Merck and Co Inc (MRK)

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Molnupiravir is a prodrug of nucleoside analogue ß-D-N4-hydroxycytidine (NHC), which could potentially be incorporated in mammalian DNA.

One study determined there was evidence that the drug could potentially drive mutagenesis in both viral RNA and mammalian DNA. “It seems unlikely that a short course of therapy would spare the host from this exposure because both RNA precursors that affect the virus and DNA precursors that would affect the host pass through the common ribonucleoside diphosphate intermediate,” concludes an article in the Journal of Infectious Diseases.

SVB Leerink analyst Dr. Geoffrey Porges predicts that FDA would restrict who has access to the drug over safety concerns, according to Barron’s.

In the Phase 3 trial of the drug, the side effects of COVID-19 are apparently worse than that of molnupiravir as patients in the placebo group were more likely to withdraw early than recipients of the drug.

An August article published in the Journal of Infectious Diseases found that ß-D-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) “displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.”

Last year, the former Head of U.S. Biomedical Advanced Research and Development Authority (BARDA) Rick Bright opposed granting additional funding to develop the drug, partly over safety concerns related to the drug. In a complaint summarized in Science, Bright wrote that “similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls.”

The Science article also quotes the Emory University chemist Raymond Schinazi who stated that his previous pharmaceutical company, Pharmasset, abandoned a similar drug in 2003 after discovering its mutagenic properties.