Update on US Food and Drug Administration Emergency Use Authorization of EVUSHELD

The US Food and Drug Administration (FDA) has stated that AstraZeneca’s EVUSHELD (tixagevimab co-packaged with cilgavimab) is not currently authorized for Emergency Use for pre-exposure prophylaxis (prevention) of COVID-19 in the US until further notice, due to the sustained high frequency of circulating SARS-CoV-2 variants that EVUSHELD does not retain in vitro neutralization against.

The FDA has notified AstraZeneca that the Agency will make a determination about reinstating authorization of EVUSHELD if the national prevalence of resistant variants decreases to 90% or less on a sustained basis. The US government recommends all EVUSHELD product be retained and properly stored in the event that variants susceptible to EVUSHELD, including those currently circulating at lower prevalence, become more prevalent in the future.

Based on in vitro pseudovirus assay laboratory data, EVUSHELD does not neutralise Omicron subvariants BQ.1, BQ.1.1, BF.7, BF.11, BA.5.2.6, BA.4.6, BA.2.75.2, XBB and XBB.1.5.1 The combined proportion of COVID-19 cases caused by these subvariants is currently greater than 90% in the US, according to the Centers for Disease Control and Prevention (CDC) Nowcast modelling data.2

AstraZeneca will continue to work with the FDA and other health authorities to collect, assess and share relevant data regarding EVUSHELD and SARS-CoV-2 variants. EVUSHELD currently remains authorized in other countries where it is approved for COVID-19 pre-exposure prophylaxis and treatment, including the EU and Japan.

Next-generation long-acting antibody Phase I/III trial underway

AstraZeneca has initiated the SUPERNOVA Phase I/III trial to investigate the safety and efficacy of a next-generation long-acting antibody (LAAB) in COVID-19 pre-exposure prophylaxis in an immunocompromised population. In in vitro lab studies, the new LAAB has been shown to neutralize all SARS-CoV-2 variants tested to date, including variants that have proved resistant to other monoclonal antibodies.3 AstraZeneca is aiming to make the new LAAB available in the second half of 2023, subject to trial readouts and regulatory reviews.  

About 2% of the global population is considered at increased risk of an inadequate response to COVID-19 vaccination and could benefit from monoclonal antibodies for COVID-19 protection.4,5

IMPORTANT SAFETY INFORMATION

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

Risk of cross-hypersensitivity with COVID-19 vaccines exist as 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.

Risk for COVID-19 Due to SARS-CoV-2 Viral Variants Not Neutralized by EVUSHELD

Certain SARS-CoV-2 viral variants may not be neutralized by EVUSHELD. Inform individuals of the increased risk, compared to other variants, for COVID-19 due to SARS-CoV-2 viral variants not neutralized by EVUSHELD. If signs and symptoms of COVID-19 occur, advise individuals to test for COVID-19 and seek medical attention, including starting treatment for COVID-19 as appropriate.

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.

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 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
  • EVUSHELD is authorized for use only when the combined frequency of non-susceptible variants nationally is less than or equal to 90%, based on available information including variant susceptibility to EVUSHELD and national variant frequencies
  • 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.

Under the EUA, all serious adverse events and medication errors potentially related to EVUSHELD use must be reported within 7 calendar days from the healthcare provider’s awareness of the event.

Serious adverse event reports and medication error reports should be submitted to FDA’s MedWatch program by:

  • Completing and submitting the form online
  • Completing and submitting a postage-paid FDA Form 3500 and returning by:
    • Mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787) or
    • Fax (1-800-FDA-0178) or
  • Contacting the FDA at 1-800-FDA-1088 to request a reporting 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 convalescent patients after SARS-CoV-2 infection. 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 protein6 and were optimized by AstraZeneca with half-life extension and reduction of Fc effector function and complement C1q binding.7 The half-life extension more than triples the durability of its action compared to conventional antibodies;8-10 data from the PROVENT Phase III trial show protection lasting six months.11 The reduced Fc effector function aims to minimise the risk of antibody-dependent enhancement of disease - a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.12

EVUSHELD is authorized for use for pre-exposure prophylaxis (prevention) of COVID-19 in the US (emergency use), EU, Japan and many other countries. EVUSHELD is approved for treatment of those with risk factors for severe SARS-CoV-2 infection in the EU, Japan and other countries. Regulatory submissions are progressing for both prevention and treatment indications around the world.

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.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) 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. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

Media Inquiries

Brendan McEvoy                    +1 302 885 2677
Jillian Gonzales                      +1 302 885 2677 

US Media Mailbox: usmediateam@astrazeneca.com

 

References

  1. US Food and Drug Administration Fact Sheet for Healthcare Providers: Emergency Use Authorization for EvusheldTM (Tixagevimab Co-Packaged with Cilgavimab). https://www.fda.gov/media/154701/download [Last accessed: January 2023]
  2. Centers for Disease Control and Prevention CDC COVID Data Tracker: Variant Proportions. https://covid.cdc.gov/covid-data-tracker/#variant-proportions [Last accessed: January 2023]
  3. AstraZeneca Data on File - REF-173560
  4. Harpaz R, et al. Prevalence of Immunosuppression Among US Adults, 2013. JAMA. 2016;316(23):2547-2548. doi:10.1001/JAMA.2016.16477
  5. AstraZeneca Data on File - REF-129335
  6. 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
  7. 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
  8. 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):6147-6153
  9. 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)
  10. 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
  11. Levin MJ, et al. Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19.   N Engl J Med. 2022;386(23):2188-2200
  12. van Erp EA, et al. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front Immunol. 2019;10(MAR)