Only antibody therapy authorized in US for pre-exposure prophylaxis

Pivotal phase III data showed robust efficacy and long-term protection with one dose in high-risk population

AstraZeneca's EVUSHELD (tixagevimab co-packaged with cilgavimab), a long-acting antibody (LAAB) combination, has received emergency use authorization (EUA) in the US for the pre-exposure prophylaxis (prevention) of COVID-19, with first doses expected to become available very soon.

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The Food and Drug Administration (FDA) granted the EUA for EVUSHELD for pre-exposure prophylaxis of COVID-19 in adults and adolescents (aged 12 and older who weigh 40kg or more) with moderate to severe immune compromise due to a medical condition or immunosuppressive medications and who may not mount an adequate immune response to COVID-19 vaccination, as well as those individuals for whom COVID-19 vaccination is not recommended. Recipients should not be currently infected with or had recent known exposure to a person infected with SARS-CoV-2.

Myron J. Levin, MD, Professor of Pediatrics and Medicine, University of Colorado School of Medicine, US, and principal investigator on the PROVENT trial, said: “Millions of people in the US and around the world remain at serious risk for COVID-19 because their immune systems do not generate a sufficient immune response, even after receiving all recommended doses of vaccine. I am excited to offer my patients EVUSHELD as an easily-administered new option that provides long-lasting protection that could help them return to their everyday lives.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “We are proud to play a leading role in fighting the COVID-19 pandemic and, with EVUSHELD, we now have the first antibody therapy authorized in the US to prevent COVID-19 symptoms before virus exposure, while also providing long lasting protection with a single dose. EVUSHELD neutralizes all previous SARS-CoV-2 variants to date, and we are working quickly to establish its efficacy against the new Omicron variant. We thank our clinical trial participants, the investigators, scientists, and government agencies and our colleagues at AstraZeneca who have all contributed to the development of EVUSHELD.”

Brian Koffman, MDCM (retired), MS Ed, Co-Founder, Executive Vice President and Chief Medical Officer of the CLL (Chronic Lymphocytic Leukemia) Society, US, said: “One of the primary questions I keep getting asked by patients is ‘When can I hug my grandchildren again?’ As a physician and person with a weakened immune system, l am filled with hope now that EVUSHELD will soon be available to those who can’t count on vaccination alone to provide the protection they need.”

EVUSHELD is a combination of two long-acting monoclonal antibodies and is the only antibody therapy authorized in the US for COVID-19 pre-exposure prophylaxis and the only COVID-19 antibody delivered as an intramuscular dose (150mg tixagevimab and 150mg cilgavimab).

About 2% of the global population is considered at increased risk of an inadequate response to a COVID-19 vaccine.^1,2 About seven million people in the US are immunocompromised and may benefit from EVUSHELD for pre-exposure prophylaxis of COVID-19.^1,3,4 This includes people with blood cancers or other cancers being treated with chemotherapy, and those taking medications after an organ transplant or who are taking immunosuppressive drugs for conditions including multiple sclerosis and rheumatoid arthritis.^5-9

The primary data supporting the EVUSHELD EUA are from the ongoing PROVENT Phase III pre-exposure prevention trial, which showed a statistically significant reduction (77% at primary analysis, 83% at median six-month analysis) in the risk of developing symptomatic COVID-19 compared to placebo, with protection from the virus continuing for at least six months. More follow-up is needed to establish the full duration of protection provided by EVUSHELD. Data from the Phase III STORM CHASER post-exposure trial and the EVUSHELD Phase I trial also supported the EUA. EVUSHELD was well-tolerated in the trials.

EVUSHELD and SARS-CoV-2 variants

Studies are underway to provide information on the impact of the new Omicron variant (B.1.1.529) on EVUSHELD.^10,11 Of the Omicron binding site substitutions relevant to EVUSHELD that have been tested to date in preclinical assays, none have been associated with escape from EVUSHELD neutralization.^10,11 In vitro findings demonstrate EVUSHELD neutralizes other recent emergent SARS-CoV-2 viral variants, including the Delta and Mu variants.¹⁰

EVUSHELD is being developed with support from the US government, including federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority in partnership with the Department of Defense; Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, under Contract No. W911QY-21-9-0001.

AstraZeneca has agreed to supply the US government with 700,000 doses of EVUSHELD. The US government has indicated that it plans to distribute these doses to states and territories at no cost and on a pro rata basis.

AstraZeneca is progressing with filings around the globe for potential emergency use authorization or conditional approval of EVUSHELD in both COVID-19 prophylaxis and treatment.

EVUSHELD is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of EVUSHELD under Section 564(b)(1) of the Food, Drug and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

IMPORTANT SAFETY INFORMATION

EVUSHELD (tixagevimab co-packaged with cilgavimab) has not been approved, but has been granted an Emergency Use Authorization (EUA) by FDA. There are limited clinical data available and serious and unexpected adverse events may occur that have not been previously reported with EVUSHELD use.

Contraindication:

EVUSHELD is contraindicated in individuals with previous severe hypersensitivity reactions, including anaphylaxis, to any component of EVUSHELD.

