7 min read.Updated: 01 Dec 2021, 06:33 PM ISTJARED S. HOPKINS, The Wall Street Journal
Oral antiviral pill was recently found to be 30% effective at reducing risk of hospitalization and death in high-risk people
An outside panel of scientific advisers to the Food and Drug Administration narrowly recommended the agency authorize the experimental Covid-19 oral antiviral from Merck & Co. and partner Ridgeback Biotherapeutics LP.
The panel, known as the Antimicrobial Drugs Advisory Committee, voted 13 to 10 in support of the FDA granting use. The recommendation is limited to high-risk people.
The panel’s blessing paves the way for the drug, called molnupiravir, to be available in the U.S. before the end of the year.
Merck plans to study whether molnupiravir is effective against the worrisome Omicron variant and is working to collect samples of the new strain to do so, Nick Kartsonis, who oversees Merck’s vaccine clinical research, told the panel.
“We expect, based on what we know about the Omicron variant, that molnupiravir would be effective against this particular variant," he said.
Evaluating molnupiravir against Omicron, he said, will take longer than assessing Covid-19 antibody drugs because Merck needs to collect a broader set of data covering the entire genome of the virus, rather than select pieces.
Merck earlier presented data to the panel showing how molnupiravir is effective against other variants, which the company and other scientists have said is due to how the drug works differently than vaccines and antibody drugs.
Molnupiravir targets machinery the virus uses to replicate, rather than the spike protein, the structure that helps the virus infiltrate cells. Omicron has several mutations to the spike protein, which researchers say could help the variant evade vaccines and drugs trained on that part of the virus.
The companies said last week that a final analysis found the drug to be about 30% effective at reducing the risk of hospitalization and death in high-risk people, lower than the 50% efficacy first announced in October after a preliminary look at the data.
Roy Baynes, Merck’s chief medical officer and head of global clinical development, said in an interview that the company’s clinical trial design was done in consultation with the FDA, including the planned interim analysis, and its 50% efficacy shouldn’t be discounted. “The trial was essentially over at that point," he said, noting how the drug was performing so well in the study that the FDA agreed enrollment should stop.
Dr. Baynes said he expects to have results from an Omicron analysis of molnupiravir “in the next several weeks."
The FDA isn’t required to follow the committee’s advice but normally does.
The vote followed a daylong meeting in which Merck and the FDA presented data about molnupiravir’s studies in trial participants and other tests. Panel members discussed concerns over safety of the drug, the changing efficacy from the study, and which patient populations taking molnupiravir could be helped.
“I can see scenarios where having this is a benefit," said Dr. Lindsey Baden, the panel chairman who voted in favor and director of clinical research in the division of infectious disease at Brigham and Women’s Hospital.
“Overall I trust our practitioners that if we educate them properly they can deploy this properly," he said.
Several panel members who voted in favor of authorization said use of molnupiravir should be limited to unvaccinated people at high risk of Covid-19 complications, and that while more data are needed on efficacy and potential side effects, the pill would fill a major gap in the pandemic because of its convenience as an oral therapy.
“I’m not sure that this is really the one we’ve been waiting for, but it’s all we’ve got right at the moment," said John Coffin, a professor of molecular biology at Tufts University who said he has been hoping for an oral treatment for Covid-19 and voted in favor of authorization.
Panel members who voted against the recommendation said they were concerned with how there wasn’t a clear explanation on why molnupiravir’s efficacy changed, and that the drug’s benefit to patients may be minimal. Some also wanted further study of molnupiravir, saying they were concerned about potential mutagenic effects.
“I was struck by a modest benefit in the highly adherent trial population, and then the unclear efficacy in the latter half of the trial when you had increasing circulation of the Delta variant," said Daniel Horton, assistant professor of pediatrics and epidemiology at Rutgers Robert Wood Johnson Medical School, who voted no. He said he is concerned about the effectiveness of the regimen in the real world, where adherence might be lower, and about potential effects on evolution of the virus if the drug is used widely.
