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November 30, 2021 – A US Food and Drug Administration (FDA) advisory panel narrowly voted 13 to 10 today to recommend emergency use authorization for the antiviral pill molnupiravir from Merck and Ridgeback Biotherapeutics to treat COVID-19.
According to the panel of experts the drug may help some high-risk patients survive a COVID-19 infection or help them stay out of the hospital, even though the risks of taking the drug aren’t yet fully known.
Emergency use requires a medication to meet a lower standard of evidence than for a full approval. The FDA is not bound by the committee’s vote, but typically follows the counsel of its advisors.
If authorized by the agency, molnupiravir would be first antiviral agent available as a pill available to treat COVID-19. Other therapies to treat the infection are available—monoclonal antibodies and the drug remdesivir—but they are given by infusion.
“This was clearly a difficult decision,” said committee member Michael Green, MD, a pediatric infectious disease expert at the University of Pittsburgh School of Medicine. “Should an alternative oral agent become available that had a better safety profile and equal or better efficacy profile, the agency might reconsider its authorization,”
Green said he voted yes, and that the drug’s ability to prevent deaths in the study weighed heavily on his decision. He said given uncertainties around the drug both the company and FDA should keep a close eye on patients taking the drug going forward.
Others didn’t agree that the drug should be allowed on the market.
“I voted no,” said Jennifer Le, PharmD, a professor of clinical pharmacy at the University of California, claiming the modest benefit of the medication didn’t outweigh all the potential safety issues.
“I think I just need more efficacy and safety data,” she said.
Initial results from Merck’s clinical trial found the pill cut the risk of hospitalization or death in patients at higher risk of severe outcomes from COVID-19 by about 50%.
But later results, released just days before the meeting, showed that the drug’s effectiveness had dropped to about 30%.
In the updated analysis, 48 of 709 patients using the drug were hospitalized or died within 29 days compared to 68 out of 699 patients who randomly got the placebo.
There was one death in the group that got molnupiravir compared to nine in the placebo group. Nearly all those deaths occurred during the first phase of the study.
On Tuesday, Merck, explained that the drug’s efficacy appeared to fall, in part, because the placebo group had experienced fewer hospitalizations and deaths than expected during the second half of the study, making the drug look less beneficial by comparison.
The company said it wasn’t sure why patients in the placebo group had fared so much better in later trial enrollments.
Serious Caveats
“The efficacy of this product is not overwhelmingly good,” said committee member David Hardy, MD, an infectious disease expert at Charles Drew University School of Medicine in Los Angeles. “And I think that makes all of us a little uncomfortable about whether this is an advanced therapeutic because it’s an oral medication rather than an intravenous medication.”
“I think we have to be very careful about how we’re going to allow people to use this,” he said.
Many who voted for authorization thought use of the drug should be restricted to unvaccinated people who were at high risk of severe COVID-19 outcomes, the same population enrolled in the clinical trial. People in the trial were considered at higher risk if they were over age 60, had cancer, chronic kidney disease, chronic obstructive pulmonary disease, were obese, or had heart disease or diabetes.
The study showed no additional benefit of the medication compared to the placebo in people who had detectable antibodies, presumably from a prior infection.
Animal studies found that the drug could disrupt bone formation. For that reason, the manufacturer and the FDA agreed that it should not be used in anyone younger than age 18.
Animal studies also indicated that the drug could cause birth defects. Merck said the drug shouldn’t be given to women who are pregnant or breastfeeding and that physicians should make sure women of childbearing age aren’t pregnant before taking the medication.
Some members of the panel felt that pregnant women and their doctors should be given the choice of whether or not to use the drug, given that pregnant women are at high risk for severe COVID-19 outcomes, and infused therapies may not be available in all settings.
But some researchers who reviewed the drug’s mechanism of action said they’d be extremely cautious.
“It’s actually quite mutagenic,” said Elizabeth Campbell, PhD, a research associate professor at The Rockefeller University in New York City. Campbell co-authored a commentary on the medication for the journal Nature.
“I wouldn’t take it if I was pregnant or if I was a child or teenager,” she said.
Other members of the committee said they too were uncomfortable authorizing the drug given its potential to cause the virus to mutate
The medication force the virus to mutate as it copies it’s RNA, eventually causing the virus to make so many errors in its genetic material that it can no long make more of itself and the immune system clears it out of the body.
But it takes a few days to work—the drug is designed to be taken for 5 consecutive days–and studies of the viral loads of patients taking the drug show that through the first 2 days, viral loads remain detectable as these mutations occur.
Studies by the FDA show some of those mutations in the spike protein are the same ones that have helped the virus become more transmissible and escape the protection of vaccines. So the question is whether someone taking the medication could develop a dangerous mutation and then infect someone else, sparking the spread of a new variant.
Nicholas Kartsonis, MD, a vice president at Merck told the panel that the company was still analyzing data on mutations and infectivity of viruses detected within the first few days of treatment.
That data lag caused some serious concern. “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 would not cover, that would be catastrophic for the whole world, actually,” said committee member James Hildreth, MD, an immunologist and president of Meharry Medical College in Nashville.
“Do you have sufficient data on the likelihood of that happening?” he asked Kartsonis
“We don’t,” Kartsonis said. He said, in theory, the risk of mutation with molnupiravir is the same as that seen with the use of vaccines or monoclonal antibody therapies.
Hildreth wasn’t satisfied with the answer.
“With all respect, the mechanism of your drug is to drive mutagenesis, so it’s not the same as the vaccine. It’s not the same as monoclonal antibodies,” he said.
Hildreth later said he didn’t feel comfortable voting for authorization given the uncertainties around escape mutants. He voted no.
“It was an easy vote for me,” Hildreth said.
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