A divided US Food and Drug Administration (FDA) advisory panel voted 13-10 to recommend Merck’s oral antiviral molnupiravir for emergency use authorisation (EUA) for adults at high risk of progressing to severe COVID-19 on Tuesday this week (30 November).
According to MedPage Today, while votes at the Antimicrobial Drugs Advisory Committee (AMDAC) were largely split, similar questions were raised on both sides of the vote about modest efficacy, especially in light of other available treatments.
Safety was of chief concern, especially among pregnant women, given that data from preclinical studies appeared to show embryo-foetal toxicity. The consensus appeared to be that the drug should not be recommended for pregnant women, but that healthcare providers didn’t have the right to deny a woman a drug if the benefits would outweigh the risks, based on shared clinical decision-making.
Others suggested a negative pregnancy test prior to administering the drug to a woman of child-bearing age, as well as a pregnancy registry to track potential adverse events. Nearly all agreed that it should not be given to a woman in the first trimester.
Of particular concern to the “no” voters was not only that efficacy against hospitalisation and death declined from the interim analysis submitted to the FDA (48% relative risk reduction) to the final analysis (30% reduction), but that when examining only the data from the post-interim analysis enrolment, there were fewer placebo patients who were hospitalised or died by day 29 versus patients receiving the intervention (4.7% vs 6.2%, respectively).
However, the lack of options in the real world is what propelled many members to vote yes.
“There’s a potential concern for a lack of availability of an alternative therapy for those at high-risk, perhaps considering the loss of efficacy with monoclonal antibodies with variants,” said Dr Michael Green of University of Pittsburgh School of Medicine, who voted yes.
“I was struck by a modest benefit in a highly adherent trial population and then the unclear efficacy in the latter half of the trial when we had increased circulation of the Delta variant,” said Dr Daniel Horton of Rutgers School of Public Health, who voted no. “I think there’s the potential for increased pressures for viral evolution in the setting of lower adherence in the real world.”
Interestingly, writes Medpage Today, even those who voted yes argued that it might only be temporary, given other similar drugs in the pipeline that could have better safety and efficacy profiles. For other committee members, potential mutagenicity was an issue, which the committee also discussed, but did not vote on.
The FDA does not have to follow the advice of its advisory committees, but it often does.
MedPage Today article – FDA Panel Narrowly Backs Merck's COVID Pill (Open access)
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Reduction in infectious SAR-CoV-2 with molnupiravir — Small US study
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Promising early findings from Merck/Ridgeback Phase 2a trial of oral COVID-19 therapeutic