New Analyses of Two AZD7442 COVID-19 Phase III Trials in High-Risk Populations Confirm Robust Efficacy and Long-Term Prevention

New data from the AZD7442 COVID-19 PROVENT prevention and TACKLE outpatient treatment Phase III trials both showed robust efficacy from a one-time intramuscular (IM) dose of the long-acting antibody (LAAB) combination.

In an analysis of the ongoing PROVENT trial evaluating a median six months of participant follow-up, one 300mg IM dose of AZD7442 reduced the risk of developing symptomatic COVID-19 compared to placebo by 83%.

About 2% of the global population is considered at increased risk of an inadequate response to a COVID-19 vaccine.1 This includes people with blood cancers or other cancers being treated with chemotherapy, patients on dialysis, those taking medications after an organ transplant or who are taking immunosuppressive drugs for conditions including multiple sclerosis and rheumatoid arthritis.2-6

The AZD7442 PROVENT trial 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 high-risk and immunocompromised participants. 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 a reduced immune response to vaccination.

There were no cases of severe COVID-19 or COVID-19-related deaths in those treated with AZD7442 at either the primary or six-month analyses. In the placebo arm, there were two additional cases of severe COVID-19 at the six-month assessment, for a total of five cases of severe COVID-19 and two COVID-related deaths.

An exploratory analysis of the TACKLE outpatient treatment trial, in patients with mild-to-moderate COVID-19, showed that one 600mg IM dose of AZD7442 reduced the risk of developing severe COVID-19 or death (from any cause) by 88% compared to placebo in patients who had been symptomatic for three days or less at the time of treatment.

A total of 90% of participants enrolled in TACKLE were from populations at high risk of progression to severe COVID-19 if they became infected, including those with co-morbidities.

In both PROVENT and TACKLE, AZD7442 was generally well tolerated. No new safety issues were identified in the six-month analysis of PROVENT.

Hugh Montgomery, Professor of Intensive Care Medicine at University College London, UK and AZD7442 principal investigator, said: “These compelling results give me confidence that this long-acting antibody combination can provide my vulnerable patients with the long-lasting protection they urgently need to finally return to their everyday lives. Importantly, six months of protection was maintained despite the surge of the Delta variant among these high-risk participants who may not respond adequately to vaccination.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “AZD7442 is the only long-acting antibody with Phase III data to demonstrate benefit in both pre-exposure prophylaxis and treatment of COVID-19 with one dose. These new data add to the growing body of evidence supporting AZD7442’s potential to make a significant difference in the prevention and treatment of COVID-19. We are progressing regulatory filings around the world and look forward to providing an important new option against SARS-CoV-2 as quickly as possible.”

Full results from PROVENT and TACKLE will be submitted for publication in a peer-reviewed medical journal and presented at a forthcoming medical meeting.

On October 5, 2021, the Company announced that it had submitted a request to the US Food and Drug Administration for Emergency Use Authorization for AZD7442 for prophylaxis of COVID-19.

AstraZeneca has agreed to supply the US Government with 700,000 doses of AZD7442 if granted an Emergency Use Authorization by the FDA and has agreements to supply to other countries.

Notes

PROVENT

PROVENT is a Phase III, randomized, double-blind, placebo-controlled, multi-center trial assessing the safety and efficacy of a single IM 300mg dose of AZD7442 compared to placebo for the prevention of COVID-19 in participants who did not have who did not have SARS-CoV-2 infection at baseline. The trial was conducted in 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.

The primary analysis reported on August 20, 2021 was based on 5,172 participants, with data cut-off May 9, 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 based on 4,991 participants, with a data cut-off of August 29, 2021. Subjects will continue to be followed for 15 months. Participants who chose to leave the PROVENT trial at any point to get vaccinated were excluded from the primary and six-month efficacy analyses.

Participants were adults 18 years-old and over who would benefit from prevention with the LAAB, defined as having increased risk for inadequate response to active immunization (predicted poor responders to vaccines or intolerant of vaccine) 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.

