New data, analyses take some of the shine off Merck’s Covid pill

New data, in addition to analyses by scientists at the Food and Drug Administration, may take some of the shine off Merck’s experimental Covid-19 pill, molnupiravir.

On Friday, the drug maker released full results from its study of the pill, molnupiravir, showing it reduced the risk of hospitalization by 30%, down from a decrease of 50% seen in an earlier analysis. In the 1,433-patient study, fewer patients died when they received the treatment. There were nine deaths in the placebo group in the final analysis, and one in the molnupiravir group.

The data were released as the FDA published its own analysis of molnupiravir ahead of a meeting of advisers being convened by the agency to vote on whether the medicine’s benefits outweigh its risks.

In that analysis, FDA researchers seemed to favor the authorization of molnupiravir but raised concerns that could mean people who are at lower risk from the disease would not be offered the pill.

The fate of molnupiravir — developed in partnership between Merck and Ridgeback Therapeutics — is important for both society’s battle against Covid-19 and Merck’s financial fortunes. Experts say that an easy-to-give, oral treatment that keeps people who contract the SARS-CoV-2 virus from being hospitalized or dying would go a long way toward helping society return to normal. Existing pills, such as hydroxychloroquine or ivermectin, have failed to deliver convincing results. Monoclonal antibodies treatments, though very effective, must be given as shots or intravenous infusions.

Pfizer recently released results on its own Covid pill, showing an 89% decrease in hospitalizations in an interim analysis.

As governments buy large amounts of both pills, the financial stakes could be enormous. During its October earnings call, Merck said molnupiravir could generate between $500 million and $1 billion this year and between $5 billion and $7 billion next year, according to a transcript STAT obtained through Senteio, a financial database provider. Geoffrey Porges, a stock analyst at the investment bank SVB Leerink, recently estimated that sales of Pfizer’s antiviral Covid pill could reach $24 billion in 2022.

The FDA’s advisory committee will convene on Tuesday to discuss Merck’s pill. The agency is seeking guidance on a few questions: Should pregnant women ever receive this drug? Could the use of this medicine result in the evolution of new, more worrisome variants of the SARS-CoV-2 virus, which causes Covid-19? And, of course, should the medicine be authorized, and for whom?

In a 68-page document independently analyzing the molnupiravir trial results, FDA experts delve into the data behind each of those questions.

The FDA does not seem concerned about one of the main worries that has been raised about molnupiravir: that it could cause mutations in people, thereby leading to cancer or other long-term health problems. A test done on bacteria, known as an Ames assay, did show a risk of mutation, called mutagenicity, the FDA says. But follow-up tests in a particular type of rat did not show a problem, and it is unlikely, the agency says, that such a problem would occur after just five days of treatment.

“Given the negative in vivo assay results, and considering the 5-day treatment duration with MOV, the Agency pharmacology/toxicology experts have concluded the risk of mutagenicity in the clinic is low,” the FDA reviewers said.

But the FDA did have a concern about whether or not molnupiravir should be given to so-called breakthrough cases, people who have been vaccinated against Covid-19 but still get infected. The agency points to a subgroup of patients in the study who had antibodies to Covid-19 who did not seem to benefit from molnupiravir. That group, though, was far too small to draw conclusions.

The FDA also had concerns about using molnupiravir in pregnant women and children. (Merck and the FDA agree that the drug should not be authorized for people under 18.) In studies in rats of a dose much higher than is given to people, researchers saw reductions in fetal body weight as well as “external, visceral, and skeletal malformations” in surviving fetuses.

The FDA proposes two ways of handling the risk in pregnant women. One approach would simply state that no pregnant women should receive the drug. A second would be to include warnings, but allow physicians to prescribe the medicine if they thought it was warranted. The FDA’s advisory committee will be asked to weigh in on which approach to take. The FDA does propose that women should take a pregnancy test before being prescribed the drug.

Nowhere in its analysis does the FDA seem to contemplate not making molnupiravir available. But adding restrictions will make the drug more difficult to give in practice, and could also make the Pfizer pill a preferred option, if data on that medicine hold up better than the data around molnupiravir have. This is a case where the opinions of the FDA’s expert panelists are likely to hold even more weight than usual.

Merck shares dipped almost 4% in morning trading. Pfizer shares rose more than 5%.