Need to know:

  • No authorized mAb for hospitalized patients makes upcoming data update relevant
  • Sixth treatment arm with a small molecule to be added to ACTIV-3 soon

An ACTIV-3 platform trial sub-study evaluating AstraZeneca’s (AZ) Covid-19 antibody cocktail AZD7442 should complete by the end of September, said principal investigator Dr Jens Lundgren. The platform trial is evaluating treatments for hospitalised patients with Covid-19.

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While Lundgren declined to enumerate the exact accrual goal for this treatment arm, by the time it is done it would have enrolled at least 1,500 patients, he said. After the last patient is added to the trial, the AZD7442-specific substudy should be in the position to have enough statistical power to detect any clinically meaningful difference with the antibody combination, said Lundgren, who also leads the Centre for Health and Infectious Disease Research at Copenhagen University Hospital.

AZD7442 is a combination of two long-acting antibodies: AZD8895 (tixagevimab) and AZD1061 (cilgavimab). The trial’s primary endpoint is time from randomisation to sustained recovery over a 90-day period.

AZD7442 and the ACTIV-3 platform

To record the required number of events, 1,000 participants are randomised and equally allocated to each investigational agent and placebo and followed for 90 days, as per the trial’s protocol. The study has an adaptive design wherein investigational treatments can be added or dropped based on efficacy signals and could enroll up to 10,000 patients.

The AZD7442 cocktail’s components were initially developed at Vanderbilt University and then licensed to AZ in June 2020. The mAb was in the news recently when a Phase III trial exploring it as a pre-exposure prophylactic met its primary endpoint. As per a 20 August press release, the mAb reduced the risk of developing a symptomatic infection by 77% compared to placebo.

AZD7442 has been passing the futility assessments and additional reviews after the initial futility analyses, Lundgren said.

Other monoclonal antibody (mAb) combinations like Regeneron PharmaceuticalsREGEN-COV have an emergency use authorization (EUA), but that is limited to those who tested positive for Covid-19 and are at risk for developing severe disease or are at high risk of exposure to an infected individual. In contrast, the ACTIV-3 study is specifically focused on finding treatments in the hospitalised setting, where no antibody therapy is currently authorised.

To date, the Phase III ACTIV-3 platform study has studied therapies like GlaxoSmithKline Vir Biotechnology’s VIR-7831, Eli Lilly’s bamlanivimab and Brii Biosciences’ BRII-196/BRII-198 cocktail. Of these, based on data with 343 patients, the BRII-196/BRII-198 cocktail did not meet a pre-specified futility analysis endpoint. Even the VIR-7831 arm did not meet futility once the disease status of the patients in the control group was considered and the data was adjusted, as per a 4 March National Institutes of Health (NIH) release. However, AZD7442 has been passing the futility assessments and additional reviews after the initial futility analyses, Lundgren said.

As per an update on 23 June, an arm to study Molecular PartnersMP0420 was added to the study. ACTIV-3 will also soon onboard a sixth agent; a small molecule with a different mode of action compared to the others studied, Lundgren said.

AZD7442 prospects in different settings

When used prior to SARS-CoV-2 exposure, AZD7442 is meant to provide long-lasting protection but through a non-vaccine route. The positive Phase III PROVENT trial had enrolled 5,197 participants who had a negative SARS-CoV-2 test at the time of screening. The company now plans to submit this data for an EUA or conditional approval.

Since the early days, the company has differentiated AZD7442 from its competitors by emphasising its extended half-life that is meant to provide protection from Covid-19 for six to 12 months. Outside of the ACTIV protocols, AstraZeneca is leading several large Phase III studies with the same combination in different settings. One of these, a study dubbed STORMCHASER was meant to explore AZD7442’s ability to prevent post-exposure symptomatic COVID-19. But the trial did not meet its primary endpoint, according to a June announcement. ACTIV-3, however, is looking at a different stage of disease, Lundgren said. Moreover, the trial’s protocol has predefined criteria for a premature study halt if a treatment is not effective, Lundgren said, adding the trial design and DSMB decisions are guiding the study appropriately.

There is no company-led trial designed to study the combination in hospitalised patients, and ACTIV-3 will provide the evidence in this setting.

AZ is sponsoring a Phase III study testing the cocktail in nonhospitalised patients with mild to moderate Covid-19. However, there is no company-led trial designed to study the combination in hospitalised patients, and ACTIV-3 will provide the evidence in this setting.

The company is supposed to supply up to 700,000 doses of the antibody combination to the US government under agreements announced in October 2020 and March 2021. There is an option to expand this further this year.

Even though the available Covid-19 vaccines are very effective, there will continue to be breakthrough infections that could lead to hospitalisation, Lundgren said. The age of the patients being recruited on this trial has changed over time, with younger participants forming the bulk of enrollees, Lundgren said. The trial has recently expanded to additional countries in Africa, while others in Asia and Europe will be soon be added to the study, making this a truly international investigation, Lundgren said.

The efficacy of mAbs against SARS-CoV-2 variants has been a critical component in their study and use. The EUA for bamlanivimab monotherapy was revoked by the FDA in April after an emergence of SARS-CoV-2 variants that were resistant to the mAb. Some of the early mAbs like bamlanivimab did have compromised efficacy toward emerging variants, Lundgren said. But the efficacy of these mAbs is constantly being tested in preclinical studies. Moreover, the ACTIV-3 study is collecting biospecimens from all enrolled patients, Lundgren said. The sequenced viral RNA can give an idea on the variant responsible for individual infections, and that can be used to analyse the efficacy data as well, he added.

ACTIV-3 was started in August 2020 and initially sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), but a recent update on now lists the University of Minnesota as the study’s sponsor. The study has a July 2022 end date.