A drug used to treat patients at risk of severe COVID-19 infection may have led to the emergence of SARS-CoV-2 viruses bearing a distinct pattern of mutations, researchers reported Monday in Nature. The new paper raises the stakes over concerns about whether molnupiravir use could lead to the emergence of new dangerous variants and extend the pandemic.
Molnupiravir, which is sold as Lagevrio, works by mutating SARS-CoV-2 and causing changes that should knock out the virus’s functionality. The mutated viruses aren’t supposed to replicate further, but researchers who looked at more than 15 million viral genome sequences found that a recognizable pattern of mutations emerged in 2022, when several countries began using the drug. They found this pattern in sequences from countries that used molnupiravir and in the age groups likely to have used the medication.
“We definitively demonstrate that molnupiravir has resulted in viable SARS-CoV-2 viruses with significant numbers of mutations, in some cases with onwards transmission of mutated viruses,” wrote Theo Sanderson, a fellow at The Francis Crick Institute in London and one of the new study’s authors.
New viral strains are an ever-present concern, and public health experts continuously worry that a more virulent or infectious COVID variant could evolve. When the Food and Drug Administration (FDA) authorized the use of molnupiravir in late 2021, Michael Z. Lin, a Stanford bioengineer, penned an opinion piece in The Washington Post calling the drug “ineffective and dangerous.” Molnupiravir, he argued, could spawn new versions of SARS-CoV-2 that evade the immune system and prolong the pandemic.
“In 2021, I wrote `A new drug to treat covid could create a breeding ground for mutant viruses,’” Lin wrote on the X social media site on Monday. “We can now write `A new drug to treat covid has created a breeding ground for mutant viruses.’”
A statement from Merck defended its product: “The authors assume these mutations were associated with viral spread from molnupiravir-treated patients without documented evidence of that transmission.” The paper relied on “circumstantial associations between the region from which the sequence was identified and timeframe of sequence collection in countries where molnupiravir is available to draw their conclusions,” the statement said.
The new study represents a blow for a drug that seemed to squeak through to federal authorization. An FDA advisory committee “narrowly endorsed” the drug in November 2021, “despite questions about the drug’s effectiveness, safety, and whether it would help the virus mutate into even more dangerous variants,” CNBC reported at the time. The FDA authorized the drug that December, a day after it also okayed Pfizer’s paxlovid, another COVID antiviral. But data showed that the two drugs had vastly different levels of efficacy. Patients who took molnupiravir had a 30 precent reduced risk of death or hospitalization, compared to an 89 percent lower chance for those on Pfizer’s drug.
Biodefense origins. Safety concerns about molnupiravir also came up during the COVID-era whistleblower complaint of Rick Bright, who headed the Biomedical Advanced Research and Development Authority (BARDA) from 2016 to 2020, when he was removed from his post at the agency tasked with developing and acquiring medical countermeasures. Bright claims he faced pressure from the Trump administration to back unproven therapies, including a Trump-favored antimalarial drug called hydroxychloroquine. In the case of molnupiravir, Bright alleged he was pushed to approve millions of dollars in funding to help manufacture the drug (at the time known as EIDD-2801) before safety data had been collected.
Before being reincarnated as a COVID therapeutic, EIDD-2801 was developed as a treatment for threats soldiers might face on the battlefield, namely equine encephalitis viruses. Emory University chemist George Painter worked on EIDD-2801 as part of a 2016 contract for the Defense Threat Reduction Agency to create a countermeasure to the mosquito-borne viruses, which had been weaponized during the Cold War. Painter’s team thought the drug might also work against other viruses, including influenza, according to an Emory news release.
In November 2019, Painter, who is the CEO of an Emory nonprofit drug development firm, met with Bright, the influential biodefense official Robert Kadlec, and others. According to Bright’s complaint, Kadlec, former President Donald Trump’s top public health preparedness official, was eager to green light the government investment in Painter’s drug, but Bright wanted to wait for more data. “Bright knew that similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls,” Bright’s complaint said.
Bright’s reticence allegedly irked Kadlec and Painter, who according to the complaint, “countered that Emory needed BARDA funding to start manufacturing as soon as possible. He insisted that EIDD-2801 could be a great asset to American national security, and warned that if BARDA did not fund its manufacturing immediately, Emory would take the drug to another country to manufacture it.” The complaint noted that Painter acknowledged, “sheepishly,” that the drug was already being manufactured in China.
The US government did end up investing heavily in molnupiravir. Emory licensed the drug to Ridgeback Biotherapeutics in March 2020, which then entered an agreement with the pharmaceutical giant Merck that May. The company announced that pending an emergency use authorization from the FDA, the government would buy $2.2 billion worth of the drug by early 2022. NPR reported last winter that due to low efficacy, doctors were reluctant to prescribe molnupiravir. Many doses were left “sitting unused.”
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