Oral antiviral, Paxlovid, receives strong support for traditional approval by FDA panel

An FDA panel suggested that nirmatrelvir-ritonavir (Paxlovid) be given full approval for the treatment of high-risk COVID-19.

The Antimicrobial Drugs Advisory Committee voted 16-1 on Thursday to support the traditional approval of the oral antiviral, which has been widely used since late 2021 under an emergency use authorizationopens in a new tab or window to reduce the risk of hospitalization or death in outpatients at risk for severe outcomes.
“Aside from oxygen, Paxlovid has been and continues to be the single most important treatment tool in this epidemic,” said Richard Murphy, MD, MPH, of the White River Junction VA Medical Center in Hartford, Vermont.

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

“It appears that the toxicities are manageable,” she added, based on the information provided.

Terry Gillespie, a patient delegate on the committee from Plainfield, Illinois, cast the lone “no” vote.

“I’m overweight, and I’ve had COVID four or five times, but Paxlovid was never offered to me,” she added. “I don’t think the doctors understand how to use it.”

The phase III EPIC-HR (high risk) trial showed an 86% relative decrease in the risk of COVID-related hospitalization or death over 28 days with a 5-day course of treatment early after symptom onset. This primary composite outcome happened at a rate of 0.7% among antiviral patients and 6.8% among placebo patients.

As debate during Thursday’s meeting went round and round, many members asked: Who is truly at high risk and who would benefit the most?

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

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

Although trial evidence revealed that nirmatrelvir-ritonavir and placebo patients experienced comparable rates of viral rebound and that rebound cases were mild in nature, committee members agreed that the public discourse surrounding rebound will be difficult to shake.

“I believe there is widespread misunderstanding, not only among physicians but also among patients,” said Sankar Swaminathan, MD, of the University of Utah School of Medicine in Salt Lake City. “A distressingly large number of patients told me, ‘Oh, I was told not to take it because of rebound.'”

Despite the near-unanimous vote in favor of complete approval, the risk-versus-benefit debate was heated.

Stephanie Troy, MD, an FDA clinical reviewer, outlined scenarios that demonstrated how, given the risks of drug-drug interactions, each person must be evaluated for benefit independently.

“Clearly, it’s important to weigh the risks of drug-drug interactions,” said Adaora Adimora, MD, MPH, of the University of North Carolina at Chapel Hill. However, Adimora approved of the drug because “it’s also clinically meaningful for the population as a whole, given the high incidence of COVID-19 in the United States.”

“This is especially important given the scarcity of effective oral agents,” she adds.

While the FDA is not obliged to heed the recommendations of its advisory committees, it usually does.