EVUSHELDTM long-acting antibody combination retains neutralizing activity against Omicron variants BA.4 and BA.5, according to new study from University of Oxford

In vitro data on new emerging Omicron variants consistent with EVUSHELD’s neutralization activity against previous variants of concern


AstraZeneca’s EVUSHELDTM (tixagevimab and cilgavimab, formerly AZD7442) retains neutralization activity against the emerging Omicron BA.4 and BA.5 (BA.4/5) variants, according to new preclinical pseudovirus assay data from the University of Oxford.1

The findings were reported online on bioRxiv, a preprint server.

These results are consistent with previous data from multiple studies showing that EVUSHELD retains potent neutralizing activity against Omicron BA.2, the current dominant circulating variant, and neutralizes all variants tested to date.2-6

Previously circulating SARS-CoV-2 variants have expanded in similar patterns; therefore it’s possible BA.4 and BA.5, which are now the dominant variants in Africa, could spread globally in a similar pattern to BA.2.6 BA.4 and BA.5 have identical S protein sequences and appear to have evolved from BA.2.1

John L. Perez, MD, MBA, MA, Senior Vice President, Head of Late Development, Vaccines & Immune Therapies, AstraZeneca, said: “By combining two antibodies with different and complementary activities against SARS-CoV-2, EVUSHELD was engineered from the start to outsmart the COVID-19 virus and to remain potent in the face of this virus’ ability to rapidly mutate. These findings further support EVUSHELD as an important option to help protect vulnerable populations such as the immunocompromised who are unable to respond adequately to COVID-19 vaccination and are at high risk for severe disease.”

Approximately 2% of the global population is considered at increased risk of an inadequate response to COVID-19 vaccination and may particularly benefit from pre-exposure prophylaxis (prevention) with EVUSHELD.7,8 This population includes people who are immunocompromised, such as cancer patients, transplant patients and anyone taking immunosuppressive medicines.3 People at increased risk of exposure to the SARS-CoV-2 virus could also benefit from protection with EVUSHELD.9 Emerging evidence indicates that protecting vulnerable populations from getting COVID-19 could help prevent viral evolution that is an important factor in the emergence of variants.10

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.

Visit EVUSHELD.com to learn more.

IMPORTANT SAFETY INFORMATION

EVUSHELD 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.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Hypersensitivity Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have been observed with 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.

Risk of Cross-Hypersensitivity with COVID-19 Vaccines

EVUSHELD contains polysorbate 80, which is in some COVID-19 vaccines and is structurally similar to polyethylene glycol (PEG), an ingredient in other COVID-19 vaccines. For individuals with a history of severe hypersensitivity to a COVID-19 vaccine, consider consultation with an allergist-immunologist prior to EVUSHELD administration.

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.

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.

AUTHORIZED USE FOR EVUSHELD

EVUSHELD 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 to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).

EVUSHELD may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the therapeutic class to which EVUSHELD belongs (i.e., anti-infectives).

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

Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients, Parents and Caregivers.

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.

You may report side effects related to AstraZeneca products by clicking here.

Notes

EVUSHELD

EVUSHELD, formerly known as AZD7442, is a combination of two long-acting antibodies - tixagevimab (AZD8895) and cilgavimab (AZD1061) - derived from B-cells donated by individuals previously infected with the 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 protein11 and were optimised by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding.12  The half-life extension more than triples the durability of its action compared to conventional antibodies;13-15 data from the Phase III PROVENT trial show protection lasting at least six months.16 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.17

There is a growing body of evidence from multiple independent in vitro and in vivo (animal model) studies supporting the potential of EVUSHELD to protect against Omicron SARS-CoV-2 subvariants.2-4,18,19 In particular, data from Washington University School of Medicine demonstrated EVUSHELD retained neutralizing activity against the highly transmissible BA.2 subvariant, which is currently the dominant strain globally.2,6 This study also showed that EVUSHELD reduced viral burden and limited inflammation in the lungs (in vivo) for Omicron BA.1, BA.1.1 and BA.2.2

EVUSHELD has marketing authorization in the European Union and was granted conditional marketing authorization by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain for pre-exposure prophylaxis of COVID-19. EVUSHELD is authorized for emergency use for pre-exposure prophylaxis of COVID-19 in the US. EVUSHELD is also authorized for use and being supplied in several other countries around the world. Regulatory filings are progressing in both prevention and treatment around the world.  

