Pill for covid-19 raises some red flags with FDA

Agency to seek expert input on risks during pregnancies

A high school student in Pristina, Kosova, gets a covid-19 shot from a health official Friday. Kosovar health authorities have started a campaign to vaccinate high school teenagers to help control the spread of covid-19 in that country.
(AP/Visar Kryeziu)
A high school student in Pristina, Kosova, gets a covid-19 shot from a health official Friday. Kosovar health authorities have started a campaign to vaccinate high school teenagers to help control the spread of covid-19 in that country. (AP/Visar Kryeziu)


Federal health regulators say an experimental covid-19 pill from Merck is effective against the virus, but they will seek input from outside experts on risks of birth defects and other potential problems during pregnancy.

The Food and Drug Administration posted its analysis of the pill ahead of a public meeting next week where academic and other experts will weigh in on its safety and effectiveness. The agency isn't required to follow the group's advice.

The FDA scientists said their review identified several potential risks, including possible toxicity to developing fetuses and birth defects that were identified in studies of the pill in animals.

Given those risks the FDA will ask its advisers Tuesday whether the drug should never be given during pregnancy or whether it could be made available in certain cases.

Under that scenario, the FDA said the drug would carry warnings about risks during pregnancy, but doctors would still have the option to prescribe it in certain cases where its benefits could outweigh its risks for patients.

Given the safety concerns, the FDA said Merck agreed that the drug would not be used in children.

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Other side effects were mild and rare, with about 2% of patients experiencing diarrhea.

Regulators also noted that Merck collected far less safety data overall on its drug than was gathered for other covid-19 therapies.

"While the clinical safety data base was small, there were no major safety concerns identified," FDA reviewers concluded.

Additionally, the FDA flagged a concern that Merck's drug led to small changes in the coronavirus' signature spike protein, which it uses to penetrate human cells. Theoretically, the FDA cautioned, those changes could lead to dangerous new variants.

The FDA will ask its independent advisers to discuss all those issues and then vote on whether the drug's overall benefits outweigh its risks.

All covid-19 drugs currently authorized by the FDA require an injection or IV and can be given only by health professionals. If authorized, Merck's drug would be the first that U.S. patients could take at home to ease symptoms and speed recovery. It is already authorized for emergency use in the United Kingdom.

The meeting marks the first time regulators have publicly reviewed a new drug for covid-19, reflecting the intense interest and scrutiny of a pill that could soon be used by millions of Americans.

The drug, molnupiravir, has been shown to significantly cut the rate of hospitalizations and deaths among people with mild-to-moderate coronavirus infections.

Merck's drug uses a novel approach to fight covid-19: it inserts tiny mutations into the coronavirus' genetic code to stop the virus from reproducing.

But that genetic effect has raised concerns that in rare cases the drug could cause birth defects or even spur more virulent strains of the virus.

Pregnant women were excluded from Merck's study, and women and men in the study were instructed to use contraception or abstain from sex.

For its part, Merck says results from two company studies in rodents show that the drug does not cause mutations or damage to DNA at the doses studied.

FDA reviewers also confirmed previously reported interim results from Merck that the pill cut the rate of hospitalization and death by about half among patients with early symptoms of covid-19 who faced increased risk because of health problems.

However, Friday morning Merck announced updated results from the same study that showed a smaller benefit from the drug.

EFFICACY LOWER

The lower efficacy is a disappointment for the drug that health officials around the world are counting on as a critical tool to save lives and reduce the covid-19 burden on hospitals. It increases the importance of a similar, apparently more effective, offering from Pfizer that is also under review by the FDA.

The rival drugmaker has submitted its own antiviral for FDA review after initial study results showed that it cut the combined rate of hospitalization and death by nearly 90%.

Pfizer's drug is part of a decades-old family of antiviral pills known as protease inhibitors, which revolutionized the treatment of HIV and hepatitis-C. They work differently than Merck's pill and haven't been linked to the kind of mutation concerns that have been raised with Merck's drug.

In briefing documents posted to the FDA's website Friday, agency reviewers did not take a position on whether the Merck drug should be authorized, although they found that the clinical trial data did not show any major safety concerns and that the drug was effective in preventing severe disease.

The reviewers said they had become aware of the updated efficacy estimate earlier this week and were still reviewing the data. A panel of advisers to the FDA is to meet Tuesday to discuss Merck's treatment and vote on whether to recommend authorizing it to treat high-risk covid-19 patients.

Among more than 1,400 adults in a company study, molnupiravir reduced the combined risk of hospitalization and death by 30%, less than the 50% initially reported based on incomplete results.

Nearly 7% of patients who received Merck's drug within five days of covid-19 symptoms ended up in the hospital and one died. That compared with 10% of patients hospitalized who were taking the placebo and nine deaths.

Dr. David Boulware, an infectious disease researcher at the University of Minnesota, said he expects the drug to receive emergency authorization. If the expert committee endorses it and the FDA heeds the recommendation, the treatment could be authorized in the United States as soon as next week.

"The reduction in hospitalization is a little bit less, but there is still a big mortality benefit if you start early," Boulware said.

Still, he said, molnupiravir will probably be deemed a lower-tier treatment, an alternative choice for people who can't get or don't want more effective treatments.

Merck didn't study its drug in people who were vaccinated for covid-19. But the FDA will ask advisers to recommend which patients may stand to benefit the most from the drug, based on vaccination status and underlying health problems.

While Merck's drug is likely to be the first pill for coronavirus in the U.S., more are expected to follow.

BRITAIN STUDY

Britain, the first country in the world to approve Merck's covid pill, is expected to start providing the therapy to its population through a national study in about 10,000 people.

Run by the University of Oxford, organizers of the study are to begin recruiting participants early next month, giving the country key data on how well the molnupiravir works in vaccinated people.

The results will allow the National Health Service to better plan the rollout of antiviral treatments to the people who need them most, the health department said in an emailed statement. The drug provides the U.K. with another tool to fight covid-19 as the country advances with an aggressive campaign to administer booster shots and Europe combats another wave of infections.

Early moves by countries including the U.K. to secure covid pills have raised concern that lower-income nations struggling to vaccinate their populations will be left behind again, though Merck and Pfizer Inc. have reached licensing agreements aimed at widening access.

Merck's drug earlier this month was authorized for use in the U.K. in people with mild to moderate covid and with at least one risk factor for developing severe illness. The U.K. also unveiled deals to secure the Merck and Pfizer antivirals.

"Molnupiravir is a ground-breaking treatment that will help the most vulnerable, and we are working at pace across the government and with the NHS to set out plans to deploy it to patients through a national study as soon as possible," the health department wrote.

The study, called Panoramic, is expected to be the initial route for giving people access to antivirals in the U.K. Patients in the study will be asked to provide updates on their health to show how the treatments are working.

Information for this article was contributed by Matthew Perrone of The Associated Press; by Rebecca Robbins of The New York Times; and by James Paton and Emily Ashton of Bloomberg News.



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