Merck & Co.'s experimental COVID-19 pill could be headed toward an emergency Food and Drug Administration clearance after a panel of outside experts voted 13-10 that the drug's benefits outweigh its risks for people most likely to develop severe disease.
Despite their overall recommendation, the advisory committee questioned the potential for the drug, called molnupiravir, to cause birth defects and to hasten the development of coronavirus mutations that could lead to new variants. As a result, they urged the FDA to limit its use in pregnant women and monitor patients for emergence of resistant strains.
The FDA is not required to follow its advisers' recommendations, but it usually does.
As an oral pill, molnupiravir could be a convenient new tool to prevent hospitalization and death from COVID-19 in people infected with the virus, particularly as the emergence of the omicron variant raises concerns worldwide about the durability of vaccine protection. Currently, the only options available to infected people not sick enough to need hospital care are antibody drugs that require an infusion or injection administered by a healthcare professional.
Yet molnupiravir's modest benefits in reducing hospitalization or death, along with its possible side effects, have raised some doubts about how broadly, or whether, it should be cleared under an emergency use authorization, or EUA.
Two months ago, Merck's case for the drug looked much more clear cut, after the company and partner Ridgeback Biotherapeutics reported clinical trial results showing treatment reduced the risk of hospitalization or death by nearly half in people with mild to moderate symptoms. The data, from a preliminary analysis, appeared so strong that trial monitors recommended Merck end the study early. The company sought FDA authorization soon thereafter.
But after collecting more data from more study participants, Merck estimated the risk reduction from molnupiravir treatment to be just 30%. Among the patients whose results were analyzed later, more of those given Merck's drug were hospitalized than those who received a placebo, resulting in the lower efficacy.
Presentations shown to FDA advisers Tuesday shed little new light on that surprising finding, other than revealing that patients who initially tested positive for coronavirus antibodies and received molnupiravir were hospitalized in greater numbers than those positive patients on placebo.
Representatives for Merck had no clear explanation for the drop in efficacy. "It doesn't really add up to us," said Nicholas Kartsonis, Merck's senior vice president for clinical research. "We expected some potential regression to the mean, but we didn't expect that we would see this absolute reduction."
The finding could support excluding vaccinated people from receiving molnupiravir, but because of testing timelines assessing antibody levels before treatment may not be practical, the FDA said. Treatment with the drug must begin within five days of symptoms beginning.
The mixed data was one reason that some of the panelists voted against molnupiravir.
"This was a difficult decision," said panel member Sascha Dublin, a senior researcher at the Kaiser Permanente Washington Health Research Institute, who voted yes. "For me, it was important to consider the results of the clinical trial in total and not get too obsessed with why the second half of the trial looked different."
Molnupiravir's modest benefit may also make it difficult to convince physicians to choose the drug over the monoclonal antibodies. "We think that monoclonal antibody therapy is likely to be more efficacious treatment," said Richard Murphy, an infectious diseases physician at the Department of Veterans Affairs White River Junction Medical Center in Vermont.
The FDA, meanwhile, is weighing molnupiravir's effectiveness against animal data suggesting an increased risk of birth defects, a question that's hung over the drug since early in its development. Animal tests also indicated a potential risk for bone and cartilage damage.
The agency is carefully weighing its use in pregnant women, while children could be restricted from taking the pill because of the risk to skeletal tissue.
"As a woman of childbearing age, I don't think I would want to take this drug, not knowing the effects that it could have on my unborn child," said Roblena Walker, a consumer representative to the panel who voted yes.
More broadly, the way in which molnupiravir works — blocking viral replication by introducing genetic mutations — also carries with it the potential to create coronavirus variants that are resistant to vaccines or other antiviral treatments.
Challenged on this point by panel member James Hildreth, CEO of Meharry Medical College, Merck's Kartsonis argued that use of vaccines or antibody treatments could equally spur resistant strains.
Hildreth, who voted no, argued the FDA needs to better understand that risk. "The potential for this drug to drive some very challenging variants into the public is a major, major concern," he said.
Pfizer is also seeking FDA authorization for an antiviral pill that it's developed, results for which appeared stronger than Merck's for molnupiravir. Details aren't yet available, however, nor are final data from the study.
Should Pfizer's pill win an EUA from the FDA, several panelists said their views of molnupiravir would change.
"If another medication becomes available with an EUA, [molnupiravir's] EUA should be revisited and have the potential to be withdrawn," Dublin said.
Ben Fidler contributed reporting
Note: This story was updated with additional comment from panelists.