The primary data supporting the EVUSHELD authorizations are from the ongoing PROVENT Phase III pre-exposure prevention trial, which showed a statistically significant reduction in the risk of developing symptomatic COVID-19 compared to placebo, with protection from the virus continuing for at least six months.16

In October 2021, AstraZeneca announced positive high-level results from the TACKLE Phase III outpatient treatment trial in which EVUSHELD provided statistically and clinically significant protection against the development of severe COVID-19 or death from any cause compared to placebo. EVUSHELD was generally well-tolerated in the trials.16,20

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.

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.

Media Inquiries

Brendan McEvoy

Jillian Gonzales

 

+1 302 885 2677

+1 302 885 2677

 

 

US Media Mailbox: usmediateam@astrazeneca.com           

###

References

  1. Tuekprakhon A, et al. Further Antibody Escape by Omicron BA.4 and BA.5 from Vaccine and BA.1 Serum. bioRxiv. Published online 2022. https://doi.org/10.1101/2022.05.21.492554 [Last accessed: May 2022]
  2.  Case JB, et al. Resilience of S309 and AZD7442 Monoclonal Antibody Treatments against Infection by SARS-CoV-2 Omicron Lineage Strains. bioRxiv. Published online March 18, 2022:2022.03.17.484787. doi:10.1101/2022.03.17.484787
  3. US Food and Drug Administration. FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR EVUSHELDTM (Tixagevimab Co-Packaged with Cilgavimab). Available at: https://www.fda.gov/media/154701/download [Last accessed: May 2022]
  4. European Medicines Agency. EVUSHELD Product Information. Available at: https://www.ema.europa.eu/en/documents/product-information/evusheld-epar-product-information_en.pdf [Last accessed: May 2022]
  5. Touret F, et al. In Vitro Activity of Therapeutic Antibodies against SARS-CoV-2 Omicron BA.1 and BA.2. Published online March 9, 2022. doi:10.21203/RS.3.RS-1415749/V1
  6. Vector Engineering Lab, et al., COVID CG. Available at: https://covidcg.org/ [Last accessed: May 2022]
  7. Harpaz R, et al. Prevalence of Immunosuppression Among US Adults, 2013. JAMA. 2016;316(23):2547-2548
  8. AstraZeneca Data on File               
  9. Centers for Disease Control. Risk of Exposure to COVID-19. Available at: https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/increased-risk-exposure.html [Last accessed: May 2022]
  10. Corey L, et al. SARS-CoV-2 Variants in Patients with Immunosuppression. N Engl J Med. 2021;385(6):562-566
  11. Dong J, et al. Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-Antibody Cocktail. Nat Microbiol. 2021;6(10):1233-1244.
  12. Loo YM, et al. AZD7442 Demonstrates Prophylactic and Therapeutic Efficacy in Non-Human Primates and Extended Half-Life in Humans. Sci Transl Med. 2022;14(635):eabl8124
  13. Robbie GJ, et al. A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults. Antimicrob Agents Chemother. 2013;57(12):6147
  14. Griffin MP, et al. Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother. 2017;61(3)
  15. Domachowske JB, et al. Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-Life Single-Dose Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J. 2018;37(9):886-892.
  16. Levin MJ, et al. Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19. N Engl J Med. Published online April 20, 2022. doi:10.1056/NEJMoa2116620
  17. van Erp EA, et al. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front Immunol. 2019;10(MAR).
  18. Dejnirattisai W, et al. SARS-CoV-2 Omicron-B.1.1.529 Leads to Widespread Escape from Neutralizing Antibody Responses. Cell. 2022;185(3):467-484.e15.
  19. VanBlargan LA, et al. An Infectious SARS-CoV-2 B.1.1.529 Omicron Virus Escapes Neutralization by Therapeutic Monoclonal Antibodies. Nature Medicine 2022. Published online January 19, 2022:1-6. doi:10.1038/s41591-021-01678-y
  20. Montgomery H, et al. Efficacy and Safety of Intramuscular Administration of AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19: The TACKLE Phase 3 Trial. Presented at the European Society of Clinical Microbiology and Infectious Diseases Congress. Lisbon, Portugal. April 23, 2022