October 01, 2021
A one-time dose of two long-acting monoclonal antibodies reduced the risk of developing symptomatic COVID by 77% in comparison with placebo (P < .001) in a randomized, double-blind, placebo-controlled, phase 3 trial in adults, according to researchers who on Thursday presented results at the Infectious Disease Week (IDWeek) 2021 Annual Meeting.
The mix of tixagevimab and cilgavimab (AZD7442, Astra Zeneca) in a 300-mg dose is delivered in two intramuscular injections.
"This is the first long-acting combination of monoclonal antibodies that represents a potential new option to augment COVID-19 prevention," said lead author Myron J. Levin, MD, a professor and pediatric infectious disease specialist at the University of Colorado Anschutz Medical Campus, in Aurora, Colorado, who presented the findings of the PROVENT trial.
Both antibodies were taken from B-cells donated by patients who had been infected with SARS-CoV-2, and they work synergistically, Levin said.
"The combination of them is better than adding results of each individually," he said. "In vitro experiments have already shown that variants of interest and concern, including the Delta variant, are successfully neutralized by this cocktail."
The trial was conducted in 87 sites in the United States, the United Kingdom, Spain, France, and Belgium. Participants included 5197 unvaccinated adults who had never been infected with SARS-CoV-2 and either were at higher risk for inadequate response to COVID-19 vaccines because they were immunocompromised or were at high risk for exposure.
"Efficacy was observed through at least 3 months," Levin said. "Preliminary pharmacokinetic modeling predicts potential protection for up to 12 months."
Raymund Razonable, MD, an infectious disease expert with the Mayo Clinic in Rochester, Minnesota, who was not involved with the trial, told Medscape Medical News he was particularly interested in this combination because the developers made use of novel technology that extends the half-life of the antibodies and because of the large number of participants in the study.
Modeling that shows protection could last up to a year is novel and important, he said.
"People won't need frequent injections," Razonable said. With postexposure prophylaxis monoclonal cocktails, people may be given a dose a month, he noted.
Razonable said, "This is something intended to prevent COVID in people who are unvaccinated. The downside to that is we want people to get vaccinated. The best strategy so far is really vaccination."
He said AZD7442 could potentially help fill the void for patients who are not able to respond to the COVID vaccines, including some who are immunocompromised or are undergoing chemotherapy.
Razonable said that although the 77% reduction for developing symptomatic COVID-19 (95% CI vs placebo, 46.0 – 90.0; P < .001) is impressive, it is a reduction in relative risk. Still unknown is how much an individual's absolute risk is reduced.
He also said it would be helpful to know how many people in the study population were immunocompromised, "because I think that's where this product will be useful for prevention."
The primary study endpoints were the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness post dose and prior to day 183 (efficacy) as well as the safety of the product.
The cocktail appeared to be well tolerated. Adverse events occurred in 35% of participants administered AZD7442 and in 34% of the placebo group. Injection-site reactions occurred in 2.4% of the AZD7442 group and in 2.1% of the placebo group. There was one case of severe or critical COVID-19; two COVID-19-related deaths occurred in the placebo group.
AZD7442 is being developed with the help of funding from the US government. Levin has received support from GlaxoSmithKline companies. Many of the co-authors are employed by AstraZeneca and hold stock in the company. Razonable has disclosed no relevant financial relationships.
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