Merck COVID-19 Medicine Linked to New Virus Mutations, Study Says

Some researchers worry the medicine may create more contagious or health-threatening variations of COVID-19, Bloomberg reported.

Mutations linked to the use of Merck’s pill, Lagevrio, have been identified in viral samples taken from dozens of patients, according to a pre-print study from researchers in the United States and at the Francis Crick Institute, Imperial College London and other British institutions.

The drug-linked mutations of the virus have not been shown to be more immune-evasive or lethal yet, according to the study published last Friday without peer review on the medRxiv website.

But their very existence highlights what some scientists say are potential risks in wider use of the drug, which was recently cleared in China.

Lagevrio works by creating mutations in the COVID-19 genome that prevent the virus from replicating in the body, reducing the chances it will cause severe illness.

Some scientists had warned before it was authorized in late 2021 that by virtue of how it works, the drug could give rise to mutations that could turn out to be problematic. The pre-print paper has reawakened those worries about the Merck drug.

“There’s always been this underlying concern that it could contribute to a problem generating new variants,” said Dr Jonathan Li, a virologist at Harvard Medical School and Brigham and Women’s Hospital in Boston. “This has largely been hypothetical, but this pre-print validates a lot of those concerns.”

Merck disputes the view that its drug is causing problematic variants.

“There is no evidence to indicate that any antiviral agent has contributed to the emergence of circulating variants,” Merck spokesman Robert Josephson said in an e-mail in response to questions about the study. “Based on available data, we do not believe that Lagevrio (molnupiravir) is likely to contribute to the development of new meaningful coronavirus variants.”

He said new mutations have emerged over the course of the pandemic due to the virus spreading uncontrollably, and Lagevrio can form an important part of the solution.

Merck pointed to research done in animals that showed its drug did not cause mutations.

The study authors assume the mutations were associated with molnupiravir treatment, but do not have direct proof that the mutations arose in patients who took their drug, Josephson said in a follow-up e-mail.

Instead, the researchers drew their conclusions from “circumstantial associations between viral sequence origin and timeframe of sequence collection in countries where molnupiravir is available”, Josephson said.

The US Food and Drug Administration, which authorized Lagevrio in late 2021, said it does not comment on third-party research and works with COVID-19 drugmakers to assess their products’ activity against variants.

Major scientific journals do not publish studies until the completion of a “peer review” process in which the research is scrutinized by outside experts.

During the pandemic, scientists increasingly started publishing their research on what are known as “pre-print servers” prior to exhaustive reviews, in an attempt to advance the science more quickly and share urgent findings.

Researchers found Lagevrio-induced mutations in small patient clusters, indicating the new versions were spreading among them.

While the biggest group they found with similar mutations was 21 people, that may not fully represent the true scope of the problem as viral samples of many patients are not analyzed, according to independent researcher Ryan Hisner, who helped write the paper.

The researchers looked at about 13 million viral genomes in databases around the world.

The drug-linked mutations were proportionally more common in countries and groups where Lagevrio was likely to be used, especially the US and Australia, where it was introduced early. The signature mutations are less frequent in Canada, France and other countries where the drug is not used.

“These effects are visible in these databases,” said Dr Theo Sanderson, a Crick Institute geneticist who led the study. “It appears that people are being treated, some of them aren’t clearing their infections, and some are passing them on.”

The risk of drug-linked mutations is too great to continue using Merck’s drug, Hisner said.

The US should explore authorizing drugs used in other countries to control COVID-19, like Xocova from Japan-based Shionogi & Co, and discontinue use of Lagevrio, said Dr Michael Lin, a Stanford University antiviral drug researcher who said he consulted with the authors but was not involved in the study.

China cleared Lagevrio in late 2022 and Shionogi said it is in the final stages of discussions with the country’s regulators over its COVID-19 drug.

“It’s a very distressing situation,” said Dr Lin. “There’s no evidence that any of these mutants is worse in any way – not yet – but it’s well agreed that you’re playing with fire if you’re creating random mutations and hoping nothing bad will come of it.”

Dr Sanderson declined to comment on whether doctors should continue using Merck’s drug, saying the study does not address the issue.  

Concerns about Lagevrio’s safety and effectiveness are longstanding. Health officials recommend against its use in pregnant women. In general, the drug should not be used when alternatives are available, according to the US National Institutes of Health.

Merck was encouraged by former Warp Speed science czar Moncef Slaoui to team up with Ridgeback Biotherapeutics to get the much-needed oral COVID-19 pill ready for widespread use. Early results showed it cut the risk of hospitalization and death by about 50 percent in non-immunized people.

Subsequent studies have indicated it is actually less effective than those early trials indicated. A study released in December showed that adding Lagevrio to standard care did not reduce hospitalizations or deaths in high-risk adults, although the time to recovery from symptoms was shortened by several days. 

However, COVID-19 treatment options are dwindling.

Variants have mutated to evade COVID-19 antibodies made by Regeneron Pharmaceuticals, Eli Lilly & Co and Vir Biotechnology.

The last one to retain effectiveness, AstraZeneca’s Evusheld, was just removed from the US market.

That leaves few alternatives for Americans: just Paxlovid and Gilead Sciences’ remdesivir, which must be infused in three daily sessions as soon as someone is diagnosed.

Some patients are not eligible to take Paxlovid because it contains a component – ritonavir – that has adverse interactions with therapies for other conditions like heart disease, which are common in people vulnerable to severe COVID-19.

Dr Raymond Schinazi, an Emory University researcher, raised concerns about Merck’s drug early on in its development. He had done his own research into it years ago before abandoning it.

He called for more monitoring to investigate whether the viruses with drug-linked mutations are having any impact after learning about the new study. 

The preprint study is “an orange flag, not a red flag yet”, Dr Schinazi said. “Proceed with caution.”