FDA Panel Backs Full Approval of Paxlovid for COVID-19

An FDA panel recommended the agency grant full approval to nirmatrelvir-ritonavir (Paxlovid) for treating high-risk COVID-19.

By a vote of 16-1 on Thursday, the Antimicrobial Drugs Advisory Committee said the totality of evidence supports the traditional approval; since late 2021, given as a 5-day oral course soon after symptoms appear, the antiviral has been widely used in the high-risk setting under an emergency use authorization.

“Besides oxygen, Paxlovid has probably been the single most important treatment tool in this epidemic, and it continues to be,” said Richard Murphy, MD, MPH, of the VA White River Junction Medical Center in Vermont.

“I was influenced by the benefit on the serious outcomes, of hospitalizations and deaths, and particularly relevant, of course, people who may not respond optimally to vaccines,” said Nina Clark, MD, of Loyola University’s Stritch School of Medicine in Maywood, Illinois.

“It seems that the toxicities are manageable,” based on what was presented, she added.

The lone “no” vote came from Terry Gillespie, a patient representative on the committee, of Plainfield, Illinois.

“I’m overweight and I’ve had COVID four to five times and never once was Paxlovid even offered to me,” she explained. “I don’t feel that the doctors really know how to use it.”

Support for the antiviral was supported by data from the phase III EPIC-HR (high risk) trial, which demonstrated an 86% relative reduction in the risk for COVID-related hospitalization or death from any cause through 28 days, with the primary composite outcome occurring at rates of 0.7% among patients assigned to the antiviral and 6.8% for those on placebo.

Subgroup analyses of EPIC-HR and a trial in standard-risk patients (EPIC-SR) showed the largest benefit with nirmatrelvir-ritonavir in unvaccinated patients without a prior infection, though the vaccinated and seropositive also experienced better outcomes, with absolute rates of hospitalization and death below 1% versus about 2% with placebo.

“I do share the concern with absolute rate … because there are side effects,” said committee chair Lindsey Baden, MD, of Harvard Medical School Boston. But he noted that “the strength of the protection of vaccination is not fixed in time, we have a moving parameter that we don’t fully understand.”

Although the evidence from trials showed that nirmatrelvir-ritonavir and placebo patients had similar rates of viral rebound, and that rebound cases were mild in nature, committee members agreed the public discourse around rebound will be difficult to shake.

“I think there is a broad lack of understanding, not only among physicians but also among patients…a distressingly large number of patients that told me oh, I was told that I shouldn’t take it because of rebound,” said Sankar Swaminathan, MD, of University of Utah School of Medicine in Salt Lake City.

On the matter of adverse events, Stephanie Troy, MD, a clinical reviewer at the FDA, described a scenario that showed how each individual must be evaluated for benefit independently, given the risks for drug-drug interactions.

“Clearly it’s important to weigh the drug drug interactions and the risks that those pose,” said Adaora Adimora, MD, MPH, of University of North Carolina at Chapel Hill, North Carolina.

But Adimora also gave the drug the thumbs up, because “it’s also clinically meaningful for the population as a whole, given the high incidence of COVID-19 in the U.S.”

“It is especially important given the limited availability of effective oral agents,” she added.

While the FDA is not required to follow the advice of its advisory committees, it typically does.