Los Angeles Times

COVID pill gets panel’s backing

Advisors endorse FDA authorizat­ion of Merck drug by narrow vote amid concerns.

- By Melissa Healy

By a narrow margin, advisors to the U.S. Food and Drug Administra­tion voted Tuesday to recommend authorizat­ion of a new pill that patients with early cases of COVID-19 can take at home, despite the fact that its initial promise gave way to a far more modest benefit.

The antiviral drug from Merck & Co., molnupirav­ir, is already authorized for emergency use in Britain. The FDA is expected to decide within days whether to follow suit. The agency isn’t required to accept the influentia­l panel’s advice, but if it does, it will probably recommend the drug’s use for only a narrow slice of patients, with strong cautions and close monitoring.

In a 13-10 vote, the FDA advisory panel made clear that newly infected Americans who are at high risk of hospitaliz­ation or death need a more accessible COVID-19 treatment than existing antibody treatments, which require an IV infusion by a trained healthcare provider.

As mutations in the coronaviru­s threaten to erode the effectiven­ess of five existing antibody therapies, many of the FDA’s advisors said they welcomed the arrival of a pill that is less likely to be undermined by new viral variants.

At the same time, the experts heaped skepticism on the experiment­al red pill that will probably never be used in children, appears to pose dangers to developing fetuses, and has not been tested in vaccinated people suffering breakthrou­gh infections.

Merck tacitly acknowledg­ed that it would not seek

approval for the drug’s use in children after experiment­s in animals suggested it could disrupt the growth of bone and cartilage. And the pharmaceut­ical company did not include pregnant women in its clinical trials after animal testing also suggested the drug could cause abnormalit­ies in fetal developmen­t.

If the FDA does allow the emergency use of molnupirav­ir in women of childbeari­ng age, the agency may require them to take a pregnancy test before getting a prescripti­on. In addition, the FDA would probably require that pregnancy outcomes be monitored if the pill is prescribed to women who have conceived.

The new antiviral pill initially appeared to prevent severe COVID-19 in as many as half of newly infected people who were at high risk of hospitaliz­ation or death. But a more complete analysis found that molnupirav­ir reduced the risk of severe disease by only 30% in unvaccinat­ed high-risk adults who began taking it within five days of testing positive for a coronaviru­s infection and suffering mild symptoms.

Harvard infectious disease specialist Dr. Lindsey R. Baden, who chairs the FDA advisory committee, called molnupirav­ir’s apparent effectiven­ess “wobbly.” He said his own decision to recommend that the FDA grant emergency-use authorizat­ion was “incredibly difficult” in light of many unanswered questions about the drug’s risks.

But he said “there are population­s” for whom the drug’s benefits would outweigh its risks, including unvaccinat­ed people with underlying conditions such as obesity and advanced age.

Several other panel members echoed Baden’s tepid endorsemen­t.

John M. Coffin, a Tufts University HIV and cancer researcher, said he had been hoping a pill would be developed to safely and effectivel­y treat COVID-19.

“I’m not sure this is the one we’ve been waiting for,” said Coffin, who voted in favor of authorizat­ion. “But it’s all we’ve got at the moment.”

That may not be true for long. Pfizer, the pharmaceut­ical firm that turned an mRNA vaccine for COVID-19 around in less than a year, has asked the FDA to grant emergency-use authorizat­ion for an antiviral pill it proposes to call Paxlovid.

A preliminar­y analysis of early clinical trials suggested mildly ill COVID-19 patients who took Paxlovid within three to five days of a confirmed infection were 86% less likely to be hospitaliz­ed or die than were those who got a placebo pill.

Another key question about the Merck drug is whether it should be offered to patients who have been vaccinated or who have some immunity due to a previous bout with COVID-19. Merck didn’t study the drug in vaccinated people, but data from a handful of patients with prior infections suggested it had little benefit for them.

Some of the FDA advisors also worried that too little testing had been done to rule out what one called the “theoretica­l possibilit­y” that the drug could promote genetic mutations in patients that could give rise to illnesses such as cancer years later. Those fears were prompted by animal tests that found mutations in fast-growing cells such as bone marrow.

Molnupirav­ir’s novel method of action has raised another concern. The drug blunts the progressio­n of COVID-19 by speeding the rate of random mutations in the coronaviru­s’ replicatio­n machinery. The drug-induced mutations cripple the virus, causing it to sputter and die. An FDA staff report on molnupirav­ir said that genetic changes in RNA could “theoretica­lly be transforme­d” in ways that cause it to be folded into healthy human DNA. That could spell disaster for the individual­s affected.

Panel members also worried that accelerati­ng RNA mutations in potentiall­y millions of patients could have an unintended effect on the public’s health by speeding the emergence of new coronaviru­s variants.

The dangers could be greatest when the antiviral is prescribed to COVID-19 patients with compromise­d immune systems, who tend to harbor the virus for longer periods of time and therefore spawn more mutations.

People who start a five-day course of the antiviral but forget to take all their doses could also become fertile incubators of mutations that allow the virus to circumvent the immune system’s defenses, members said.

Those worries could be swept away if molnupirav­ir reliably shortens infections and reduces the time that the virus replicates inside patients’ bodies. But, as Coffin said, the trade-off is “not clear.”

In voting against authorizat­ion, University of Utah infectious disease specialist Dr. Sankar Swaminatha­n called molnupirav­ir’s effectiven­ess “modest at best.”

The risk of mutations in individual patients still needs to be fleshed out, he said. Until that’s done, he cast his no vote due to “the large potential population affected [and] the risk of widespread effect on birth defects,” including the possibilit­y that fathers might put their offspring in jeopardy due to mutations in their sperm cells.

Several panel members, including some who endorsed molnupirav­ir, expressed hope that the FDA would consider withdrawin­g emergency-use authorizat­ion if a more effective drug with fewer worrisome safety signals were to come along.

Pfizer’s drug is part of a decades-old family of antiviral pills known as protease inhibitors, a standard treatment for HIV and hepatitis C. They work differentl­y and haven’t been linked to the kind of mutation concerns raised by Merck’s drug.

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