FDA advisers narrowly recommend authorization of first antiviral pill to treat covid-19

The drug, molnupiravir, was developed by Merck and Ridgeback Biotherapeutics as a five-day regimen to be taken at home within five days of the onset of coronavirus symptoms. The FDA is not bound by the 13 to 10 vote but typically follows its external advisers' recommendations. The drug could have an immediate impact on the pandemic if authorized - just as the ominous new omicron variant has emerged, jolting the world with the prospect of a longer and more complicated pandemic.

Merck has pledged to manufacture enough medicine to treat 10 million patients by the end of the year, and the United States has preordered enough medicine to treat 3.1 million people. There are other treatments, monoclonal antibodies, that are harder to administer but are more effective, which led experts to debate who should receive the drug. An easy-to-use medicine that could be taken at home would offer an additional tool to reduce the strain on hospitals as a potential winter surge looms.

When given to people at high risk of developing severe illness, molnupiravir cut the risk of death or hospitalization by 30 percent in patients infected with a range of variants including delta, gamma and mu. Molnupiravir has not yet been tested against the omicron variant, but because it works in a different way than vaccines and monoclonal antibodies that train their firepower on the coronavirus spike protein, it is expected to hold up against a wide range of variants.

"As new variants have been becoming available, we have been testing them for the activity of molnupiravir," said Nicholas Kartsonis, senior vice president of clinical research for infectious diseases and vaccines at Merck. "We expect, based on what we know about the omicron variant, that molnupiravir would be effective against this particular variant."

But one committee member cautioned that it was an assumption that the drug would be more variant-proof than vaccines or other treatments.

"If we take a look at the omicron variant and see the number of mutations that virus has, I think in many ways we don't really understand which direction the virus may even be going in terms of changing," said W. David Hardy, a scientific and medical consultant at Charles Drew University School of Medicine and Science. "To assume this drug . . . is going to work when the monoclonals don't is a big jump. We have no assurance of that."

A second oral pill regimen - it was developed by Pfizer - is also being reviewed by the FDA. That drug could offer advantages that will make it the choice of physicians: That medicine was more effective at preventing hospitalization and death and doesn't carry safety concerns about its use in pregnant patients. The advisory committee debated whether people who are pregnant should be eligible to receive molnupiravir.

Much of the expert committee's debate Tuesday focused on the many unknowns about those safety issues, which are intertwined with how molnupiravir works. The drug becomes incorporated into the viral genome, causing genetic mistakes that disable the virus.

There are two concerns about potential unintended consequences: first, that molnupiravir could scramble the genome in the patient's own cells, causing cancer, genetic diseases or birth defects. The company requested authorization for adults, but said that it should not be recommended for people who are pregnant or breastfeeding and said that people of childbearing age should use contraception during the treatment.

But the short duration of treatment and a gold standard laboratory test in rats designed to flag drugs that have the potential for mutagenesis - the process in which genetic change happens - suggested there was not a major risk to adult patients.

The concern that the drug could cause genetic mutations "in a clinical setting appears to be low," said Robert H. Heflich, director of the Division of Genetic and Molecular Toxicology at the FDA's National Center for Toxicological Research.

The second concern is that the drug might induce genetic changes to the virus that fuel the rise of new, threatening variants. FDA reviewers showed data demonstrating that in seven people treated with the drug, viral samples taken after treatments contained worrisome mutations seen in known variants, although the patients cleared the virus.

"Even if the probability is very low, 1 in 10,000 or 1 in 100,000, that this drug would induce an escape mutant for which the vaccines we have do not cover, that would be catastrophic for the whole world," said James E.K. Hildreth, president of Meharry Medical College.

But FDA reviewers said those mutations also emerge naturally.

"It is unclear to us if molnupiravir would have a substantial impact on the evolutionary patterns that are already happening," said Patrick R. Harrington, senior clinical virology reviewer at FDA.

Other questions that arose, without resulting in satisfying answers, included why the drug didn't appear to work in people with type 2 diabetes. It also was less effective against the delta variant.

Additionally, when preliminary data on the drug was released in early October, molnupiravir appeared to cut risk of death and hospitalization in half, a finding so persuasive that the trial was halted at its midpoint. After continued follow-up of patients, the drug appeared less impressive, with risk of death and hospitalization reduced by 30 percent.

There are already three treatments, called monoclonal antibodies, authorized in the United States to help keep high-risk people from ending up in the hospital. Monoclonals are highly effective, but they are more cumbersome to administer and their uptake has often been uneven. Unlike pills that can be picked up at a pharmacy and taken at home, monoclonals are given through lengthy infusions or injections that are less convenient than a doctor prescribing a pill - and new variants can pose a threat to their use.

"As we enter the winter months, another surge is imminent, potentially in the setting of emerging new variants of concern," Kartsonis said. "We remain in dire need of novel, effective, well tolerated and conveniently administered therapies to treat covid-19 in the outpatient."