If the FDA authorizes molnupiravir, Merck has agreed to provide the U.S. government with 3.1 million courses of the drug for about $2.2 billion.
Merck expects to package and distribute molnupiravir shortly after an FDA authorization, but timing will depend on how quickly it can complete prescribing information, which is determined by regulators, a spokeswoman said.
The U.S. government is expected to allocate the pills to states to filter among pharmacies, hospitals and doctor’s offices for dispensing.
A course of treatment is eight pills daily for five days, starting within five days of showing symptoms.
Molnupiravir could become a valuable addition to the growing toolbox of Covid-19 treatments, doctors and researchers say, because physicians could prescribe the drug for people to take at home when they first develop symptoms, to avoid being hospitalized.
Antibody treatments cleared for use are expensive to administer by injection or infusion, and usually require people to visit hospitals or clinics.
Despite molnupiravir’s lowered efficacy, some doctors say the drug could still be a helpful treatment because of its convenience and the limited supply of other treatments.
The FDA is also weighing authorization of an antiviral from Pfizer Inc. that was found to be 89% effective at reducing risk of hospitalization and death. The FDA hasn’t scheduled a meeting of outside advisers to discuss Pfizer’s drug, which goes by the brand name Paxlovid.
In addition to the vote, members of the panel, which consists of about two dozen infectious disease specialists and other scientists, raised concerns that molnupiravir in pregnant women could potentially cause birth defects.
Merck isn’t recommending the drug be used in pregnancy, and the FDA is considering prohibiting such use. Pregnant women weren’t included in the Merck-Ridgeback trial.
Members said molnupiravir shouldn’t be recommended for use in pregnant women, but some didn’t say it should be prohibited because expectant mothers at high-risk of severe Covid-19 may want to take it if other therapies aren’t available.
The panel also talked about whether the treatment could lead to new variants. During the trial, FDA staff said, testing found small tweaks in the spike protein of the coronavirus in some study subjects, which the staff said could theoretically lead to new variants. Merck and Ridgeback said the drug isn’t prone to prompting the virus to develop resistance.
Some panel members said they voted against authorization because of this concern.
Merck and Ridgeback requested emergency-use authorization in October, after a preliminary look at study results found the drug cut in half the risk of people with mild to moderate symptoms becoming hospitalized or dying.
Last week, though, the companies said a final analysis in the 1,433-subject study found efficacy was 30%.
Merck officials discussed with the panel several notable differences that appeared in the second half of the study and might explain the less-effective results.
In the first half of the study that served as the basis for the preliminary analysis, 7.3% of the subjects who received molnupiravir became hospitalized, compared with 14% in the placebo arm, according to the FDA. Yet in the second half, 6.2% of subjects on the drug became hospitalized, compared with 4.7% of placebo subjects.
During the first half of the study, no participants on molnupiravir died, compared with eight in the placebo group. Yet in the second half, one person died in each arm.
Merck hasn’t been able to determine why the efficacy changed after the preliminary analysis, Dr. Kartsonis told the panel, but noted the second half of the study enrolled an older population, more women and more subjects in Europe. He also said second-half subjects were almost all infected with the Delta variant, and there were more patients who were antibody positive, which may mean researchers were enrolling people later in the course of disease.
“It doesn’t really add up to us," Dr. Kartsonis said.
More analysis from the FDA is due Tuesday after the agency said last week that its analysis of the drug might change because of the additional efficacy data.
In its initial review, the FDA staff said the drug was effective at reducing the risk of hospitalization and death, but it didn’t say whether the agency should authorize the drug.
The agency said no major safety concerns turned up in late-stage testing. The FDA also found the treatment presented a low risk of mutation, known as mutagenicity.
Some scientists have expressed concern about the safety of the drug and whether it might cause mutations in cells that are harmful to people. Merck and Ridgeback have said the drug is safe, and testing in humans found it didn’t lead to the mutations.
Molnupiravir is designed to work by introducing errors into the genetic code of the virus, thereby disrupting its ability to replicate.
This story has been published from a wire agency feed without modifications to the text
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