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Merck
The announcement of its antiviral molnupiravir had halved hospitalizations in a trial of high-risk Covid-19 patients was greeted 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, however, warn that the method it uses to kill the virus that causes Covid-19 carries potential dangers that could limit the usefulness of the drug.
Molnupiravir works by getting incorporated into the genetic material of the virus and then causing a large 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 these cells replicate.
If this were to occur 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 performed extensive animal testing which shows this is not a problem. “The totality of the data from these studies indicates that molnupiravir is not mutagenic or genotoxic in mammalian systems in-vivo,” said a spokesperson for Merck.
Scientists who have studied NHC, the compound that molnupiravir creates in the body after ingestion, say Merck needs to be careful.
“Proceed with caution and at your own risk,” wrote Raymond Schinazi, professor of pediatrics and director of the division of biochemical pharmacology at Emory University School of Medicine, who has studied NHC for decades, in an e-mail to Barron.
Scientists are divided on the severity of this risk, and in the absence of detailed data from Merck’s animal testing and long-term human safety data, it’s difficult to know for sure.
Security concerns suggest that the stock market’s reaction to the positive molnupiravir data on Friday may have been overstated. Shares of Merck jumped 8.4% on Friday, while shares of vaccine maker Covid-19
Modern
(MNRA) fell 11.4% and shares of
Regeneron Pharmaceuticals
(REGN), which developed one of the main monoclonal antibodies against Covid-19, fell 5.7%.
For biotechnology
(VIR), which has developed another monoclonal antibody in partnership with
GlaxoSmithKline
(GSK), fell 21.1%.
“It was kind of wishful thinking,” SVB Leerink analyst Dr Geoffrey Porges said on Friday of investor reactions.
Investors viewed Merck’s pill as a pandemic cure-all that would be in everyone’s medicine cabinet, he said, adding that “that just won’t be the case with this drug.”
Porges says that when the Food and Drug Administration clears molnupiravir, he expects regulators to place severe limitations on who can use it. The agency, he said, will have difficult questions to answer about the conditions of access for people at risk of becoming pregnant. “I think it will indeed be a controlled substance,” he says.
Molnupiravir came to Merck through a partnership with a private company called Ridgeback Biotherapeutics, which licensed the drug to a non-profit biotech company owned by Emory University. Molnupiravir is a so-called prodrug, which metabolizes in the body to create NHC, which has been studied for decades.
Schinazi, who is a professor at Emory but has not worked on molnupiravir, has a long history with NHC and has written a number of articles on the compound. He was one of the founders of the biotech company Pharmasset, which he said considered developing NHC as a treatment for hepatitis C in 2003, but chose not to do so due to the risk that it can cause mutations. Pharmasset created the hepatitis C drug Sovaldi, and
Gilead Sciences
(GILD) ultimately bought the company for $ 11 billion.
Schinazi said Barron that he did not believe that molnupiravir should be given to pregnant women or young people of childbearing potential, until more data became available. Merck’s trials of molnupiravir excluded pregnant women; scientists leading the trial asked male participants to “refrain from heterosexual intercourse” while taking the drug, according to the federal government website that tracks clinical trials.
An article 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 to the host may not be zero,” the authors concluded. “Evaluation of the usefulness of this drug should be done in those who are likely to benefit the most, with monitoring to assess potential long-term genotoxic side effects. “
One of the article’s authors, Dr Shuntai Zhou, a scientist at UNC’s Swanstrom Lab, said he and his colleagues reported their first findings to Merck in July 2020, about a year before his publication. article.
“There are concerns that this will cause long-term mutating effects, even cancer,” Zhou said.
Zhou says he’s certain the drug will integrate into the DNA of mammalian hosts. “Biochemistry won’t lie,” he says. “This drug will be incorporated into DNA.”
The impact it will have when he is there is unknown, given the different systems used by human cells to limit the impact of mutations.
Scientists at Merck responded to the UNC article in a subsequent issue of the Journal of Infectious Disease, saying their testing of molnupiravir in animals did not find higher mutation rates. Merck scientists have also disputed details of the UNC authors’ methods. In a response, scientists at UNC maintained their methods and wrote that they believed molnupiravir should only be used in people at high risk for severe Covid-19 disease until its risks at long term are better understood.
Some experts have advised caution on the part of Merck and regulators.
“Given the possibility that the drug can be incorporated into cellular DNA, it will be very important to demonstrate the absence of cancer in animal models and in humans”, explains Nathaniel Landau, professor in the microbiology department of the NYU Grossman School of Physician who is not involved in any research on NHC or molnupiravir. “While this looks good in preliminary animal models, it will be important not to rush this clinical use until you are very sure that it does not cause cancer, even at very low frequencies.”
Molnupiravir’s first contact with public attention, long before Merck began working with Ridgeback, came in May 2020, when the former head of the US government’s Biomedical Advanced Research and Development Authority said in a complaint. of denunciation that he had been forced to finance molnupiravir. , then known as EIDD-2801, but objected, in part for security reasons. Former BARDA chief Dr Rick Bright told Bloomberg in March that Merck’s involvement had “softened” his concerns.
Indeed, Merck’s reputation for rigor has allayed the concerns of some observers. SVB Leerink analyst Daina Graybosch notes that molnupiravir data released last week came much later than some investors had expected. “Merck took a long time to develop this,” says Graybosch. “They didn’t necessarily say it explicitly… but I think they’ve done a lot of work to get comfortable with that risk.”
Graybosch, who covers Merck for SVB Leerink, raised its target price for the share on Monday to $ 104 from $ 101. Still, his view of the molnupiraver is muted. “The continued halo effect provided by molnupiravir in the eyes of the public and investors may have more impact than its direct effect on the income statement [Merck’s profit and loss statement]She wrote in a note on Monday.
Merck said it performed two separate animal tests in which it administered monulpiravir at higher doses and for longer than it would in humans. Tests have shown that monulpiravir is not mutagenic, the company said.
“Patient safety is at the forefront of our company’s shared mission and vision: to save and improve lives,” Merck said in a statement to Barron. “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 manufacture and distribution of our drugs, vaccines and other products, safety, quality and efficacy are our primary considerations.
Merck shares closed up 2.2% on Monday, while Moderna shares fell another 4.5% and Vir shares fell another 0.8% on the day.
Write to Josh Nathan-Kazis at [email protected]
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