Pre-exposure prophylaxis (prevention) trial reduced risk of symptomatic COVID-19, with no severe disease or COVID-19-related deaths in EVUSHELD group
Data published in the New England Journal of Medicine
WILMINGTON, Del., April 20, 2022 – Detailed results from the PROVENT Phase III pre-exposure prophylaxis (prevention) trial showed that AstraZeneca’s EVUSHELDTM (tixagevimab and cilgavimab), formerly AZD7442, reduced the risk of developing symptomatic COVID-19 by 77% in the primary analysis and by 83% in the six-month follow-up analysis, compared to placebo. There were no cases of severe disease or COVID-19 related deaths in the EVUSHELD group through the six-month follow-up.
More than 75% of PROVENT participants at baseline had co-morbidities that put them at high risk for severe COVID-19 if they were to become infected, including people who are immunocompromised and may have an inadequate immune response to vaccination.
Additional pharmacokinetic data showed that EVUSHELD concentrations remained elevated in serum for six months after administration, supporting that a single dose could provide long-term protection against COVID-19 lasting at least six months.
The data were published online today in the New England Journal of Medicine.
Myron J. Levin, MD, Professor of Pediatrics and Medicine, University of Colorado School of Medicine, US, and PROVENT principal investigator on the trial, said: “While COVID-19 vaccines have been highly effective at reducing hospitalization and death, cases continue to surge and many individuals remain at high risk, including immunocompromised individuals and those who cannot be vaccinated. These important data now published in the New England Journal of Medicine provide confidence that one easily administered intramuscular dose of EVUSHELD could provide vulnerable populations long-lasting protection. In addition, EVUSHELD has been shown to neutralize BA.2, currently the dominant circulating COVID-19 variant.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: "These data add to the growing body of evidence supporting the use of EVUSHELD to help prevent symptomatic and severe COVID-19, especially for those individuals who can’t respond adequately to vaccination and need additional protection. EVUSHELD is now available in many countries around the world, and we are progressing filings in pre-exposure prophylaxis, as well as mild-to-moderate treatment.”
In the primary efficacy analysis, a single 300mg intramuscular (IM) dose of EVUSHELD reduced the risk of developing symptomatic COVID-19 compared to placebo by 77% (95% confidence interval [CI] 46, 90; p<0.001) at a median follow up of 83 days. Symptomatic COVID-19 occurred in 8/3441 (0.2%) and 17/1731 (1.0%) participants in the EVUSHELD and placebo groups, respectively.
Compared to the primary analysis, the extended follow-up analysis demonstrated greater reduction in COVID-19 incidence in the EVUSHELD group, with an 83% relative risk reduction (95% CI 66, 91) with EVUSHELD compared to placebo at a median follow up of 196 days. Symptomatic COVID-19 occurred in 11/3441 (0.3%) and 31/1731 (1.8%) participants in the EVUSHELD and placebo groups, respectively. Efficacy was generally consistent across participant subgroups, where evaluable.
There were no cases of severe/critical COVID-19, COVID-19-related deaths or hospitalizations in the EVUSHELD group by the six-month follow-up analysis; there were five cases of severe/critical disease, seven hospitalizations and two COVID-19-related deaths in the placebo group.
EVUSHELD was generally well tolerated in PROVENT, and no safety issues were identified at either the primary or six-month analysis. Adverse events accrued at similar rates in the EVUSHELD and placebo groups. The most common adverse event was injection-site reaction, occurring in 2.4% of participants in the EVUSHELD group and 2.1% of participants in the placebo group.
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 with EVUSHELD. This population includes people who are immunocompromised, such as those with cancer or transplant patients or anyone taking immunosuppressive medicines. People at increased risk of exposure to the SARS-CoV-2 virus could also benefit from protection with EVUSHELD.
AstraZeneca previously announced positive high-level results from the TACKLE Phase III trial in the treatment of mild-to-moderate COVID-19. Full results are being presented at the upcoming European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) and have been submitted for publication in a peer-reviewed medical journal.
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 (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.
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.
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.
The most common adverse events are headache, fatigue and cough.
Use in Specific Populations:
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.
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.
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.
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
o 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
o 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:
o For treatment of COVID-19, or
o 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.
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.
PROVENT is a Phase III, randomized, double-blind, placebo-controlled, multi-center trial assessing the efficacy and safety of a single IM 300mg dose of EVUSHELD compared to placebo for the prevention of SARS-CoV-2 RT-PCR positive symptomatic COVID-19 in participants who did not have a SARS-CoV-2 infection at baseline. The trial was conducted at 87 sites in the US, UK, Spain, France and Belgium. 5,197 participants were randomized in a 2:1 ratio to receive a single IM dose of either 300mg of AZD7442 (n = 3,460) or saline placebo (n = 1,737), administered in two separate, sequential IM injections. It is the first Phase III trial prospectively designed to evaluate a monoclonal antibody for pre-exposure prophylaxis of symptomatic COVID-19, with targeted inclusion of participants at increased risk of inadequate response to vaccination or were at high risk for severe COVID-19 disease.
The primary analysis reported on August 20, 2021 was based on 5,172 participants, with a data cut-off of May 5, 2021. The primary efficacy endpoint was the first case of any SARS-CoV-2 RT-PCR positive symptomatic illness occurring post dose prior to day 183. The six-month assessment was conducted using a data cut-off of August 29, 2021. Subjects will be followed for a total of 15 months. Participants who chose to get vaccinated at any timepoint during the PROVENT trial were included in the efficacy analyses until the day of vaccination.
Participants were adults 18 years-old and older who would benefit from prevention with EVUSHELD, defined as having increased risk for inadequate response to active immunization (predicted poor responders to vaccines or intolerant to vaccination) or having increased risk for SARS-CoV-2 infection, including those whose locations or circumstances put them at appreciable risk of exposure to the SARS-CoV-2 virus. Participants at the time of screening were unvaccinated and had a negative point-of-care SARS-CoV-2 serology test.
More than 75% of PROVENT participants had baseline co-morbidities and other characteristics that are associated with an increased risk for severe COVID-19 should they become infected, including those with immunosuppressive disease or taking immunosuppressive medications, diabetes, severe obesity or cardiac disease, chronic obstructive pulmonary disease, chronic kidney and chronic liver disease. Approximately 43% of participants were 60 years and over.
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 protein 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; data from the Phase III PROVENT trial show protection lasting at least six months. 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.
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 the BA.1, BA.1.1 and BA.2 Omicron SARS-CoV-2 subvariants. 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. This study also showed that EVUSHELD reduced viral burden and limited inflammation in the lungs (in vivo) across all Omicron variants.
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.
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 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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