignments to commercialize selected products containing or comprising antibodies directed against the applicable target, which option may be exercised upon the payment of a specified option fee for each program. Upon exercise of an option, Adimab will assign to us all right, title and interest in the antibodies of the optioned research program and will grant us a worldwide, royalty-free, fully paid-up, non-exclusive, sublicensable license under the Adimab platform technology to research, develop, make, use, and sell the antibodies for which we have exercised our options and products containing or comprising those antibodies.

Under the Adimab Collaboration Agreement, we are obligated to use commercially reasonable efforts to develop, seek marketing approval for, and commercialize one product that contains an antibody discovered in each research program for which we exercise our option to obtain licenses and assignments.

Under the agreement, we are obligated to pay Adimab a quarterly fee of $1.3 million in exchange for Adimab and its affiliates agreeing not to assist in the discovery or optimization of or to direct certain third parties to discover or optimize antibodies that are intended to bind to coronaviruses or influenza viruses, which obligation may be cancelled at our option at any time. For so long as we are paying such quarterly fee (or earlier (i) if we experience a change of control after the third anniversary of the Adimab Collaboration Agreement or (ii) Adimab owns less than a specified percentage of our equity), Adimab and its affiliates will not assist or direct certain third parties to discover or optimize antibodies that are intended to bind to coronaviruses or influenza viruses with limited exception. We may also elect to decrease the scope of Adimab’s exclusivity obligations and obtain a corresponding decrease in the quarterly fee. For each agreed upon research program that is commenced, we are obligated to pay Adimab quarterly for its services performed during a given research program at a specified full-time equivalent rate; a discovery delivery fee of $0.2 million; and an optimization completion fee of $0.2 million. For each option exercised by us to commercialize a specific research program, we are obligated to pay Adimab an exercise fee of $1.0 million.

We are obligated to pay Adimab up to $18.0 million upon the achievement of specified development and regulatory milestones for each product under the agreement that achieves such milestones. We are also obligated to pay Adimab royalties of a mid single-digit percentage based on annual aggregate worldwide net sales of products, subject to reductions for third-party licenses. The royalty term will expire for each product on a country-by-country basis on the later of (i) 12 years after the first commercial sale of such product in such country and (ii) the expiration of the last valid claim of any patent claiming composition of matter or method of making or using any antibody identified or optimized under the Adimab Collaboration Agreement in such country.

In addition, we are obligated to pay Adimab for Adimab’s performance of certain validation work with respect to certain antigens acquired from a third party. In consideration for this work, we are obligated to pay Adimab royalties of a low single-digit percentage based on annual aggregate worldwide net sales of products that contain such antigens for the same royalty term as antibody-based products, but we are not obligated to make any milestone payments for such antigen products.

The Adimab Collaboration Agreement will expire (i) if we do not exercise any option, upon the conclusion of the last Evaluation Term for the research programs, or (ii) if we exercise an option, on the expiration of the last royalty term for a product in a particular country, unless the agreement is earlier terminated. We may terminate the Adimab Collaboration Agreement at any time upon advance written notice to Adimab. In addition, subject to certain conditions, either party may terminate the Adimab Collaboration Agreement in the event of a material breach by the other party that is not cured within specified cure periods. Following termination, we are prohibited from (i) researching, developing, manufacturing or commercializing, any products containing antibodies discovered under the agreement, (ii) practicing, licensing, assigning, granting options to, or otherwise covenanting away rights to the foregoing products, and (iii) licensing or otherwise granting covenants not to sue third parties for the foregoing products.

Through December 31, 2021, we had made aggregate payments of $2.6 million to Adimab under the Adimab Collaboration Agreement.

Research Collaboration and License Agreement with The Scripps Research Institute

In August 2021, we entered into a research collaboration and license agreement, or the Research Agreement, with The Scripps Research Institute, or TSRI. Under the terms of the Research Agreement, TSRI will perform research activities to identify vaccine candidates for the prevention, diagnosis or treatment of influenza or beta coronaviruses, or the Research Program, which is expected to be completed by August 2023. As of December 31, 2021, we had paid TSRI an aggregate of $1.5 million in funding, which is credited against research funding payable by the Company under the Research Agreement. Additionally, we are obligated to make specified payments to TSRI to the extent that TSRI complies with certain exclusivity covenants.

