A Food and Drug Administration advisory panel on Tuesday narrowly endorsed the uPse of Merck and Ridgeback Biotherapeutics' oral Covid treatment pill, despite questions about the drug's effectiveness, safety and whether it would help the virus mutate into even more dangerous variants.
The FDA's Antimicrobial Drugs Advisory Committee voted 13 to 10 to recommend emergency authorization of molnupiravir, an oral antiviral drug initially hailed as a potential game changer in the battle against Covid since it can be taken at home instead of at a hospital like other treatments. It's designed to treat adults with mild to moderate symptoms of Covid-19 who are at high risk of severe disease. The 800 milligram pill is taken every 12 hours for five days after symptom onset.
The drug needs final authorization from the FDA and Centers for Disease Control and Prevention before it's available to the public on an emergency basis. The FDA doesn't have to take the panel's advice, but it often does.
Many members of the advisory committee described the vote as a difficult one, in which they had to carefully weight the risks and benefits of a drug that raised unanswered questions, but could help adults at risk of severe Covid.
Merck originally said the drug was more than 50% effective in preventing hospitalizations and death, but a more full set of data presented to the FDA on Tuesday noted the drug is just 30% effective.
The FDA and Merck both recommended against using the drug in kids and pregnant women. Molnupiravir was found to be lethal to embryos in pregnant rats, also causing birth defects and reducing fetal body weight. It also caused other defects that interfered with bone growth in young pups, along with other abnormalities, the data shows.
Molnupiravir works by prompting the virus that causes Covid to mutate and produce errors inhibiting its ability to replicate and spread. However, some doctors and scientists worried that it could also enable the virus to mutate in a way that makes vaccines and treatments less effective.
"Even if the probability is very low, 1 in 10,000 or 100,000, that this drug would induce an escape mutant from which the vaccines we have do not cover, that could be catastrophic for the whole world actually," Dr. James Hildreth, CEO of Meharry Medical College in Nashville, Tenn., told the panel.
Nicholas Kartsonis, Merck's senior vice president of clinical research, said the company does not have data on the chances such a mutation could evolve. However, Kartsonis noted that Merck has not seen an increased rate of unusual changes to the spike protein, which the virus uses to attach to human cells, compared with a placebo group in clinical trials. Hildreth told Kartsonis that it is incumbent on Merck to estimate the likelihood of escape mutants.
"We are exploring the feasibility of using currently available public SARS CoV-2 to sequence databases to monitor for the emergence of these novel variants in the replicase complex as well as the spike proteins," Kartsonis said.
Patrick Harrington, the FDA's senior virology reviewer, said its unclear whether changes in the the spike protein associated with molnupiravir could substantially impact the evolution of the virus more broadly.
"For molnupiravir to affect Sars-CoV-2 evolution beyond a treated individual, the variants would also have to be transmissible, and at this time we do not know if this is possible to a significant degree," Harrington told the panel.
Merck submitted its application in October for the FDA to authorize molnupiravir on an emergency basis. No oral anti-viral medications have been cleared to treat Covid so far. Pfizer is similarly seeking approval for its own oral Covid treatment pill that it said was 89% effective in preventing hospitalization and death when administered with a popular HIV drug.
Merck, in its initial application and presentation to the FDA advisory committee on Tuesday, said the pill was 50% effective at reducing the risk of hospitalization or death in an interim analysis of 762 patients. However, analysis of the full population of about 1,400 participants showed lower efficacy rate of 30%, according to the company.
In a post-interim analysis of 646 participants, hospitalization and deaths were actually higher in the group that took the pill, at 6.2%, compared with those in the placebo group who didn't take the drug, at 4.2%.
Kartsonis told the FDA committee that the drop in hospitalization and death in the placebo group compared to those who took molnupirivar "doesn't add up."
"The second part of the study was after the interim analysis enrolled an older population, enrolled patients with older age and more diabetes," Kartsonis said. "One would have thought indeed that would be the case —- that you would see more mortality."
"However, there were also more women in the second part of the study, and that's been associated with what we can see with less risk, as well as more patients who were antibody positive," he said.
Participants in the trial were unvaccinated adults who faced a heightened risk of severe Covid because they were older than 60 or had pre-existing conditions such as diabetes, obesity, kidney disease, serious heart conditions, pulmonary disease and cancer.
Kartsonis told the FDA advisory committee that based on the interim analysis of 762 participants, molnupiravir significantly reduced the risk of hospitalization or death during the clinical trial, with nine out of 10 deaths occurring in the placebo group, which didn't receive the medication.
Merck did not identify any safety concerns associated with molnupiravir during the clinical trial, according to Kartsonis. A small number of patients experienced diarrhea, nausea and dizziness, he said.
"Our hospitals currently have more than 50,000 Americans struggling with this disease and as we enter the winter months, another surge is imminent, potentially in the setting of emerging variants of concerns," Kartsonis said. "We remain in dire need of novel effective well-tolerated and conveniently administered therapies to treat COVID 19" in outpatient settings, he added.
FDA scientists, in a briefing prepared for the committee, said animal studies found that the drug can result in reduced fetal body weight and abnormal bone formation. Merck never intended for pregnant women to use molnupiravir and did not include them in the clinical trial.
Mark Seaton, a research officer with the FDA's division of pharmacology and toxicology for infectious diseases, told the advisory panel that malformations of the eye, kidney and skeleton in rat fetuses indicate molnupiravir could cause harm to human fetuses if administered to pregnant women. However, the abnormal bone and cartilage formation observed in animals is not thought to be relevant to adult humans, according to Seaton.
Dr. Janet Cragin, a medical officer at the CDC's birth defects division, said it wouldn't be ethical to prescribe molnupiravir during pregnancy given the potential side effects, but denying the drug to a pregnant woman suffering from Covid is also problematic.
"I'm not sure you can ethically tell a pregnant woman who has Covi-19 that she can't have the drug if she decided that's what she needs," Cragin said, noting that her views do not represent the CDC.
"Pregnancy itself can be considered a risk factor for progression to severe Covid illness," she said. "We know that respiratory illnesses increase in severity and can become life threatening as pregnancy progresses and that's certainly true of Covid."
Dr. Hildreth, the CEO of Meharry Medical College, was unequivocal in his opposition.
"Do we want to reduce the risk for the mother by 30% of harm, while exposing the embryo and fetus to much higher risk of harm by using this drug? And my answer is no," Hildreth said. "And there's no circumstance in which I would advise a pregnant woman to take this drug."
Robert Heflich, director of the FDA's genetic and molecular toxicology division, said the risk of molnupiravir altering human genes in a clinical setting is low, given that the drug clearly was not mutagenic during a study in rodents. That study showed no increased mutation frequency in the liver or bone marrow of rodents, according to Merck.
However, the study was conducted as a follow-up to a previous investigation using rodents that was inconclusive about whether molnupiravir is mutagenic. Molnupiravir was found to be mutagenic during in vitro investigations using bacteria and hamster cells.
The data on whether molnupiravir is associated with gene mutation was a source of contention during the public comment portion of the meeting. Some experts and members of the public expressed concern that a single study was the basis for the conclusion about potential human risk. However, FDA experts said they believe the risk of gene mutation is low given molnupiravir's short five-day treatment period.
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