Warnings and Precautions:

Hypersensitivity Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have been observed with IgG1 monoclonal antibodies like EVUSHELD. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy. Clinically monitor individuals after injections and observe for at least 1 hour.

Clinically Significant Bleeding Disorders

As with any other intramuscular injection, EVUSHELD should be given with caution to individuals with thrombocytopenia or any coagulation disorder.

Cardiovascular Events

A higher proportion of subjects who received EVUSHELD versus placebo reported myocardial infarction and cardiac failure serious adverse events. All of the subjects with events had cardiac risk factors and/or a prior history of cardiovascular disease at baseline. A causal relationship between EVUSHELD and these events has not been established. Consider the risks and benefits prior to initiating EVUSHELD in individuals at high risk for cardiovascular events, and advise individuals to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular event.

Adverse Reactions:

The most common adverse events are headache, fatigue and cough.

Use in Specific Populations:

Pregnancy

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. EVUSHELD should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.

Lactation

There are no available data on the presence of tixagevimab or cilgavimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk.

Pediatric Use

EVUSHELD is not authorized for use in pediatric individuals under 12 years of age or weighing less than 40 kg. The safety and effectiveness of EVUSHELD have not been established in pediatric individuals.

AUTHORIZED USE

EVUSHELD (tixagevimab co-packaged with cilgavimab) is authorized for use under an EUA for the pre-exposure prophylaxis of COVID-19 in adults and pediatric individuals (12 years of age and older weighing at least 40 kg):

• 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).

EVUSHELD has been authorized by FDA for the emergency use described above. EVUSHELD is not FDA-approved for any use, including use for pre-exposure prophylaxis of COVID-19.

EVUSHELD is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of EVUSHELD under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

LIMITATIONS OF AUTHORIZED USE

• EVUSHELD is not authorized for use in individuals:
  • For treatment of COVID-19, or
  • For post-exposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2
• Pre-exposure prophylaxis with EVUSHELD is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended. Individuals for whom COVID-19 vaccination is recommended, including individuals with moderate to severe immune compromise who may derive benefit from COVID-19 vaccination, should receive COVID-19 vaccination
• In individuals who have received a COVID-19 vaccine, EVUSHELD should be administered at least two weeks after vaccination

See Full Fact Sheet for Healthcare Providers for examples of medical conditions or treatments that may result in moderate to severe immune compromise and an inadequate immune response to COVID-19 vaccination, the justification for emergency use of drugs during the COVID-19 pandemic, information on available alternatives, and additional information on COVID-19.

The FDA Letter of Authorization is available for reference, as well as the Fact Sheet for Patients, Parents And Caregivers.

SARS-CoV-2 Viral Variant

There is a potential risk of treatment failure due to the development of viral variants that are resistant to tixagevimab and cilgavimab administered together. Prescribing healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area, where data are available, when considering prophylactic treatment options.

Reporting Adverse Events

The prescribing healthcare provider and/or your designee must report all SERIOUS ADVERSE EVENTS and MEDICATION ERRORS potentially related to EVUSHELD within 7 calendar days from the healthcare provider’s awareness of the event (1) by submitting FDA Form 3500 online, (2) by downloading FDA Form 3500 and then submitting by mail or fax, or (3) contacting the FDA at 1-800-FDA-1088 to request this form.

In addition, please fax a copy of all FDA MedWatch forms to AstraZeneca at 1-866-742-7984.

Report adverse events by visiting https://contactazmedical.astrazeneca.com, or calling AstraZeneca at 1-800-236-9933.

Notes

EVUSHELD

EVUSHELD, formerly known as AZD7442 is a combination of two LAABs - tixagevimab (AZD8895) and cilgavimab (AZD1061) - derived from B-cells donated by convalescent patients after SARS-CoV-2 virus. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the human monoclonal antibodies bind to distinct sites on the SARS-CoV-2 spike protein¹³ and were optimized by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding. The half-life extension more than triples the durability of its action compared to conventional antibodies and could afford up to 12 months of protection from COVID-19 following a single administration;^14-16 data from the Phase III PROVENT trial show protection lasting at least six months.¹⁷ The reduced Fc receptor binding aims to minimize the risk of antibody-dependent enhancement of disease - a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.¹⁸ EVUSHELD is delivered as an IM dose of 150mg tixagevimab and 150mg cilgavimab administered in two separate, consecutive injections.

In August 2021, AstraZeneca announced that EVUSHELD demonstrated a statistically significant reduction in the risk of developing symptomatic COVID-19 in the PROVENT trial; efficacy was 83% compared to placebo in a six-month analysis announced on November 18, 2021. In October 2021, AstraZeneca announced positive high-level results from the EVUSHELD TACKLE Phase III outpatient treatment trial. EVUSHELD is also being studied as a potential treatment for hospitalized COVID-19 patients as part of the National Institute of Health’s ACTIV-3 trial and in an additional collaborator hospitalization treatment trial.

Under the terms of the licensing agreement with Vanderbilt, AstraZeneca will pay single-digit royalties on future net sales.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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