FDA Advisory Panel narrowly approves Merck’s Covid oral treatment pill, despite reduced effectiveness – .

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FDA Advisory Panel narrowly approves Merck’s Covid oral treatment pill, despite reduced effectiveness – .


The medicinal pill is seen with the Merck logo and the words “Molnupiravir” and “COVID-19” displayed on a background screen in this illustrative photo taken in Poland on November 5, 2021.
Jakub Porzycki | NurPhoto | Getty Images
A Food and Drug Administration advisory group narrowly approved the upse of the Covid oral treatment pill from Merck and Ridgeback Biotherapeutics on Tuesday, despite questions about the drug’s effectiveness, safety and whether it would help the virus mutate in 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. It is designed to treat adults with mild to moderate symptoms of Covid-19 who are at high risk of serious illness. The 800 milligram pill is taken every 12 hours for five days after symptoms appear.

The drug requires final clearance from the FDA and the Centers for Disease Control and Prevention before it is made available to the public in an emergency. The FDA is not obligated to follow the panel’s advice, but it often is.

Merck initially said the drug was over 50% effective in preventing hospitalizations and deaths, but a more comprehensive set of data presented to the FDA on Tuesday indicated that the drug was only 30% effective.

The FDA and Merck have both advised against the use of the drug in children and pregnant women. Molnupiravir has been shown to be fatal in embryos of pregnant rats, also causing birth defects and reducing the body weight of the fetus. It also caused other defects that interfered with bone growth in young puppies, as well as other abnormalities, according to the data.

Molnupiravir works by inducing the virus that causes the Covid mutation and producing errors that inhibit its ability to replicate and spread. However, some doctors and scientists were concerned that this would also allow 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 will induce an escape mutant that the vaccines we have do not cover, it could be catastrophic for the whole world in fact,” Dr James Hildreth, CEO of Meharry Medical College in Nashville, Tenn., Told the panel.

Nicholas Kartsonis, senior vice president of clinical research at Merck, said the company did not have data on the chances that such a mutation could evolve. However, Kartsonis noted that Merck did not see an increase in the rate of unusual changes in the spike protein, which the virus uses to attach to human cells, compared to a placebo group in clinical trials. Hildreth told Kartsonis that it was up to Merck to estimate the probability of the mutants escaping.

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

Patrick Harrington, the FDA’s senior virology reviewer, said it was not clear whether changes in the spike protein associated with molnupiravir could have a substantial impact on the evolution of the virus more broadly.

“For molnupiravir to affect the course of Sars-CoV-2 beyond a treated individual, the variants would also need to be transmissible, and at the moment we do not know if this is possible to a significant extent,” a Harrington told the panel.

Merck filed its request in October for the FDA to clear molnupiravir on an emergency basis. So far, no oral antiviral drugs have been authorized to treat Covid. Pfizer is also seeking approval for its own oral Covid treatment pill which it said was 89% effective in preventing hospitalization and death when given with a popular anti-HIV drug.

Merck, in its initial request and presentation to the FDA 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, analysis of the full population of around 1,400 participants showed a 30% lower efficacy rate, 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, at 6.2%, compared to those in the placebo group who did not take the drug. at 4.2%.
Kartsonis told the FDA committee that the decline in hospitalizations and deaths in the placebo group compared to those who took molnupirivar “does not match.”

“The second part of the study took place after the interim analysis recruited an older population, older patients and more diabetics,” Kartsonis said. “You 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 this was associated with what we can see with less risk, as well as more antibody positive patients,” he said. -he declares.

The trial participants were unvaccinated adults who faced an increased risk of severe Covid because they were over 60 or had pre-existing conditions such as diabetes, obesity, kidney disease, illness 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 in the clinical trial. placebo group, which did not receive the drug.

Merck did not identify any safety issues associated with molnupiravir during the clinical trial, according to Kartsonis. A small number of patients suffered from diarrhea, nausea and dizziness, he said.

“Our hospitals currently have over 50,000 Americans struggling with this disease and as we move into the winter months another increase is imminent, potentially as part of emerging variants of concerns,” Kartsonis said. “We urgently need new effective, well-tolerated and conveniently administered therapies to treat COVID 19” on an outpatient basis, he added.

FDA scientists, in a briefing prepared for the committee, said animal studies have found that the drug can lead to reduced fetal body weight and abnormal bone formation. Merck never planned for pregnant women to use molnupiravir and did not include them in the clinical trial.

Mark Seaton, a researcher in the FDA’s Division of Pharmacology and Toxicology of Infectious Diseases, told the advisory committee that eye, kidney and skeletal defects in rat fetuses indicate that molnupiravir may harm human fetuses. ‘it is administered to pregnant women. However, the abnormal bone and cartilage formation seen in animals is not considered relevant to adult humans, according to Seaton.

Dr Janet Cragin, a doctor in the Congenital Anomalies Division of the CDC, said it would be unethical to prescribe molnupiravir during pregnancy given the potential side effects, but denying the drug to a pregnant woman with Covid is also problematic.

“I’m not sure you can morally tell a pregnant woman with Covi-19 that she can’t have the drug if she decides it’s what she needs,” Cragin said, noting that her opinions do not represent the CDC.

“Pregnancy itself can be considered a risk factor for progression to severe Covid disease,” she said. “We know that respiratory illnesses increase in severity and can become fatal as pregnancy progresses and this is certainly true for Covid. “

Dr Hildreth, CEO of Meharry Medical College, was unequivocal in his opposition.

“Do we want to reduce the risk to the mother by 30% of damage, while putting the embryo and fetus at a much higher risk of damage by using this drug?” And my answer is no, ”Hildreth said. “And there is no circumstance in which I would advise a pregnant woman to take this medicine. “

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, since the drug was clearly not mutagenic in a clinical setting. rodent study. This study showed no increase in the frequency of mutations in the liver or bone marrow of rodents, according to Merck.

However, the study was conducted as part of a previous rodent study that could not determine whether molnupiravir is mutagenic. Molnupiravir has been shown to be mutagenic in in vitro studies using bacteria and hamster cells.

The data as to whether molnupiravir is associated with a gene mutation was a source of contention during the public comment portion of the meeting. Some experts and members of the public have expressed concern that a single study was the basis for the conclusion about the potential risk to humans. However, FDA experts said they believe the risk of gene mutation is low given the short five-day treatment period for molnupiravir.

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