What’s Taking the FDA So Long on COVID Drug Molnupiravir?

O n October 1, pharmaceutical companies Merck and Ridgeback Biotherapeutics announced that their investigational oral antiviral drug Molnupiravir reduced the risk of hospitalization or death by about 50 percent compared with placebo for patients with mild or moderate COVID-19. Now the breakthrough drug from the two American companies has been approved — in the United Kingdom. Americans will have to wait at least a month more.

The drug is so exciting because it will be the first effective antiviral pill against COVID-19. Remdesivir, the only FDA-approved antiviral for COVID-19, must be administered intravenously in a hospital or in a similar medical setting, making it much more cumbersome and expensive to utilize. Monoclonal antibody treatments are expensive, hard to manufacture, and must also be administered intravenously. Molnupiravir would be the first treatment that patients could take at home.

Molnupiravir was studied in 762 newly diagnosed, high-risk patients who had one or more risk factors for severe COVID-19 — they were either over 60 years old or had diabetes, obesity, or heart disease. Subjects who received the drug were half as likely to be hospitalized as those who had received placebo. While eight people in the placebo group died, none in the drug group did. Side effects were no more common with the drug than with placebo.

The study was stopped early, with the consent of the FDA, when an independent monitoring board concluded the drug was so effective that it would be unethical to continue giving placebo. An earlier study indicated that the drug may also decrease disease transmission by lowering the viral levels in the nasopharynx and clearing the virus more quickly.

The companies applied to the FDA for an emergency-use authorization (EUA). But the FDA announced on October 14 that it would convene an outside expert advisory committee — something it is not required to do — to consider the data supporting the use of Molnupiravir more than six weeks later, on November 30. Even if the committee were to render a decision immediately, FDA authorization would not occur until well into December.

Why in the middle of a pandemic is it taking so long for the FDA to move forward? The study that was halted a month ago was a Phase 3 trial, meaning that there had been previous smaller Phase 1 and 2 studies showing the drug’s safety and effectiveness. If the data were compelling enough to stop the study early and the U.K. was able to authorize the treatment, why will the FDA’s advisory panel not meet for another month? Surely the FDA could move with more dispatch.

These questions take on added urgency now that Pfizer has just announced encouraging results for an oral COVID-19 drug it is developing. Its drug, Paxlovid, may be even more effective than Molnupiravir in reducing the risk of hospitalization. Pfizer plans on applying for an EUA soon.

The FDA is undoubtedly concerned about Molnupiravir’s safety. The drug works by incorporating itself into the virus’s genetic material (RNA) and blocking its ability to replicate. This has created some concern that there could be a similar effect on human DNA or RNA, causing mutations leading to birth defects or tumors. Studies of high doses in rats did show such mutations. But Britain’s regulators said that the dosage is lower in humans and that mutations and birth defects were not observed in other animals or humans. Merck also said it has not seen such mutations in human cells. Nevertheless, Merck excluded pregnant woman from its study and required subjects to use contraception.

Delaying review for another one or two months will not produce enough data to uncover rare mutations. The FDA could quickly authorize the drug with restrictions against use by pregnant women and by couples that are trying to become pregnant. Initial authorization could be limited to the elderly who are the population most vulnerable to COVID-19 and are beyond their reproductive years. Careful post-authorization studies should be mandated to ensure that any side effects are rapidly uncovered.

Despite the delays, Merck has gone ahead with production and committed to supply 10 million courses of treatment by the end of 2021. Hopefully they will have someone in the U.S. to administer them to.