Approximately 43% of participants were 60 years and over. In addition, more than 75% 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.

AstraZeneca is progressing with filings around the globe for potential emergency use authorization or conditional approval of AZD7442 in both prophylaxis and treatment.

TACKLE

TACKLE is a Phase III, randomized, double-blind, placebo-controlled, multi-center trial assessing the safety and efficacy of a single 600mg IM dose of AZD7442 compared to placebo for the outpatient treatment of COVID-19. 903 participants were randomized (1:1) to receive either AZD7442 (n = 452) or saline placebo (n = 451), administered in two separate, sequential IM injections. The primary analysis was reported on October 11, 2021.

Participants were adults 18 years-old and over who were non-hospitalized with mild-to-moderate COVID-19 and symptomatic for seven days or less. Participants had a documented laboratory-confirmed SARS-CoV-2 infection, as determined by a molecular test (antigen or nucleic acid) from any respiratory tract specimen (e.g. oropharyngeal, nasopharyngeal, or nasal swab or saliva) collected no more than three days prior to day one.

The primary efficacy endpoint was the composite of either severe COVID-19 or death from any cause through day 29. Subjects will continue to be followed for 15 months.

Approximately 13% of participants were 65 years and over. In addition, 90% had baseline co-morbidities and other characteristics that put them at high risk of progression to severe COVID-19, including cancer, diabetes, obesity, chronic lung disease or asthma, cardiovascular disease or immunosuppression.

AZD7442

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 protein7 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 administration8-10; data from the Phase III PROVENT trial show protection lasting at least six months, with the Phase I trial showing high neutralizing antibody titers for at least nine months.11 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.12

AZD7442 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.

AZD7442 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.

In preclinical experiments, data show the LAABs were able to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease.13 Additional in vitro findings demonstrate AZD7442 neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta and Mu variants.14

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.

References

1. Oliver, S MD. Data and clinical considerations for additional doses in immunocompromised people. ACIP Meeting July 22, 2021. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf. [Last accessed: November 2021].
2. Centers for Disease Control and Prevention. Altered immunocompetence. General best practice guideline for immunization: Best Practices Guidance of the Advisory Committee on Immunization Practices. [Online]. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html. [Last accessed: November 2021].
3. 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.
4. Rabinowich L, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients, Journal of Hepatology (2021), doi: https://doi.org/10.1016/j.jhep.2021.04.020.
5. Deepak P, et al. Glucocorticoids and B cell depleting agents substantially impair immunogenicity of mRNA vaccines to SARS-CoV-2. medRxiv [Preprint]. 2021 Apr 9:2021.04.05.21254656. doi: 10.1101/2021.04.05.21254656. PMID: 33851176; PMCID: PMC8043473.
6. Simon D, et al. SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases. Ann Rheum Dis. 2021 May 6: annrheumdis-2021-220461. doi: 10.1136/annrheumdis-2021-220461. Epub ahead of print. PMID: 33958324.
7. Dong J, et al. Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail. bioRxiv. 2021; doi: 10.1101/2021.01.27.428529.
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): 6147-53.
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): e01714-16.
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. Loo Y-M, et al. AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans. medRxiv. Cold Spring Harbor Laboratory Press; 2021 [preprint] Available from: https://www.medrxiv.org/content/10.1101/2021.08.30.21262666v1.
12. van Erp EA, et al. Fc-mediated antibody effector functions during respiratory syncytial virus infection and disease. Front Immunol. 2019; 10: 548.
13. Zost SJ, et al. Potently neutralizing and protective human antibodies against SARS-CoV 2. Nature. 2020; 584: 443–449.
14. ACTIV. National Center for Advancing Translational Sciences OpenData Portal. SARS-CoV-2 Variants & Therapeutics, All Variants Reported in vitro Therapeutic Activity. Available at: https://opendata.ncats.nih.gov/variant/activity [Last accessed: November 2021].

View source version on businesswire.com: https://www.businesswire.com/news/home/20211118005506/en/