New Single-Dose Antibody Injection Effective at Preventing Both Initial COVID-19 Infections and Disease Progression in High-Risk Individuals

The subject of the trials is designated AZD7442 and consists of a single intramuscular injection of a long-acting antibody (LAAB) combination, specifically a combination of two such human monoclonal antibodies - tixagevimab and cilgavimab - derived from B-cells donated by convalescent patients after infection by the SARS-CoV-2 virus. The antibodies were initially developed at Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020.

The two trials, designated PROVENT and TACKLE, were randomized, double-blind, placebo-controlled, and multi-center (at multiple sites in the US, UK, Belgium, Spain, and France). PROVENT was designed to assess safety and efficacy of AZD7442 as a prophylactic vaccine-alternative - a first for a monoclonal antibody treatment - that is intended to prevent COVID-19 infections in immunocompromised and other high-risk individuals, including:

• Individuals undergoing chemotherapy
• Individuals with immunosuppressive disease or taking immunosuppressive drugs for such conditions as MS and rheumatoid arthritis
• Individuals with severe obesity or cardiac disease, chronic obstructive pulmonary disease, chronic kidney, and chronic liver disease
• Organ transplant recipients
• Diabetics
• Any other individuals for whom vaccines might have reduced efficacy

TACKLE was designed to assess safety and efficacy in treating COVID-19 infection in its early mild-to-moderate stages in a similar population, before progressing to a more severe stage or death, while avoiding the need for the infusion process required by some other monoclonal antibody treatments.

More than 75% of PROVENT participants had co-morbidities and other characteristics that put them at high risk if they became infected, and 43% were aged 60 years or more. A total of 5197 unvaccinated participants were initially randomized in a 2:1 ratio and received a single dose of either 300 mg of AZD7442 or saline placebo, respectively. The cut-off date for a six-month assessment was August 29, 2021, by which time the Delta variant had become responsible for nearly all new SARS-CoV-2 infections in the United States. After six months, there had been no cases of severe COVID-19 or COVID-19-related deaths in the treatment group, but five cases of severe COVID-19 and two COVID-19-related deaths in the placebo group; the data showed that a single dose of AZD7442 reduced the risk of developing symptomatic COVID-19 by 83% compared to placebo. Participants will continue to be followed for 15 months.

Following the license agreement with Vanderbilt, AstraZeneca worked on optimizing the antibodies, extending their half-lives so as to more than triple the period of time for which they retain efficacy compared to conventional antibodies. While the PROVENT trial demonstrates protection lasting at least six months, other evidence indicates that a single dose may offer protection for as long as 12 months.

In the TACKLE trial, all participants had mild-to-moderate COVID-19, were not yet hospitalized, and had been symptomatic for no more than seven days. Of the 903 participants, 90% had baseline co-morbidities and other characteristics that put them at a high risk of progression to severe disease, and about 13% were aged 65 or more. They were randomized in a 1:1 ratio to receive either one 600 mg dose of AZD7442 or saline placebo. The antibody treatment was found to reduce the risk of developing severe COVID-19 or death from any cause by 88% compared to placebo in individuals who had been symptomatic for no more than three days at the time of treatment. Participants will continue to be followed for 15 months.

The antibody treatment was shown to be generally well tolerated, and any adverse events were balanced between the treatment and placebo groups. The full results of the trials are to be submitted for publication in a peer-reviewed medical journal and will also be presented at a medical conference. AstraZeneca applied to the FDA for an Emergency Use Authorization (EUA) for the prophylaxis treatment in early October, and is currently awaiting a decision from the agency. If the EUA is granted, the company is scheduled to supply the US Government, which has provided support for development of the treatment, with 700,000 doses. In addition, AZD 7442 is being considered as a treatment for hospitalized COVID-19 patients as part of NIH's ACTIV-3 ("Therapeutics for Inpatients With COVID-19 (TICO)") trial.

Although the effectiveness of AZD7442 against the newly emerging Omicron variant cannot be predicted at this early stage, additional in vitro findings published by NIH demonstrate AZD7442 neutralizes other recent SARS-CoV-2 variants, including Delta and Mu.

• Robert G. Edwards, Ph.D.

  Director of Regulatory Science