Pursuant to the terms of the Research Agreement, we were granted an exclusive option to acquire an exclusive, worldwide, sublicensable license under TSRI’s rights in certain patent rights and know-how for the exploitation of any vaccine product containing, comprised of, or derived from, any vaccine candidate identified or developed under the Research Agreement, subject to certain exceptions, conditions and reserved rights. As of December 31, 2021, we have not exercised this option.

To the extent any licensed product covered by the Research Agreement is commercialized, the Company is obligated to pay TSRI royalties of a low single-digit percentage on a product-by-product and country-by-country basis based on a percentage of net sales, subject to reduction and floor. Royalties are payable for each product on a country-by-country basis through the later of (i) the expiration of the last valid claim of any patent covering such product in such country or (ii) 12 years from the first commercial sale of such product. The Research Agreement will expire when no further royalties are due to TSRI.

Cell Line License Agreement with WuXi

We are also party to a Cell Line License Agreement with WuXi, entered into as of December 2, 2020. See “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Contractual Obligations and Commitments” and “—Manufacturing Strategy.”

License Agreement with Biocon Biologics Limited

In July 2021, we entered into a license agreement with Biocon to combat the ongoing COVID-19 crisis in southern Asia. Under the license agreement, we granted Biocon exclusive rights to manufacture and commercialize an antibody treatment in India and additional select emerging markets based on the commercial process developed for adintrevimab. As part of the agreement, Biocon will be granted access to the data from our ongoing Phase 2/3 adintrevimab clinical trials and access to our anticipated EUA package, as well as regulatory submissions, to support approval or emergency authorization in India and other select emerging markets.

Competition

The biotechnology and pharmaceutical industry is characterized by the rapid evolution of technologies and understanding of disease etiology, intense competition and a strong emphasis on intellectual property. We believe that our approach, strategy, scientific, development and manufacturing capabilities, know-how, partnerships and experience provide us with competitive advantages. However, we expect substantial competition from multiple sources, including major pharmaceutical, specialty pharmaceutical and existing or emerging biotechnology companies, academic research institutions, governmental agencies and public and private research institutions worldwide. Many of our competitors, either alone or through collaborations, have

significantly greater financial resources and expertise in research and development, preclinical testing, conducting clinical trials, manufacturing, obtaining regulatory approvals and marketing approved products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These entities also compete with us in recruiting and retaining qualified scientific, clinical, manufacturing and management personnel, establishing clinical trial sites and enrolling patient in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. As a result, our competitors may discover, develop, license or commercialize products before or more successfully than we do.

We face competition from segments of the pharmaceutical, biotechnology and other related markets that pursue the development of antibody and small molecule antivirals targeting COVID-19. Companies that have authorized or late-stage COVID-19 antibody-based programs include AstraZeneca plc, Brii Biosciences Limited, Celltrion Healthcare Co, Ltd., Eli Lilly and Co, Regeneron Pharmaceuticals, Inc. in collaboration with Roche Pharmaceuticals, SAB Biotherapeutics, Inc. and Vir Biotechnology, Inc. in collaboration with GlaxoSmithKline. In addition, companies that have approved or authorized antiviral programs for the treatment of COVID-19 include Merck and Co., Inc. (oral), Pfizer Pharmaceuticals (oral), and Gilead (IV). Beyond antibody and small molecule antiviral treatments, we also face competition from SARS-CoV-2 vaccines that are either available under EUA, approved or in development for the prevention of COVID-19.

We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize drugs that are safer, better tolerated, more effective, more convenient to administer, less expensive, more resistant to viral escape, or receive a more favorable label than our product candidates. Some of our competitors have already obtained EUAs from the FDA for the treatment of mild to moderate COVID-19 in high risk patients and the prevention of COVID-19 in immunocompromised patients, and others in the future may obtain FDA or other regulatory approval or authorization more rapidly than we may, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of our product candidates, if approved, are likely to be their efficacy, safety, convenience, price and the availability of reimbursement from government and other third-party payors.

