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
Detailed results from the PROVENT Phase III pre-exposure prophylaxis (prevention) trial showed that AstraZeneca’s Evusheld (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.1 There were no cases of severe disease or COVID-19 related deaths in the Evusheld group through the six-month follow-up.1
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.1
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.1
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 hospitalisation 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 neutralise 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 300 mg 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.1
Compared to the primary analysis, the extended follow-up analysis demonstrated a 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.1
There were no cases of severe/critical COVID-19, COVID-19-related deaths or hospitalisations in the Evusheld group by the six-month follow-up analysis; there were five cases of severe/critical disease, seven hospitalisations and two COVID-19-related deaths in the placebo group.1
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.1
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.2,3 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.4-8
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.9
PROVENT is a Phase III, randomised, double-blind, placebo-controlled, multi-centre 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 randomised 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 20 August 2021 was based on 5,172 participants, with a data cut-off of 5 May 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 29 August 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 immunisation (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 protein10 and were optimised by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding.11 The half-life extension more than triples the durability of its action compared to conventional antibodies;12-14 data from the Phase III PROVENT trial show protection lasting at least six months.1 The reduced Fc receptor binding 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.15
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.16-18 Data from Washington University School of Medicine demonstrated Evusheld retained neutralising activity against the highly transmissible BA.2 subvariant, which is currently the dominant strain globally.18,19 This study also showed that Evusheld reduced viral burden and limited inflammation in the lungs (in vivo) across all Omicron variants.18
Evusheld has marketing authorisation in the European Union and was granted conditional marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain for pre-exposure prophylaxis of COVID-19. Evusheld is authorised for emergency use for pre-exposure prophylaxis of COVID-19 in the US. Evusheld is also authorised 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 (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation 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.
1. 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
2. Harpaz R, et al. Prevalence of Immunosuppression Among US Adults, 2013. JAMA. 2016;316(23):2547-2548. doi:10.1001/JAMA.2016.16477
3. AstraZeneca Data on File
4. Centers for Disease Control and Prevention. ACIP Altered Immunocompetence Guidelines for Immunizations. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html [Last accessed: April 2022]
5. Boyarsky BJ, et al. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA. 2021;325(17):1784-1786. doi:10.1001/JAMA.2021.4385
6. Rabinowich L, et al. Low Immunogenicity to SARS-CoV-2 Vaccination Among Liver Transplant Recipients. Journal of Hepatology. 2021;75(2):435-438. doi:10.1016/j.jhep.2021.04.020
7. Deepak P, et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. medRxiv. Published online April 9, 2021. doi:10.1101/2021.04.05.21254656
8. Simon D, et al. SARS-CoV-2 Vaccination Responses in Untreated, Conventionally Treated and Anticytokine-treated Patients with Immune-mediated Inflammatory Diseases. Annals of the Rheumatic Diseases. 2021;80(10):1312-1316. doi:10.1136/ANNRHEUMDIS-2021-220461
9. AstraZeneca news release. AZD7442 reduced risk of developing severe COVID-19 or death in TACKLE Phase III outpatient treatment trial. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html [Last accessed April 2022]
10. Dong J, et al. Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-antibody Cocktail. Nature Microbiology. 2021;6(10):1233-1244. doi:10.1038/s41564-021-00972-2
11. Loo YM, et al. AZD7442 Demonstrates Prophylactic and Therapeutic Efficacy in Non-human primates and extended half-life in humans. Science Translational Medicine. 2022;14(635):eabl8124. doi:10.1126/scitranslmed.abl8124
12. Robbie GJ, et al. A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults. Antimicrobial Agents and Chemotherapy. 2013;57(12):6147. doi:10.1128/AAC.01285-13
13. 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. Antimicrobial Agents and Chemotherapy. 2017;61(3). doi:10.1128/AAC.01714-16
14. 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. doi:10.1097/INF.0000000000001916
15. van Erp EA, et al. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front Immunol. 2019;10(MAR). doi:10.3389/FIMMU.2019.00548
16. 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. doi:10.1016/J.CELL.2021.12.046
17. 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. doi:10.1038/s41591-021-01678-y
18. 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. doi:10.1101/2022.03.17.484787
19. World Health Organization. Weekly Epidemiological Update on COVID-19 - 5 April 2022. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---5-april-2022 [Last accessed April 2022]