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With the release of updated data, oral antiviral molnupiravir to treat high-risk COVID-19 showed only a 30% reduction in the risk of hospitalization and death, according to briefing documents from FDA staff.

The agent's sponsor, Merck, submitted data from the interim analysis of its phase III trial with the request for emergency use authorization (EUA). This data, first published via press release in early October, showed a 50% risk reduction in all-cause hospitalization and death through day 29 (7.3% vs 14.1% for intervention and placebo groups, respectively). But had 386 patients receiving molnupiravir at the requested 800-mg dose, agency staff said.

In the , 710 patients received the drug at that dose. The rate of all-cause hospitalization or death was 6.8% in the intervention group and 9.7% in the placebo group, for a relative risk reduction of 30% (95% CI 1%-51%), the agency said in an addendum to the current analysis.

The FDA's Antimicrobial Drugs Advisory Committee (AMDAC) will meet Tuesday to vote on whether the drug's benefits outweigh its risks, and to discuss use of molnupiravir in pregnant women, as well as issues with viral mutations linked with the drug. Neither of the latter two issues will be subject to a vote.

In including data from the addendum, FDA staff noted that "the review issues and benefit/risk assessments may [...] differ from the original assessments provided in the briefing document which was based on the interim analysis."

The bulk of safety and efficacy data was from trial MK-4482-002, Part 2, an outpatient trial. FDA staff noted the drug had no benefit for hospitalized patients and Merck stopped that trial, MK-4482-001, Part 1, due to lack of benefit.

The majority of the initial briefing document examined risk management strategies about which types of patients could benefit most from the drug. FDA staff proposed using the same CDC criteria as monoclonal antibody treatments to define patients at high risk of severe disease. They added that vaccination status could also be considered, as vaccinated patients have lower risk of hospitalization and death versus unvaccinated individuals.

Data also suggested that molnupiravir appears to have no effect on risk of hospitalization or death in seropositive patients (2.9% in both intervention and control groups).

Given the lack of clinical data on the drug in pregnancy, FDA staff proposed some scenarios: either not authorizing molnupiravir for pregnant patients or shared clinical decision-making, where providers would weigh benefits and risks for each patient.

FDA staff did not recommend an EUA for lactating patients or pediatric patients, given risks of embryo-fetal toxicity, bone and cartilage toxicity, and mutagenicity.

They also mentioned the potential risk of viral mutation associated with use of the drug, specifically "an increased rate of amino acid changes in the SARS-CoV-2 spike protein." However, FDA staff said these mutations did not appear to be associated with clinical outcomes, such as hospitalization or death. They added that while there may not be individual patient changes, there may be implications for population health if the spike protein evolves.

FDA staff then raised the point that the clinical safety database of 593 adults -- 515 outpatients, 72 hospitalized patients, and six healthy volunteers -- is much smaller than those for monoclonal antibody treatments, which ranged from 1,350 to 2,100 patients, and are targeted to the same type of high-risk patient group. However, FDA staff added that "while the database was small, there were no major safety concerns."

There were no deaths reported in participants who received molnupiravir, and 10 deaths among the placebo group. FDA staff added that most severe adverse events were treatment-related.

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