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain patent and other proprietary protection in the United States and in other countries for commercially important technology, current and future inventions, improvements and know-how related to our business; defend and enforce our patents and other intellectual property; preserve the confidentiality of our trade secrets; and operate without infringing, misappropriating or otherwise violating the valid enforceable patents and proprietary rights of third parties. Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities. With respect to both licensed and company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same. Our pending PCT patent applications are not eligible to become issued patents until, among other things, we file a national stage patent application within 30 months in the countries in which we seek patent protection. Furthermore, our pending U.S. provisional patent applications are not eligible to become issued patents until, among other things, we file a non-provisional U.S. patent application within one year of filing of the U.S. provisional patent application with the USPTO. If we do not timely file any national stage patent applications or non-provisional U.S. patent applications, we may lose our priority date with respect to our PCT and provisional U.S. patent applications and any patent protection on the inventions disclosed in such patent applications. See “Risk Factors—Risks Related to Our Intellectual Property.”

We actively seek to protect our proprietary technology, inventions and other intellectual property that is commercially important to the development of our business by a variety of means, such as seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. We also may rely on trade secrets and know-how relating to our proprietary technology platform, on continuing technological innovation and on in-licensing opportunities to develop, strengthen and maintain the strength of our position in the antibody field that may be important for the development of our business. We also intend to seek patent protection or rely upon trade secret rights to protect other technologies that may be used to discover and validate targets, as well as to manufacture and develop novel antibody products. Additional regulatory protection may also be afforded through data exclusivity, market exclusivity and patent term extensions where available.

We file patent applications directed to compositions comprising our antibodies, classes of antibodies covering our product candidates, use of such antibodies for preventing and treating disease, diagnostic methods, pharmaceutical compositions, combination therapies, and methods of manufacturing. We continue to review new inventions for patent filings.

Adintrevimab and ADG10

As of March 30, 2022, we own one patent family for which we have one PCT patent application (WO2021/207597, published October 14, 2021), two issued U.S. patents (U.S. 11,192,940, issued December 7, 2021 and U.S. 11,220,536, issued January 11, 2022), one allowed U.S. patent application (U.S. Publication 2021/0388067, published December 16, 2021), one pending U.S. non-provisional patent application, and two foreign patent applications in Argentina and Taiwan. This patent family is directed to broadly neutralizing anti-coronavirus antibodies, including ADG20 (adintrevimab) and ADG10, and uses thereof. These patents and patent applications and any additional U.S. non-provisional patent applications or foreign patent applications timely filed based upon such applications, if issued, are expected to expire in 2041, without taking into account any possible patent term adjustment or extension.

As of March 30, 2022, we own a second patent family for which we have filed one PCT patent application and two foreign patent applications in Argentina and Taiwan. This patent family is directed to additional broadly neutralizing anti-coronavirus antibodies, combination therapies, and uses thereof. These patent applications and any additional U.S. non-provisional patent applications or foreign patent applications timely filed based upon such applications, if issued, are expected to expire in 2042, without taking into account any possible patent term adjustment or extension.

As of March 30, 2022, we own four additional patent families for which we have filed provisional U.S. patent applications. The first patent family is directed to methods of treating and preventing disease based on data obtained from adintrevimab clinical trials and includes eighteen U.S. provisional patent applications. The second patent family is directed to adintrevimab formulations, combination therapies, and uses thereof and includes one U.S. provisional patent application. The third patent family is directed to additional broadly neutralizing anti-coronavirus antibodies, combination therapies, and uses thereof and includes two U.S. provisional patent applications. Any U.S. non-provisional patent applications timely filed based upon these U.S. provisional patent applications, if issued, are expected to expire in 2042, without taking into account any possible patent term adjustment or extension. The fourth patent family is directed to methods of treating or preventing coronavirus infection using anti-coronavirus antibodies, and any U.S. non-provisional patent applications timely filed based on this U.S. provisional patent application, if issued, is expected to expire in 2043, without taking into account any possible patent term adjustment or extension.

