By Josh Nathan-Kazis

Updated: October 8, 2021



Merck ‘s announcement that its antiviral molnupiravir had halved hospitalizations in a trial of high-risk Covid-19 patients was met with enthusiasm on Friday, inspiring a vision of a world in which treating a Covid-19 infection could be as trivial as swallowing a few pills.

Some scientists who have studied the drug warn, however, that the method it uses to kill the virus that causes Covid-19 carries potential dangers that could limit the drug’s usefulness.

Molnupiravir works by incorporating itself into the genetic material of the virus, and then causing a huge number of mutations as the virus replicates, effectively killing it. In some lab tests, the drug has also shown the ability to integrate into the genetic material of mammalian cells, causing mutations as those cells replicate.

If that were to happen in the cells of a patient being treated with molnupiravir, it could theoretically lead to cancer or birth defects.

Merck (ticker: MRK) says it has run extensive tests in animals that show that this isn’t an issue. “The totality of the data from these studies indicates that molnupiravir is not mutagenic or genotoxic in in-vivo mammalian systems,” a Merck spokesperson said.

Scientists who have studied NHC, the compound that molnupiravir creates in the body after it is ingested, however, say that Merck needs to be careful.

“Proceed with caution and at your own peril,” wrote Raymond Schinazi, a professor of pediatrics and the director of the division of biochemical pharmacology at the Emory University School of Medicine, who has studied NHC for decades, in an email to Barron’s.

Scientists are split on how serious a risk this is, and in the absence of detailed data on Merck’s animal tests, and long-term human safety data, it’s difficult to know for sure.

The safety concerns suggest that the stock market’s reaction to the positive molnupiravir data on Friday might have been overblown. Shares of Merck jumped 8.4% Friday, while shares of Covid-19 vaccine maker Moderna (MNRA) fell 11.4%, and shares of Regeneron Pharmaceuticals (REGN), which developed one of the leading monoclonal antibodies for Covid-19, fell 5.7%. Vir Biotechnology (VIR), which developed another of the monoclonal antibodies in partnership with GlaxoSmithKline (GSK), was down 21.1%.

“It was sort of, in effect, wishful thinking,” says SVB Leerink analyst Dr. Geoffrey Porges of investors’ reactions on Friday.

Investors saw Merck’s pill as a pandemic panacea that would sit in everyone’s medicine cabinet, he says, adding, “that’s just not going to be the case with this drug.”

Porges says that when the Food and Drug Administration authorizes molnupiravir, he expects regulators to impose severe limitations on who can use it. The agency, he says, will have difficult questions to answer about what conditions to put on access for people who may become pregnant. “I think it is effectively going to be a controlled substance,” he says.

Porges later clarified his comment, saying that he expects that distribution and access to molnupiravir will be limited, not that it will be treated as a “controlled substance” under U.S. law, as are some addictive and illicit drugs.

Molnupiravir came to Merck through a partnership with a private firm called Ridgeback Biotherapeutics, which licensed the drug from a not-for-profit biotech concern owned by Emory University. Molnupiravir is what’s known as a prodrug, which metabolizes in the body to create NHC, which has been studied for decades.

Schinazi, who is a professor at Emory but did not work on molnupiravir, has a long history with NHC, and has written a number of papers on the compound.  He was a founder of the biotech Pharmasset, which he says considered developing NHC as a treatment for hepatitis C in 2003, but chose not to because of the risk that it could cause mutations. Pharmasset created the hepatitis C drug Sovaldi, and Gilead Sciences (GILD) eventually bought the company for $11 billion.

Schinazi told Barron’s that he did not believe that molnupiravir should be given to pregnant women, or to young people of reproductive age, until more data is available. Merck’s trials of molnupiravir have excluded pregnant women; the scientists running the trial asked male participants to “abstain from heterosexual intercourse” while taking the drug, according to the federal government website that tracks clinical trials.

A paper published in the Journal of Infectious Diseases in May by Schinazi and scientists at the University of North Carolina reported that NHC caused mutations in animal cell cultures in a lab test designed to detect such mutations.

“The risks for the host may not be zero,” the authors concluded. “Evaluating the utility of this drug should be done in those likely to receive the greatest benefit, with monitoring provided to assess potential long-term genotoxic side effects.”