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Data from the pivotal trial for the COVID-19 antiviral pill molnupiravir detailed the waning efficacy that troubled FDA reviewers and advisors.

An interim analysis of the phase II/III MOVe-OUT trial showed a substantial benefit with a 5-day course started within 5 days of symptom onset in ambulatory, but high-risk, unvaccinated adults, reported Carisa De Anda, PharmD, of Merck in Kenilworth, New Jersey, and colleagues in the .

All-cause hospitalization and death through day 29 were nearly halved compared with placebo (7.3% vs 14.1%, P=0.001) in the first half of patients randomized.

However, that 6.8 percentage point advantage dropped to just 3.0 percentage points (6.8% molnupiravir vs 9.7% placebo, P=0.001) in the full analysis of all 1,433 participants randomized before the trial was stopped early for efficacy.

Still, the researchers called it "an improvement in an outcome that is potentially meaningful for patients, health care systems, and public health."

The small molecule drug has broad spectrum activity against RNA viruses like SARS-CoV-2 by increasing the viral mutation rate to the point that the virus can no longer replicate and dies through so-called viral error catastrophe.

Oral medications will be essential in the fight against COVID-19, although vaccines remain the primary mode of protection, noted Richard Whitley, MD, of the University of Alabama at Birmingham, in an accompanying . That's especially true for the developing world, with whom drugmaker Merck has indicated it will share the patents through the WHO for generic production there.

The FDA's analysis of the data released ahead of its November 30 advisory panel meeting for consideration of an emergency use authorization (EUA) suggested that the mediocre results should be weighed against the drug's mutagenic and teratogenic potential.

The advisory committee narrowly voted in favor of an EUA, 13-10, but even those who voted yes acknowledged the modest efficacy and safety concerns.

"I was struck by a modest benefit in a highly adherent trial population and then the unclear efficacy in the latter half of the trial when we had increased circulation of the Delta variant," said Daniel Horton, MD, of Rutgers School of Public Health, who voted no, at the panel meeting. "I think there's the potential for increased pressures for viral evolution in the setting of lower adherence in the real world."

There were other potential explanations for the lessening of the drug effect besides predominant circulating variant, Whitley pointed out. The researchers noted that "comparison of patient characteristics does not suggest a clear, single cause for the difference between the interim and the all-randomized analyses, which may have been the result of the accumulation of lesser effects of multiple factors."

In the trial, subgroup analysis didn't favor molnupiravir for patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes.

Among the almost half of patients whose viral sequence was available, molnupiravir appeared active against the Delta, Gamma, and Mu variants circulating at the time. Omicron had not yet emerged at the time of the trial, which started screening patients in May and completed enrollment in October.

Importantly, the trial included only patients with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for progression to severe illness (including age >60 years, obesity, diabetes, or cardiovascular disease).

While the trial mandated that double-blind treatment with molnupiravir or placebo begin within 5 days of infection or symptom onset, this occurred within 72 hours in 47.7% of participants.

Whitley emphasized, though, that "we must strive for therapy to begin within 72 hours in all patients, as shown in studies of influenza." Phase II trials of molnupiravir have also shown lower efficacy in patients who had symptoms for more than 3 to 5 days or required hospitalization, he noted.

Pregnant women were also excluded from the MOVe-OUT trial, given that the drug is mutagenic in Chinese hamster ovary cells. While Whitley cited "a body of data that address concerns related to the potential mutagenicity and genotoxicity of molnupiravir," the FDA reviewers did not recommend an EUA for people who are lactating or for children, given risks of embryo-fetal toxicity and bone and cartilage toxicity.

In the trial, adverse events and those considered related to treatment were similar between groups. The most common adverse events deemed related to the trial regimen were diarrhea (1.7% with molnupiravir vs 2.1% with placebo), nausea (1.4% vs 0.7%), and dizziness (1.0% vs 0.7%).

Even so, the small safety database means careful monitoring for the emergence of side effects will be required, Whitley said.

The other frontrunner in the race to develop an oral medication effective against COVID-19 in the outpatient setting is Pfizer's protease inhibitor nirmatrelvir (Paxlovid); Gilead's remdesivir (Veklury), an intravenous therapy, has shown success in the outpatient setting as well, and an .

"Data for both medications demand peer review," Whitley wrote. "The availability of medications with different mechanisms of action offers the opportunity for creating combination therapies that are potentially synergistic and less likely to lead to resistance."

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