Trade Secrets and Proprietary Information

We also rely, in some circumstances, on trade secrets to protect our technology, including our proprietary scientific, business and technical information and know-how that is not or may not be patentable or that we elect not to patent. We seek to protect our proprietary information, data and processes, in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and partners. Although these agreements are designed to protect our proprietary information, we cannot be certain that our trade secrets and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques. Although we generally require all of our employees to assign their inventions to us, and require all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information or technology to enter into confidentiality agreements, we cannot provide any assurances that all such agreements have been duly executed with all third parties who may have helped to develop our intellectual property or who had access to our proprietary information, or that our agreements will not be breached. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

Government Regulation

In the United States, biologic products are licensed by the FDA for marketing under the Public Health Service Act, or the PHS Act, and regulated under the Federal Food, Drug, and Cosmetic Act, or the FDCA. Both the FDCA and the PHS Act and their corresponding regulations govern, among other things, the testing, manufacturing, safety, purity, potency, efficacy, labeling, packaging, storage, record keeping, distribution, marketing, sales, import, export, reporting, advertising and other promotional practices involving biologic products. FDA clearance must be obtained before clinical testing of biologic products. FDA licensure also must be obtained before marketing of biologic products. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Development Process

The process required by the FDA before a biologic product may be marketed in the United States generally involves the following:

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completion of nonclinical laboratory tests and animal studies according to Good Laboratory Practices, or GLPs, and applicable requirements for the humane use of laboratory animals or other applicable regulations;

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preparation of clinical trial material in accordance with Good Manufacturing Practices, or GMPs;

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submission to the FDA of an application for an Investigational New Drug Application, or IND, which must become effective before human clinical trials may begin;

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approval by an institutional review board, or IRB, reviewing each clinical site before each clinical trial may be initiated;

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performance of adequate and well-controlled human clinical trials according to Good Clinical Practices, or GCPs, and any additional requirements for the protection of human research subjects and their health information to establish the safety, purity, potency and efficacy of the proposed biologic product for its intended use;

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submission to the FDA of a BLA for marketing approval that includes substantive evidence of safety, purity, potency, and efficacy from results of nonclinical testing and clinical trials;

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satisfactory completion of an FDA inspection prior to BLA approval of the manufacturing facility or facilities where the biologic product is produced to assess compliance with GMPs to assure that the facilities, methods and controls are adequate to preserve the biologic’s identity, strength, quality and purity;

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potential FDA audit of the nonclinical and clinical study sites that generated the data in support of the BLA;

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potential FDA Advisory Committee meeting to elicit expert input on critical issues, including a vote by external committee members;

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FDA review and approval, or licensure, of the BLA and payment of associated user fees, when applicable; and

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compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS, and the potential requirement to conduct post-approval studies.

Before testing any biologic product candidate in humans, the product candidate enters the preclinical testing stage. Nonclinical tests include laboratory evaluations of product chemistry, pharmacology, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate. The conduct of the nonclinical tests must comply with federal regulations and requirements, including GLPs.

The clinical study sponsor must submit the results of the nonclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some nonclinical testing typically continues after the IND is submitted. An IND is an exemption from the FDCA that allows an unapproved product to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational product to humans. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA requests certain changes to a protocol before the trial can begin or places the clinical trial on hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA may also impose clinical holds on a biologic product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA.

Clinical trials may involve the administration of the biologic product candidate to healthy volunteers or subjects under the supervision of qualified investigators, generally physicians not employed by or under the study sponsor’s control. Clinical trials involving some products for certain diseases may begin with testing in patients with the disease. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research subjects or his or her legal representative provide informed consent. Further, each clinical trial must be reviewed and approved by an independent IRB at or servicing each institution at which the clinical trial will be conducted. IRBs are charged with protecting the welfare and

rights of study participants and consider such items as whether the risks to individuals participating in clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee.

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

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Phase 1. The biologic product is initially introduced into healthy human subjects and tested for safety. In the case of some biologic products for rare diseases, the initial human testing is often conducted in patients.

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Phase 2. The biologic product is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the biologic product for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.

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Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy, potency and safety in an expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the biologic product and provide an adequate basis for product labeling. In biologics for rare diseases where patient populations are small and there is an urgent need for treatment, Phase 3 trials might not be required if an adequate risk/benefit can be demonstrated from the Phase 2 trial.

Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.

During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the biologic has been associated with unexpected serious harm to patients.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the physical characteristics of the biologic as well as finalize a process for manufacturing the product in commercial quantities in accordance with GMP requirements. To help reduce the risk of the introduction of adventitious agents with the use of biologics, the PHS Act emphasizes the importance of manufacturing control for biologic products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the identity, strength, quality, potency and purity of the final biological product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the biological product candidate does not undergo unacceptable deterioration over its shelf life.

