New study results disclosed by Merck & Co. on Friday indicated its COVID-19 pill molnupiravir may not be as effective as the company previously stated, a finding that could change how the Food and Drug Administration and its advisers view the drug at an upcoming meeting.
In October, Merck said the drug reduced hospitalizations and deaths by nearly 50% in a large trial among people who had mild or moderate COVID-19. That announcement was based on a preliminary results from 775 trial participants, and the data were so convincing that outside study monitors directed Merck to stop testing early.
The result positioned Merck to bring the first oral COVID-19 treatment to market, a potentially significant tool to control outbreaks and protect vulnerable people. The company quickly filed for an emergency clearance in the U.S., an application FDA advisers will scrutinize at a public hearing Tuesday. The Biden administration has already preordered more than 3 million treatment courses. The drug was cleared for use in the U.K. on Nov. 4, and a regulatory review is underway in Europe as well.
But the final study results Merck announced Friday, from all 1,433 volunteers enrolled in the study, raise questions about the drug's benefit. Overall, treatment reduced the relative risk of hospitalization and death in the trial by 30% versus placebo. Roughly 10% of the 699 people who received a placebo were hospitalized or died, compared to about 7% of the 709 patients treated with molnupiravir, Merck said.
Nine people given a placebo died, according to Merck, versus only one who was treated with molnupiravir. The drug's side effect profile was consistent with what the company previously reported.
Briefing documents posted by the FDA on Friday indicated the agency is ready to authorize molnupiravir based on the interim study results, but struggling to decide who should be eligible for treatment. Merck has sought clearance for people with mild or moderate COVID-19 who are at "high risk" of worse outcomes, a similar group to those who can receive infused or injectable antibody drugs from Regeneron, Eli Lilly and Vir Biotechnology.
But staff scientists raised some concerns about molnupiravir, including around evidence from animal studies of impaired bone and cartilage growth as well as the potential for birth defects. And because molnupiravir works by introducing a series of errors into a virus' genetic code, FDA scientists questioned whether the drug might trigger unwanted long-term effects or create new coronavirus variants.
Additionally, the available safety data is limited, meaning rare side effects that haven't been detected in testing could occur when the drug is cleared for use in the broader population, FDA reviewers said.
The agency plans to ask its advisors who should be authorized to receive the drug. The FDA and Merck agree that children won't be eligible, and molnupiravir hasn't proven effective for patients who are already hospitalized. But the agency suggested treatment may not be authorized for pregnant women, too.
The drug also didn't help patients who were "seropositive," or had antibodies against the coronavirus because of a previous infection, though the FDA appears wary of excluding that group — or vaccinated people — as a whole. Each have some risk of hospitalization or death, particularly the subsets of people more likely to develop severe disease, the agency said.
All of these conclusions were reached before Merck released its final efficacy results, which indicated lower effectiveness for the drug overall. Surprisingly, among the half of study participants who weren't included in the initial analysis, 4.7% given placebo were hospitalized or died, compared to 6.2% of those who received molnupiravir.
Merck didn't offer any explanations for why the drug seems to have performed worse, though Jefferies analysts speculated there may have been more seropositive patients involved, driving efficacy downward.
In an amendment to its briefing documents, the FDA indicated its assessment of molnupiravir may now differ from the original review. The agency will provide "additional key safety and efficacy results" at Tuesday's hearing.
The limitations could disadvantage Merck's drug from a COVID-19 pill developed by Pfizer which is also being reviewed by the FDA. Though it can be difficult to compare medicines across trials, Pfizer's drug, known as Paxlovid, lowered the risk of hospitalization and death by about 90% in a large study. That number could also change once the final numbers are tallied, however.
Paxlovid is administered with ritonavir, an HIV medicine that's meant to extend Paxlovid's effects but interacts with many other types of drugs and could therefore limit use.
Pfizer shares climbed 6% on Friday, while Merck's sank by about 4%.
Merck is developing molnupiravir in partnership with Ridgeback Biotherapeutics, which licensed the drug from Emory University.