In this illustration photo, taken in Poland on Nov.
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An advisory body to the Food and Drug Administration on Tuesday endorsed the use of Merck and Ridgeback Biotherapeutics’ oral Covid treatment pill despite questions about the drug’s effectiveness and safety and whether it would help the virus mutate into even more dangerous variants.
The FDA’s Advisory Committee on Antimicrobial Drugs voted 13-10 in favor of recommending an emergency approval of molnupiravir, an oral antiviral drug that was originally hailed as a potential game changer in the fight against Covid. It is designed to treat adults with mild to moderate symptoms of Covid-19 who are at high risk of developing serious illness. The 800 milligram pill is taken every 12 hours after symptoms appear for five days.
The drug requires final approval from the FDA and the Centers for Disease Control and Prevention before being made available to the public in an emergency. The FDA does not need to follow the panel’s advice, but it often does.
Merck originally said the drug was more than 50% effective in preventing hospitalizations and death, but a more complete dataset presented to the FDA on Tuesday found the drug was only 30% effective.
Both the FDA and Merck advised against using the drug in children and pregnant women. Molnupiravir has been found to be fatal to embryos from pregnant rats, and to cause birth defects and reduce the weight of the fetus. It also caused other defects that disrupted bone growth in young puppies, along with other abnormalities, the data show.
Molnupiravir works by causing the virus to mutate the Covid, and creating errors that inhibit its ability to replicate and spread. However, some doctors and scientists feared that this could also allow the virus to mutate, making vaccines and treatments less effective.
“Even if the odds are very small, 1 in 10,000 or 100,000, that this drug will cause an escape mutant that the vaccines we have don’t cover, it could actually be catastrophic for the whole world,” Dr. James Hildreth, CEO of Meharry Medical College in Nashville, Tennessee, told the panel.
Nicholas Kartsonis, senior vice president of clinical research at Merck, said the company had no data on the chances of such a mutation developing. However, Kartsonis noted that in clinical trials, Merck did not see an increased rate of unusual changes in the spike protein that the virus uses to attach to human cells when compared to a placebo group. Hildreth told Kartsonis that it was Merck’s job to estimate the likelihood of flight mutants.
“We are investigating the possibility of using currently available public SARS-CoV-2 databases to sequence databases to monitor the occurrence of these new variants in the replicase complex as well as the spike proteins,” said Kartsonis.
Patrick Harrington, FDA senior virology reviewer, said it was unclear whether changes in the spike protein associated with molnupiravir could significantly affect the development of the virus in general.
“In order for molnupiravir to affect the development of Sars-CoV-2 beyond a treated individual, the variants would also have to be transmissible, and we do not currently know whether this is possible to any significant extent,” Harrington told the panel.
Merck filed its application for emergency approval of molnupiravir with the FDA in October. So far, no oral antiviral drugs have been approved for the treatment of Covid. Pfizer is similarly filing for approval for its own oral Covid treatment pill, which it claims was 89% effective in preventing hospital stays and death when administered with a popular HIV drug.
Merck said in its first use and presentation to the FDA advisory committee on Tuesday that the pill reduced the risk of hospitalization or death by 50% in an interim analysis of 762 patients. However, the analysis of the total population of around 1,400 participants showed a lower effectiveness rate of 30%, according to the company.
In a post-interim analysis of 646 participants, hospitalizations and deaths were actually higher in the group who took the pill (6.2%) than in the placebo group who did not take the drug (4.2%).
Kartsonis told the FDA committee that the decline in hospital stays and deaths in the placebo group when compared to those who took molnupirivar was “inconsistent”.
“The second part of the study, after including an older population in the interim analysis, was patients with older age and more diabetes,” said Kartsonis. “Indeed, one would have thought that would be the case – that you would see more mortality.”
“However, there were more women in the second part of the study, and that was linked to what we can see with less risk and more patients with antibody positive,” he said.
Participants in the study were unvaccinated adults who were at increased risk of severe Covid because they were older than 60 or had previous illnesses such as diabetes, obesity, kidney disease, severe heart disease, lung 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 who did not receive the drug.
According to Kartsonis, Merck did not identify any safety concerns with molnupiravir during the clinical trial. A small number of patients had diarrhea, nausea and dizziness, he said.
“Our hospitals currently have more than 50,000 Americans struggling with the disease, and another spike is imminent as the winter months begin, possibly amid emerging varieties of concerns,” said Kartsonis. “We still urgently need novel, effective, well-tolerated and easily administered therapies for the treatment of COVID 19” in the outpatient setting, he added.
FDA scientists said in a brief prepared for the committee that animal studies found the drug may lead to decreased fetus body weight and abnormal bone formation. Merck never intended that pregnant women use molnupiravir and did not include it in the clinical trial.
Mark Seaton, a research fellow with the FDA’s Department of Pharmacology and Toxicology for Infectious Diseases, told the advisory panel that malformations of the eye, kidney and skeleton in rat fetuses suggest that molnupiravir could harm human fetuses if given to pregnant women. However, the abnormal bone and cartilage formation observed in animals is not considered relevant to adult humans, according to Seaton.
Dr. Janet Cragin, a doctor in the CDC’s Department of Birth Defects, said it would not be ethical to prescribe molnupiravir during pregnancy given the potential side effects, but denying the drug to a pregnant woman with Covid was also problematic.
“I’m not sure if you can ethically tell a pregnant woman with Covi-19 that if she decides she needs it, she can’t get the drug,” Cragin said, noting her views on the CDC represented.
“Pregnancy itself can be seen as a risk factor for progression to severe Covid disease,” she said. “We know that as pregnancy progresses, respiratory diseases can become more severe and life-threatening, and that certainly applies to Covid.”
Dr. Hildreth, the CEO of Meharry Medical College, clearly disagreed.
“Do we want to reduce the risk of harm to the mother by 30%, while the embryo and fetus are at a much higher risk of harm from using this drug? And my answer is no,” Hildreth said. “And there is no point in which I would advise a pregnant woman to take this drug.”
Robert Heflich, director of the FDA’s Department of Genetic and Molecular Toxicology, said the risk of molnupiravir altering human genes in a clinical setting was small because the drug was clearly not mutagenic during a study in rodents. According to Merck, this study did not show an increased mutation frequency in the liver or in the bone marrow of rodents.
However, the study was carried out as a follow-up to an earlier rodent study that did not provide a clear indication of whether molnupiravir is mutagenic. Molnupiravir was found to be mutagenic in in vitro studies with bacteria and hamster cells.
The data on whether molnupiravir is linked to a gene mutation was a subject of controversy during the public comment at the meeting. Some experts and members of the public expressed concern that a single study would be the basis for drawing conclusions about the potential risk to humans. However, FDA experts said they consider the risk of gene mutation to be low, given molnupiravir’s short five-day treatment period.