There are also various laws and regulations regarding laboratory practices, the experimental use of animals and the use and disposal of hazardous or potentially hazardous substances in connection with the research. In each of these areas, the FDA and other regulatory authorities have broad regulatory and enforcement powers, including the ability to levy fines and civil penalties, suspend or delay issuance of approvals, seize or recall products and withdraw approvals.

Information about certain clinical trials must be submitted within specific timeframes to the NIH for public dissemination on its clinicaltrials.gov website. Sponsors or distributors of investigational products for the diagnosis, monitoring or treatment of one or more serious diseases or conditions must also have a publicly available policy on evaluating and responding to requests for expanded access requests.

U.S. Review and Approval Processes

After the completion of clinical trials of a biological product, FDA approval of a BLA must be obtained before commercial marketing of the product. The BLA must include results of product development, laboratory and animal studies, human studies, information on the manufacture and composition of the product, proposed labeling and other relevant information. The testing and approval processes require substantial time and effort, and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.

Under the Prescription Drug User Fee Act, as amended, or the PDUFA, each BLA may be accompanied by a significant user fee. Under federal law, the submission of most applications is subject to an application user fee. The sponsor of an approved application is also subject to an annual program fee. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Within 60 days following submission of the application, the FDA reviews the BLA to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. The application also needs to be published and submitted in an electronic format that can be processed through the FDA’s electronic systems. If the electronic submission is not compatible with the FDA’s systems, the BLA can be refused for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA reviews the BLA to determine, among other things, whether the proposed product is safe, potent and effective for its intended use, has an acceptable purity profile and is being manufactured in accordance with GMPs to assure and preserve the product’s identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel products or products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the biological product approval process, the FDA also will determine whether a REMS is necessary to assure the safe use of the biological product. If the FDA concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS; the FDA will not approve the BLA without a REMS, if required.

Before approving a BLA, the FDA may inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with GMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical trial sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements. To assure GMP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.

Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not satisfy its regulatory criteria for approval and deny approval. Data obtained from clinical trials are not always conclusive, and the FDA may interpret data differently than the sponsor interprets the same data. If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that usually describes all of the specific deficiencies in the BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials. Additionally, the complete response letter may include recommended actions that the applicant might take to place the application in a condition for approval. If a complete response letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing or dispensing in the form of a risk management plan, or otherwise limit the scope of any approval. In addition, the FDA may require post-marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biological product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized. As a condition for approval, the FDA may also require additional nonclinical testing as a Phase 4 commitment.

One of the performance goals agreed to by the FDA under the PDUFA is to review and render a decision on standard BLAs within 10 months of filing and priority BLAs within six months of filing. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs, and its review goals are subject to change from time to time. The review process and the PDUFA goal date may be extended by three months if the FDA requests or if the BLA sponsor provides additional

information or clarification regarding information already provided in the submission within the three months preceding the PDUFA goal date.

Emergency Use Authorization (EUA)

In emergency situations, such as a pandemic, and with a declaration of a public health emergency by the Secretary of the Department of Health and Human Services, or HHS, the FDA has the authority to allow unapproved medical products or unapproved uses of cleared or approved medical products to be used to diagnose, treat or prevent serious or life-threatening diseases or conditions caused by chemical, biological, radiological or nuclear warfare threat agents when there are no adequate, approved and available alternatives.

Under this authority, the FDA may issue an EUA if the following four statutory criteria have been met: (1) a serious or life-threatening condition exists; (2) evidence of effectiveness exists; (3) a risk-benefit analysis shows that the benefits of the product outweigh the risks; and (4) no other alternatives exist for diagnosing, preventing or treating the disease or condition. The “may be effective” standard for EUAs requires a lower level of evidence than the “effectiveness” standard that FDA uses for product clearances or approvals in non-emergency situations. The FDA assesses the potential effectiveness of a possible EUA product on a case-by-case basis using a risk-benefit analysis. In determining whether the known and potential benefits of the product outweigh the known and potential risks, the FDA examines the totality of the scientific evidence to make an overall risk-benefit determination. Such evidence, which could arise from a variety of sources, may include (but is not limited to) results of domestic and foreign clinical trials, in vivo efficacy data from animal models, in vitro data, as well as the quality and quantity of the available evidence.

