Top-line results from molnupiravir in 1,433 patients show the drug reduced hospitalization or death by 30% when it was administered within 5 days of symptom onset. Rosier interim results, showing a 48% reduction, analysed fewer people; molnupiravir didn’t have an edge in the second half of the trial.
In the FDA’s advisory committee meeting on the drug, experts voted narrowly in favour of authorization. But 10 panellists felt that the drug’s benefits did not justify its risks.
Because molnupiravir induces errors in viral RNA, one key concern is that it could theoretically speed up the evolution of this viral foe. This risk is greatest in immunocompromised patients, who may incubate and shed virus for longer, and in patients who take lower doses or shorter drug courses than prescribed. Merck’s counterargument — that the virus was undetectable at the end of treatment in the clinic, suggesting that mutant viruses that arise are quickly cleared — did not convince all the committee members.
Another issue is that molnupiravir might be incorporated into human DNA, causing mutations in rapidly dividing human tissues including fetuses. These mutagenic concerns are not new: Pharmasset reportedly abandoned development of structurally related compounds in 2003 due to their mutagenic potential.
Molnupiravir causes mutations in the Ames test, which assesses mutagenic potential in bacterial cells. One follow-up study in mice produced inconclusive results, and another showed that the drug was not mutagenic in whole animals, Merck showed. Some committee members questioned Merck’s models and controls.
Molnupiravir also induced fetal mutations in rats. “The FDA should not approve it for pregnant women except in exceptional circumstances,” summarized David Eastmond, a toxicologist at the University of California and an FDA advisory committee member.