Astrazeneca plc said it has received about $486 million from the U.S. government to support the development and supply of a long-acting antibody combination under evaluation for the prevention and treatment of COVID-19. Phase III trials of the candidate, AZD-7442, are slated to begin later this month, the company told BioWorld.

One trial will enroll more than 6,000 adults for the prevention of COVID-19 with additional trials set to enroll about 4,000 adults for the treatment of the infection, the Cambridge, U.K.-based company said.

Ambitions and funding for the program, part of the federal government's Operation Warp Speed, appear to be racing ahead. They're even outpacing the completion of Astrazeneca's phase I healthy volunteers study of the combo and pre-empting the normal development path, which would include a phase II trial to establish the candidate's efficacy ahead of larger studies. No phase II trial is planned, according to the company.

Astrazeneca reported the first participants dosed in the placebo-controlled phase I study 48 days ago. At last update of the trial's study record in ClinicalTrials.gov, its estimated enrollment was to be 48 patients, ages 18 to 55 and with a body mass index of less than 30 kg/m2. The primary endpoint is the number of participants who experience adverse events.

As it ramps up, the company is making up to 100,000 doses of AZD-7442, which it will supply to the government around the end of this year, though it wasn't immediately clear on Monday who the recipients of such doses would be. If it desires, the U.S. government could acquire up to an additional 1 million doses of the experimental therapy in 2021 under a separate agreement, the company said.

The latest agreement built on previous funding of more than $25 million from U.S. government agencies for the discovery an evaluation of monoclonal antibodies, Astrazeneca said. Should the phase III trials prove successful and AZD-7442 become an approved medicine, Astrazeneca said it anticipates providing it at "commercial terms" during and after the current pandemic.

Preclinical promise

Discovered by Vanderbilt University Medical Center and licensed to Astrazeneca in June, AZD-7442 contains two monoclonal antibodies isolated from the blood of a couple from Wuhan, China, who were diagnosed with COVID-19 after traveling to Toronto. Both monoclonal antibodies, AZD-8895 and AZD-1061, have been optimized by the company for extended half-life and reduced Fc receptor binding to minimize the risk of antibody-dependent enhancement of disease.

In preclinical testing at Vanderbilt, the antibodies were found to "bind to distinct sites on the S protein and either alone or in combination reduce the viral ‘burden’ in infected mice and protect them from weight loss and lung inflammation," according to the university's Center for Technology Transfer & Commercialization. They also found that one of the antibodies tested and later licensed to Astrazeneca, COV2-2196, and another antibody, COV2-2381, given alone "protected rhesus macaques from SARS-CoV-2 infection," the center said.

The combination could potentially afford six to 12 months of protection from COVID-19 following a single administration, Astrazeneca said. Which of the six antibodies the company licensed from Vanderbilt could move ahead into the phase III study wasn't immediately clear.

At least two other high-profile antibody duos are in play.

REGN-COV2 from Regeneron Pharmaceuticals Inc. was recently provided to President Donald Trump. The first information from what the company called "a descriptive analysis of a seamless phase 1/2/3 trial" of the combination showed that "it reduced viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19," the company said on Sept. 29. The U.S. Biomedical Advanced Research and Development Authority (BARDA) has awarded the company a $450 million contract to manufacture and supply filled and finished REGN-COV2 to the U.S. government.

Another combination therapy candidate is Eli Lilly and Co.’s pairing of LY-CoV555 and LY-CoV016. With an ongoing phase II trial showing the SARS-CoV-2 neutralizing antibodies have so far reduced viral load, symptoms and COVID-19-related hospitalization and ER visits, the company has asked the FDA to consider an emergency use authorization (EUA) for one of the components, LY-CoV555. A separate EUA for the combination could follow in November.

Ongoing support amid a crisis

Support for Astrazeneca's antibody combination adds to an earlier commitment of up to $1.2 billion federal officials made to accelerate the company’s COVID-19 vaccine program, AZD-1222. A U.S. government-supported phase III trial of that candidate, an experimental adenovirus vector-based vaccine, began recruiting up to 30,000 adults at trial centers across the country in August. Global trials of the candidate were put on hold during September following an unexplained illness in one person who received the vaccine, but have since restarted in many countries, except the U.S. and Russia.

Prospects for the vaccine bloomed in Australia on Oct. 9, with the Therapeutic Goods Administration announcing it had granted a provisional determination to Astrazeneca Pty Ltd. in relation to the vaccine candidate. The company is now eligible to apply for provisional registration for the vaccine.

The U.S. CDC on Monday reported more than 7.74 million total U.S. cases of COVID-19 and more than 214,100 deaths. The U.S. daily COVID-19 incidence continues to climb, according to the Johns Hopkins Center for Health Security. Globally, 37.7 million COVID-19 cases have been confirmed, leading to about 1,079,000 deaths.

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