Once granted, an EUA will remain in effect and generally terminate on the earlier of (1) the determination by the Secretary of HHS that the public health emergency has ceased or (2) a change in the approval status of the product such that the authorized use(s) of the product are no longer unapproved. After the EUA is no longer valid, the product is no longer considered to be legally marketed and one of the FDA’s non-emergency premarket pathways would be necessary to resume or continue distribution of the subject product.

The FDA also may revise or revoke an EUA if the circumstances justifying its issuance no longer exist, the criteria for its issuance are no longer met, or other circumstances make a revision or revocation appropriate to protect the public health or safety.

On January 31, 2020, the Secretary of HHS issued a declaration of a public health emergency related to COVID-19. On February 4, 2020, HHS determined that COVID-19 represents a public health emergency that has a significant potential to affect national security or the health and security of U.S. citizens living abroad and, subsequently, declared on March 24, 2020 that circumstances exist to justify the authorization of emergency use of certain medical products, during the COVID-19 pandemic, subject to the terms of any authorization as issued by the FDA. The declaration of the Secretary of HHS has been further updated, and the FDA has issued numerous guidances to sponsors seeking to obtain EUAs to diagnose and treat COVID-19.

Post-Approval Requirements

Maintaining substantial compliance with applicable federal, state and local statutes and regulations requires the expenditure of substantial time and financial resources. Rigorous and extensive FDA regulation of biological products continues after approval, particularly with respect to GMP. We will rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of any products that we may commercialize. Manufacturers of our products are required to comply with applicable requirements in the GMP regulations, including quality control and quality assurance and maintenance of records and documentation.

Following approval, the manufacturing facilities are subject to biennial inspections by the FDA, and such inspections may result in an issuance of FDA Form 483 deficiency observations, an untitled letter, or a warning letter, which can lead to plant shutdown and other more serious penalties and fines. Prior to the institution of any manufacturing changes, a determination needs to be made whether FDA approval is required in advance. If not done in accordance with FDA expectations, the FDA may restrict supply and may take further action. Annual product reports are required to be submitted annually. Other post-approval requirements applicable to biological products include reporting of GMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse events, reporting updated safety and efficacy information and complying with electronic record and signature requirements.

After a BLA is approved, the product also may be subject to official lot release. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot. The FDA also may perform certain confirmatory tests on lots of some products, such as viral vaccines, before releasing the lots for distribution by the manufacturer. In addition, the FDA may conduct laboratory research related to the regulatory standards on the safety, purity, potency and effectiveness of biological products. Systems need to be put in place to record and evaluate adverse events reported by healthcare providers and patients and to assess product complaints. An increase in severity or new adverse events can result in labeling changes or product recalls. Defects in manufacturing of commercial products can result in product recalls.

We also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or inpatient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities and promotional activities involving the internet. Discovery of previously unknown problems or the failure to comply with applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market, as well as possible civil or criminal sanctions. Failure to comply with applicable U.S. requirements at any time during the product development process, approval process or after approval may subject an applicant or manufacturer to administrative or judicial civil or criminal sanctions and adverse publicity. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval or license revocation, clinical hold, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect.

Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological products are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with GMPs and other laws. Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality control to maintain GMP compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved BLA, including withdrawal of the product from the market. In addition, changes to the manufacturing process or facility generally require prior FDA approval before being implemented, and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Expedited Review and Approval Programs

The FDA has various programs, including fast track designation, priority review, accelerated approval and breakthrough therapy designation, that are intended to expedite or simplify the process for the development and FDA review of biological products that are intended for the treatment of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs. The purpose of these programs is to provide important new biological products to patients earlier than under standard FDA review procedures. To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a biological product is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need. The FDA will determine that a product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety factors. In addition to other benefits, such as the ability to have greater interactions with the FDA, the FDA may initiate review of sections of a fast track BLA before the application is complete, a process known as rolling review.

IVVD US Equity

IVVD · 10-K · period ended 2021-12-31

Item 1. Business.

IVVD US Equity☆

IVVD · 10-K · period ended 2021-12-31

Item 1. Business.

IVVD US Equity