Merck’s COVID-19 pill and the ‘unknown risk’ of DNA mutation
In a University of North Carolina study, the drug induced low levels of mutations in hamster cells, leading some experts to suggest the drug be limited to patients at high risk.
The COVID-19 pill developed by Merck and Ridgeback Biotherapeutics appears to reduce the risk of hospitalization by inducing mutations in the coronavirus, preventing it from making copies of itself.
Preliminary results from a clinical trial were so promising that the companies stopped it early and asked the Food and Drug Administration this month for emergency authorization to market the antiviral drug.
But in a study led by University of North Carolina researchers earlier this year, the drug also induced low levels of mutations in the DNA of hamster cells — in theory, suggesting it could pose a slight risk of cancer.
“Risks for the host may not be zero,” the authors wrote in the Journal of Infectious Diseases.
Scientists from Merck, based in Kenilworth, N.J., pushed back against the study in a letter to the journal’s editor, saying the cell experiments, conducted in a lab dish, were not relevant to how the drug would affect an entire animal — much less a human being. The UNC authors then replied with their own letter, defending their methods and urging that until further studies are conducted, the drug’s use should be limited to those at risk of severe consequences of COVID.
The back-and-forth between the scientists is crammed with technical terms that defy straightforward description. But there is no question the stakes are big. Pending authorization of the drug by the FDA, the U.S. government has agreed to buy $1.2 billion worth of the pills — at roughly $700 per course of treatment, enough to treat 1.7 million people.
And well into year two of the pandemic, despite the availability of highly effective vaccines that prevent most hospitalizations, thousands of new patients are admitted to U.S. hospitals each week.
Evidence that the drug helps
The scientific dispute was first reported in Barron’s, days after Merck reported that the drug, called molnupiravir, appeared to reduce the risk of hospitalization and death by half.
That finding came from an international clinical trial in which high-risk adults with mild to moderate COVID were randomly chosen to receive either the drug or a placebo.
Among volunteers who got the placebo, 14.1% were either hospitalized or died within 29 days (53 out of 377 people), while just 7.3% of those who got the drug (28 out of 385) were hospitalized. No one in that group died — prompting Anthony Fauci, the nation’s chief infectious-disease scientist, to call the results “very impressive.”
The complete data have yet to be published. But more details, such as the age and preexisting health conditions of trial participants, will be disclosed before the FDA takes action. None of the participants had been vaccinated.
Physicians say that if authorized for emergency use, molnupiravir would be a valuable weapon against COVID because the oral pills are so easy to use. A previously approved treatment called remdesivir, on the other hand, must be given intravenously.
The “vir” at the end of both names means they are antivirals — designed to work by attacking the virus directly, rather than by treating patients’ symptoms or giving an assist to their immune systems.
How the drug works
Molnupiravir, the drug from Merck and Miami-based Ridgeback, is called a nucleoside analogue. That means its molecules are chemical cousins of one of the building blocks of RNA, the genetic material inside the coronavirus.
The similarity enables the molecules to incorporate themselves into the virus RNA and cause mutations in the process, said Brianne Barker, a Drew University biologist who studies the immune system’s response to viruses.
But these mutations would not cause the virus to become more transmissible or virulent. The drug has more of a scattershot effect, adding more and more mutations in chemical “bases” throughout the virus genome until it can no longer copy itself — a phenomenon called “error catastrophe.”
“As the virus keeps reproducing, more and more of the wrong bases are being made,” she said.
Yet in the UNC cell experiments, the drug also appeared to cause low levels of mutation in DNA — the basis for the genetic code in humans. The issue is whether the dose in question poses any real risk.
In their letter challenging the UNC study, the Merck scientists noted that the hamster cells were exposed to the drug for 32 days, “substantially longer than the 3-to-6-hour exposure duration typically used per established guidelines.” What’s more, the Merck team said it conducted its own experiments in lab rats, not isolated cells, and found no evidence that the drug caused DNA mutations.
More study needed?
Ronald Swanstrom, one of the authors of the UNC study, agreed that the drug was promising. A biochemistry professor at the university’s medical school in Chapel Hill, he said his team’s findings are simply a sign that more study is needed.
“It’s really an unknown risk,” he said of the mutations. “It’s someplace between an inconsequential risk and an important risk.”
Results from experiments in cells and lab animals often do not translate to humans. But if there is a slight chance the drug could cause DNA mutations in those who take it, perhaps it makes sense to give it only to people above a certain age, he said. That’s because they are at higher risk of severe COVID, and also are old enough that any low level of mutation would not lead to cancer before they die of other causes.
“I’m not against them giving out the drug,” he said. “What I would like to see the FDA require is that they limit it to people who would really benefit.”
Barker, who was not involved with the UNC study, agreed that more studies would be useful. She said the tests that the UNC team used were “sensitive,” meaning they were able to detect DNA mutations at very low levels — possibly so low as to pose no health threat.
To err on the safe side, she said, “maybe this means that we don’t use this in people of childbearing age.”
Derek Lowe, a pharmaceutical chemist who writes about drug discovery for Science magazine, made the same suggestion in a blog post this week. With that restriction in place, “the compound looks like it can find a valuable place in fighting the pandemic,” he wrote.
Like most drug studies, the Merck trial excluded pregnant and breastfeeding women. And women of childbearing age were asked to use contraception or abstain from intercourse, as were men of all ages.
An FDA advisory panel is expected to review the study results within weeks, and agency authorization could come soon after that. In the meantime, Lowe, Fauci, and others offer a commonsense reminder: It is far better to rely on vaccines and other preventive measures.
“It decreased the risk, this pill did, of hospitalizations and death by 50%,” Fauci said on CNN’s State of the Union. “You know the way to decrease the risk by 100%? Don’t get infected in the first place.”