Merck’s experimental pill for Covid-19 should be accompanied by other treatments as soon as they’re available to cut the risk of drug resistance that would limit its effectiveness, Wellcome foundation director Jeremy Farrar said. While yet to be cleared by regulators, Merck’s molnupiravir has been hailed as a potential breakthrough, as it could be relatively cheap and easy to make, doesn’t require infusion and has shown it reduces the risk of hospitalization in a trial.
Yet it may need to be combined with other drugs to head off resistance, Farrar said. Resistance occurs when viruses and bacteria evolve to blunt or defeat drugs’ mechanism of attack. It’s a constant concern for antivirals and antibiotics and has already been seen with Covid treatments such as Eli Lilly’s antibody therapy.
Farrar suggested Merck’s pill would be no exception, despite optimism that it may be a potent new weapon to fight the pandemic. “The thought that you could have an oral drug readily available that you could take as soon as you have a suspicion of infection — that’s a huge step forward globally,” Farrar said. But he emphasized the importance of combining it with other drugs as soon as possible to “delay the onset of resistance.”
While this is always a concern for anti-infectives, the likelihood that it will become a severe problem for molnupiravir appears to be low, said Nick Kartsonis, senior vice-president of clinical research for infectious diseases and vaccines at Merck Research Labs. Earlier experiments with other viruses showed that the evolution of resistant mutations was rare, he said.
The course of treatment is short, meaning that viruses get few chances to evolve into resistant forms. Another reason lies in the drug’s mechanism of action. Pioneered by researchers at Emory University and other academic centers and later licensed by Merck’s partner Ridgeback Therapeutics, molnupiravir works by introducing errors into the coronavirus’s genetic material. The errors are then replicated until the virus is defunct. Merck’s analysis has shown that the errors induced by the drug are spread more or less randomly throughout the viral genome. That means that the virus has fewer opportunities to develop mutant forms that will overcome those errors. “That in and of itself makes resistance a tough thing,” Kartsonis said. Still, although Merck isn’t pursuing combinations right now, molnupiravir may be more effective if used with other drugs that prove successful, Kartsonis said. That may also lower the potential for resistance even further, he said. Attacking Pathogens Many drugs have been far more effective in combination than when used on their own. The first drugs developed for HIV, when used singly, quickly stopped working because resistant strains evolved that could defeat the drugs’ attack. By attacking pathogens from several angles, drug cocktails make the evolution of such variants less likely. Now, HIV combination treatments stay effective in individual patients for years.
Numerous other companies are working on pills to treat Covid through a variety of approaches. Pfizer began late-stage trials of an oral treatment this summer and expects data before the end of the year. Israel-based Redhill Biopharma Ltd.’s experimental therapy, opaganib, cut deaths in a group of patients with moderately severe Covid, according to data released earlier this month. Wellcome itself has pledged £8 million ($11 million) for a project, called Covid Moonshot, to find a drug that would block a key protein the coronavirus uses to replicate. An early study published last week showed molnupiravir has the potential to cut the rate of hospitalization and death by around 50 per cent in mild to moderate Covid patients. A widely available Covid pill could be “massively important” in developing countries where hospital access is limited and vaccinations aren’t readily available, Farrar said. – Bloomberg