Is molnupiravir a turkey? Merck slips out drop in efficacy of COVID-19 antiviral over Thanksgiving

The efficacy of Merck’s COVID-19 antiviral has fallen sharply. While most Americans were sleeping off Thanksgiving, Merck revealed the relative risk reduction fell from 50% to 30% in the final analysis of its phase 3 data, sending its stock sliding down.

Merck released an interim analysis of data from a phase 3 trial of molnupiravir at the start of last month. At that time, 7.3% of patients on molnupiravir had been hospitalized or died through Day 29, compared to 14.1% of people who received placebo. The 48% relative risk reduction, coupled to the absence of deaths in the molnupiravir arm, led Merck to race to regulators with the data.

The drug looks less effective in the final analysis. After factoring in patients who became evaluable after the interim analysis, the rates of hospitalization or death in the molnupiravir and placebo arms were 6.8% and 9.7%, respectively, reducing the relative risk reduction to 30%. The figures reflect the fact that between the interim and final analyses there were five more hospitalizations in the molnupiravir arm than the control cohort, as well as the same number of deaths (one).

Analysts at Jefferies put forward two theories for why the risk reduction fell between the interim and final analyses. Either molnupiravir’s efficacy “incrementally worsened in the later portion of the study after the interim,” or the antiviral performed comparably to the early part of the trial but was made to look worse by the re-adjudication of events.

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The analysts think it is more likely that the efficacy of molnupiravir fell in the later part of the study, extending the gap to the almost 90% interim efficacy achieved  by Pfizer’s Paxlovid. That view is underpinned by details of the interim analysis provided in briefing documents created for this week’s advisory committee meeting.

In the documents, the FDA and Merck discuss the efficacy of molnupiravir in seropositive people. The study excluded vaccinated people, but some people had antibodies against SARS-CoV-2 from earlier infections. In the subgroup of people with anti-SARS-CoV-2 antibodies, the rates of hospitalization or death were 2.9% regardless of whether patients received molnupiravir or placebo.

The FDA has cautioned against reading too much into the finding given the interim analysis featured just 139 seropositive patients, but the Jefferies analysts see the subgroup as a potential pointer to why overall efficacy fell later in the study. “We suspect it's possible the post interim part of the study had more seropositive patients which drove down the efficacy of MOV to 30% from ~50% in the interim,” the analysts wrote in a note to investors.

The efficacy of molnupiravir and rival COVID-19 antivirals, notably Pfizer’s Paxlovid, in seropositive patients will shape whether the drugs have a future in vaccinated patients, an indication in which the front-runners are yet to deliver data.