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.”
One of the paper’s authors, Dr. Shuntai Zhou, a scientist at the Swanstrom Lab at UNC, said that he and his colleagues had flagged their initial findings to Merck in July 2020, roughly a year before his paper was published.
“There is a concern that this will cause long-term mutation effects, even cancer,” Zhou says.
Zhou says that he is certain that the drug will integrate itself into the DNA of mammalian hosts. “Biochemistry won’t lie,” he says. “This drug will be incorporated in the DNA.”
What impact it will have when it’s there is unknown, given the various systems human cells use to limit the impact of mutations.
Merck scientists responded to the UNC paper in a subsequent issue of the Journal of Infectious Disease, saying that their tests of molnupiravir in animals had not found higher mutation rates. The Merck scientists also took issue with details of the UNC authors’ methods. In a reply, the UNC scientists stood by their methods, and wrote that they believed that molnupiravir should only be used in people at high risk of serious illness from Covid-19 until its long-term risks are better understood.
Some experts have advised caution on the part of Merck and regulators.
“Given the possibility that the drug could be incorporated into cellular DNA, it will be very important to demonstrate a lack of cancer in animal models and in humans,” says Nathaniel Landau, a professor in the department of microbiology at the NYU Grossman School of Medicine who is not involved in any of the NHC or molnupiravir research. “Even though it looks good in preliminary animal models, it will be important not to rush this into clinical use before being very confident that it does not cause cancer even at very low frequencies.”
Molnupiravir’s first brush with public attention, long before Merck began its collaboration with Ridgeback, came in May 2020, when the former head of the U.S. government’s Biomedical Advanced Research and Development Authority said in a whistleblower complaint that he had been pressured to provide funding for molnupiravir, then known as EIDD-2801, but had objected, partially due to safety concerns. The former BARDA head, Dr. Rick Bright, told Bloomberg this past March that the involvement of Merck had “softened” his concerns.
Indeed, Merck’s reputation for rigor has eased some observers’ worries. SVB Leerink analyst Daina Graybosch notes that the data on molnupiravir released last week came far later than some investors had expected. “Merck took a really long time to develop this,” Graybosch says. “They haven’t necessarily said this explicitly…but I think they’ve been doing a lot of work to get comfortable around this risk.”
Graybosch, who covers Merck for SVB Leerink, raised her target price on the stock on Monday, to $104 from $101. Still, her outlook on molnupiraver is muted. “The continued halo effect provided by molnupiravir in the eyes of the public and investors could be more impactful than its direct effect on P&L [Merck’s profit and loss statement],” she wrote in a Monday note.
Merck said it ran two separate tests in animals in which it gave monulpiravir at higher doses, and for longer, than it would in humans. The tests showed that monulpiravir is not mutagenic, the company said.
“Patient safety is at the forefront of our company’s joint mission and vision: to save and improve lives,” Merck said in a statement to Barron’s. “Our top priority is to ensure the safety of the patients who receive our drugs and vaccines. In everything we do—from research and development to the manufacturing and distribution of our medicines, vaccines and other products—safety, quality and efficacy are our primary considerations.”
Merck shares closed up 2.2% Monday, while Moderna shares fell another 4.5%, and Vir shares dropped another 0.8% on the day.