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Merck’s Antiviral Could Be Just What Covid Was Waiting For

At the beginning of October, Merck announced that its drug candidate molnupiravir, an oral antiviral, was shown to halve the risk of hospitalization or death from Covid-19 when given to high-risk people within the first five days of infection. Merck is seeking emergency use authorization from the Food and Drug Administration, with the possibility of the drug being rolled out late this year. The United States has already ordered 1.7 million courses of the drug, and the United Kingdom almost half a million courses

In a stark departure from the moves of the major vaccine manufacturers, Merck is making the drug widely available to the whole world. The company has signed deals with several Indian manufacturers, and the drug will be manufactured and sold in over 100 countries, mainly in Africa and Asia. The company itself expects to produce 10 million courses by the end of this year, although it’s still waiting on local regulators’ green light. This is great news for economically developing countries, where a cheap and effective treatment could help bridge the gap as they await vaccines—and it’s especially notable as the first Covid-19 drug in a pill you can pop. Remdesivir, the only currently approved antiviral treatment in the US and UK, has useful but lackluster effects: It doesn’t save lives, but it does speed up recovery. It also requires delivery through an IV, and is costly and finicky to manufacture. 

But with antiviral drugs often comes antiviral resistance; you seldom get one without the other. Some scientists worry that the virus will soon learn to thwart the drug’s mode of attack, and that the likelihood of resistance will be exacerbated by such a massive global deployment. “The history of antivirals is littered with the emergence of resistance,” says Saye Khoo, a professor of pharmacology at the University of Liverpool and an antiviral researcher. It’s long been a problem that has plagued influenza treatment: There’s a whole class of FDA-approved antiviral drugs that are no longer recommended for use now that influenza viruses have learned to outwit them. 

Any antiviral drug likely to have such widespread use will require keen vigilance for any signs that the virus is fighting back. “With any antiviral drug, we need to be alert to the possibility of resistance,” says Daniel Kuritzkes, chief of Brigham and Women’s Hospital’s infectious diseases division and professor of medicine at Harvard Medical School. “We have certainly seen resistance emerge for most of the drugs we use.”

Once it’s infected a body, a virus makes copies of itself inside human cells using its own replication machinery, akin to a photocopier. Introducing an antiviral like molnupiravir into the mix is comparable to inserting a piece of paper that looks very much like one of the building blocks of the virus. The photocopier, not spotting the imposter, incorporates the faulty component into its genome, jamming the mechanism and effectively nuking itself out of existence. 

But there's a possibility that SARS-CoV-2 could do an end run around the drug; any variant that happens to be less susceptible to the drug’s modus operandi could survive and become more dominant, pushing the virus’s evolution toward resistance. And SARS-CoV-2 has already shown its propensity for outsmarting certain treatments: In July 2021 the US halted shipments of an antibody therapy from Eli Lilly after detecting resistance in newer variants of the virus. 

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One source of comfort is that the treatment course’s brevity—four pills twice a day for five days—means there is less opportunity for resistance to develop, compared to the lifelong courses of treatment for HIV. And SARS-CoV-2 is not quite as agile as viruses such as HIV or hepatitis C; it tends to make copies of itself at a more leisurely pace, giving it less time for a hardier variant to evolve. Plus, researchers have yet to see any resistance develop against remdesivir, the existing Covid-19 antiviral. “I'm not worried for a while,” says Monica Gandhi, an infectious disease specialist and professor of medicine at UC San Francisco. “Right now, I think of it as the very early stages of HIV, and it’s like a miracle to get anything.”But if people stop taking their pills too early, viral resistance may be more likely to occur, as some of the virus may linger in the body and resistant strains can multiply. Mark Denison, a professor of pathology, microbiology, and immunology at Vanderbilt University and one of the scientists behind the drug, told Endpoints News that he’s specifically worried about people not finishing the full course of treatment once they begin to feel better. “Ultimately, it depends not on the virus or the drugs—it depends on human beings,” he said. Gandhi echoes the danger of not finishing courses: “That can really increase the development of possible resistance.”

“As emerging variants worsen the Covid-19 pandemic across the globe, we must evaluate potential treatments with these variants in mind,” a Merck spokesperson says. They add that trials of molnupiravir demonstrated “consistent efficacy” across the Gamma, Delta, and Mu variants, suggesting that existing strains of SARS-CoV-2 have not yet succeeded in developing resistance against the drug.

Merck is not the only player in the game. In fact, despite humanity limping through most of the pandemic with a near-empty arsenal of treatments for Covid-19, the antiviral drug race is beginning to tighten. Atea Pharmaceuticals and Roche are collaborating on the development of a similar nucleoside analog antiviral drug, and Pfizer is testing an antiviral with a different mechanism of action: a SARS-CoV-2 protease inhibitor, which works by blocking a step the virus uses to fuse itself with a human cell. The results from the two drugs are expected in the coming months. 

The arrival of more antiviral drugs might be the key to preventing resistance from building. When the first antiviral drug against HIV was approved by the FDA in 1987, it quickly became clear that the virus was too quick; in some patients, resistance was developing in a matter of days. Within a few years, more drugs were approved, and an antiviral cocktail became standard treatment, making it much more difficult for the virus to build resistance. In particular, a blend of drugs that each interfere with different points of the virus’s replication process makes it much tougher for a virus to evade all the attacks.  

Ultimately, the same approach might be needed for Covid-19. “I think absolutely that a combination would make more sense. Because that isn’t just what we do in HIV because of resistance—we also do it because it’s more effective,” says Gandhi. A multi-prong approach is better at suppressing a virus, and requires lower doses of each drug, resulting in milder side effects. But we need to rationally design these combinations, says Khoo. “Very often in the past, in other diseases, we’ve seen, companies are very, very keen to keep combinations in-house,” says Khoo. “And I think that we don’t have that luxury for Covid.”

It’s too soon to tell how the virus will react to molnupiravir and whether it will successfully outmaneuver its mode of ambush. But it’s worth keeping an eye on, Khoo says. “There’s always the possibility that resistance may arise. We don’t know that it will, but there’s always the possibility it might.”

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