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FDA Advisory Panel Narrowly Approves Merck’s Oral Covid Pills Despite Decreased Efficacy

The medicine pill is visible with the Merck logo and the words Molnupiravir and COVID-19 displayed on the screen in the background in this photo taken in Poland on November 5, 2021.

Jakub Porzycki | NurPhoto | Getty Images

An FDA advisory panel on Tuesday narrowly endorsed oral pills to treat Covid from Merck and Ridgeback Biotherapeutics, despite questions about the drug’s efficacy, safety, and whether it could mutate the virus into even more dangerous variants. …

The FDA’s Antimicrobial Advisory Committee, by 13 votes to 10, recommended emergency authorization for molnupiravir, an oral antiviral drug that was initially heralded as a potential game changer in the battle against Covid. It is designed to treat adults with mild to moderate symptoms of Covid-19 who are at high risk of severe illness. An 800 mg tablet is taken every 12 hours for five days after symptoms start.

The drug requires final approval from the FDA and the Centers for Disease Control and Prevention before it becomes available to the public in an emergency. The FDA is not obligated to heed the advice of the panel, but it often does.

Merck originally said the drug was more than 50% effective in preventing hospitalizations and death, but a more complete set of data presented to the FDA on Tuesday showed the drug was only 30% effective.

The FDA and Merck recommend that children and pregnant women not use the drug. Molnupiravir has been found to be fatal to embryos in pregnant rats, as well as to cause birth defects and reduce fetal weight. It also caused other defects that interfered with bone growth in young puppies, along with other abnormalities, the data shows.

Molnupiravir works by inducing a virus that causes Covid to mutate and cause errors that prevent it from replicating and spreading. However, some doctors and scientists feared that this could also cause the virus to mutate, making vaccines and treatments less effective.

“Even if the probability is very small, 1 in 10,000 or 100,000, that this drug will cause a runaway mutant for which the vaccines we have do not cover, in fact it could have disastrous consequences for the whole world.” p James Hildreth, CEO of Meharri College of Medicine in Nashville, Tennessee, the group said.

Nicholas Kartsonis, Merck’s senior vice president of clinical research, said the company had no data on the chances of developing such a mutation. However, Kartsonis noted that in clinical trials, Merck did not observe an increased rate of unusual changes in the spike protein, which the virus uses to attach to human cells, compared to the placebo group. Hildreth told Kartsonis that Merck should assess the likelihood of the mutants escaping.

“We are exploring the possibility of using the currently available publicly available SARS CoV-2 in sequence databases to track the emergence of these new variants in the replicase complex as well as spike proteins,” said Kartsonis.

Patrick Harrington, senior virology columnist for the FDA, said it was unclear if changes in the spike protein associated with molnupiravir could significantly affect the evolution of the virus more broadly.

“For molnupiravir to influence the evolution of Sars-CoV-2 outside of the treated individual, the variants must also be transmissible, and at this time we do not know if this is largely possible,” Harrington told the group.

In October, Merck applied to the FDA for an emergency use of molnupiravir. Oral antiviral drugs have not yet been approved for the treatment of Covid. Pfizer is also seeking approval for its own oral Covid pill, which it says is 89% effective in preventing hospitalization and death when used with a popular HIV drug.

Merck, in its initial statement and submission to the FDA’s advisory committee on Tuesday, said the pill was 50% effective in reducing the risk of hospitalization or death in an interim analysis of 762 patients. However, according to the company, analysis of the entire population of about 1,400 participants showed a lower level of effectiveness – 30%.

In a post-interim analysis of 646 participants, hospitalization and mortality were actually 6.2% higher in the pill group, compared to the placebo group, which did not take the drug, by 4.2%.

Kartsonis told the FDA committee that the drop in hospital admissions and deaths in the placebo group compared to those on molnpirivar “does not add up.”

“The second part of the study was carried out after the interim analysis included the elderly population, patients with older age and more severe diabetes,” said Kartsonis. “One would think that this is indeed the case – that you will see more mortality.”

“However, there were more women in the second part of the study as well, and this is because we see less risk and also more patients who test positive for antibodies,” he said.

The study participants were unvaccinated adults who faced an increased risk of severe Covid because they were over 60 or had preexisting medical conditions such as diabetes, obesity, kidney disease, serious heart disease, lung disease, and cancer.

Kartsonis told an FDA advisory committee that, based on an interim analysis of 762 participants, molnupiravir significantly reduced the risk of hospitalization or death in a clinical trial, with nine out of 10 deaths occurring in the placebo group that did not receive the drug.

Merck has not identified any safety issues with molnupiravir during the clinical trial, Kartsonis said. A small number of patients experienced diarrhea, nausea and dizziness, he said.

“We currently have more than 50,000 Americans battling this disease in our hospitals, and another surge is inevitable as we enter the winter months, perhaps in the context of emerging problem options,” said Kartsonis. “We remain in dire need of new, effective, well-tolerated and comfortable COVID 19 treatments” on an outpatient basis, he added.

FDA scientists, in a briefing prepared for the committee, said studies in animals have shown that the drug can lead to a decrease in fetal weight and abnormal bone formation. Merck never planned to use molnupiravir in pregnant women or included them in clinical trials.

Mark Seaton, FDA FDA Infectious Disease Pharmacology and Toxicology Researcher, told the advisory group that eye, kidney, and skeletal malformations in fetal rats indicate that molnupiravir may harm the human fetus when administered to pregnant women. However, Seaton said the abnormal bone and cartilage formation seen in animals does not apply to adults.

Dr. Janet Crajin, a medical officer at the CDC’s Birth Defects Unit, said it would be unethical to prescribe molnupiravir during pregnancy given the potential side effects, but refusing the drug to a pregnant woman suffering from Covid is also problematic.

“I’m not sure what it is ethically possible to tell a pregnant woman who has Covi-19 that she cannot take the drug if she has decided that this is what she needs,” Craigin said, noting that her views do not reflect the CDC.

“Pregnancy itself can be seen as a risk factor for the progression of severe Covid disease,” she said. “We know that respiratory illnesses are becoming more serious and can become life-threatening as pregnancy progresses, and this is certainly true of Covid.”

Dr. Hildreth, CEO of Meharri College of Medicine, strongly opposes.

“Do we want to reduce the risk to the mother by 30%, putting the embryo and fetus at a much higher risk of harm when using this drug? And my answer is no, ”Hildreth said. “And there are no circumstances under 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 human genes being altered by molnupiravir in a clinical setting is low given that the drug was clearly not mutagenic in a rodent study. According to Merck, this study showed no increase in mutation rates in the liver or bone marrow of rodents.

However, this study was carried out as a continuation of a previous study using rodents, which did not lead to a conclusion about whether molnupiravir is mutagenic. In vitro studies using bacteria and hamster cells have shown the mutagenic effect of molnupiravir.

Data on whether molnupiravir is related to a gene mutation sparked controversy during part of the public comment at the meeting. Some experts and members of the public expressed concern that a single study was the basis for a conclusion about the potential risk to humans. However, FDA experts said they believed the gene mutation risk was low given the short five-day treatment period with molnupiravir.


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