FDA Committee Endorses Full Approval of Paxlovid for COVID-19 Treatment

Today, the US Food and Drug Administration (FDA) Antimicrobial Drugs Advisory Committee (AMDAC) voted in favor of approving a New Drug Application (NDA) for Paxlovid.

Since December 22, 2021, Paxlovid has been available under Emergency Use Authorization (EUA). With this vote, AMDAC has recommended Pfizer’s Paxlovid be officially approved to treat adults with mild-to moderate COVID-19, who are at high risk of severe or fatal disease progression.

During a daylong meeting, AMDAC reviewed data presentations from Pfizer, Inc. and the FDA. After considering the evidence and asking detailed follow-up questions, 16 of 17 AMDAC voting members responded “YES” to the following question:

Is the overall benefit-risk assessment favorable for Paxlovid when used for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death?

For decades, NDAs have been a vehicle for the regulation and control of new drugs in the United States. This approval indicates the FDA's Antimicrobial Drugs Advisory Committee believes there is sufficient evidence that the benefits of Paxlovid outweigh the risks.

“I’d say besides oxygen, Paxlovid has been the single most important treatment tool in this epidemic, and it continues to be,” AMDAC member Richard Murphy said, explaining his affirmative vote. “We still have many groups that stand to benefit from the use of Paxlovid.”

Paxlovid is an orally administered combination of nirmatrelvir and ritonavir copackaged tablets. The indicated dosage is for patients to receive nirmatrelvir 300 mg + ritonavir 100 mg twice a day for 5 days.

Prior to this Paxlovid approval, remdesivir was the only FDA-approved therapy for the treatment of mild-to-moderate COVID-19 disease. Molnupiravir remains available under EUA for mild-to-moderate disease.

Efficacy

A key issue discussed during today’s AMDAC meeting was whether Paxlovid would retain efficacy in adults who are vaccinated against COVID-19 or had a prior COVID-19 infection. The FDA noted the vast majority of Americans have baseline COVID-19 immunity. They cited data from the US Centers for Disease Control and Prevention, which found 79% of all adults and 94% of adults ≥ 65 years had completed a primary COVID-19 vaccine series, while 19% of all adults and 41% of adults ≥ 65 years had also received a booster dose. Even unvaccinated individuals, however, were found to have high levels of seropositivity.

“Regardless of vaccination status or prior infection, trial results support the efficacy of Paxlovid for the treatment of high-risk adults with mild-to-moderate COVID-19,” said Debra Birnkrant, MD, director of the FDA Division of Antivirals.

Birnkrant also noted Paxlovid is expected to retain efficacy against new and emerging COVID-19 variants, most notably of the predominant Omicron lineage. “Review of nonclinical virology, genomic surveillance, and clinical virology data…show that Paxlovid is expected to retain clinical efficacy in high-risk adults with COVID-19 caused by the SARS-CoV-2 Omicron variant.”

Safety

Safety reviews completed independently by Pfizer and the FDA concluded that Paxlovid had a favorable safety profile. The most common adverse events were dysgeusia and diarrhea, which occurred at slightly higher rates in Paxlovid recipients than in placebo recipients across clinical trials.

Across all studies, 96% of adverse events were mild-to-moderate in severity, with ≤ 2% of patients choosing to discontinue treatment due to adverse events.

Pfizer explicitly addressed COVID-19 rebound, which they argued the press and social media inaccurately labelled as “Paxlovid rebound.”

“The vast majority of patients exhibit no rebound with respect to either symptoms or asymptomatic viral load rebound,” said James Rusnak, MD, PhD, senior vice president and chief development officer of Internal Medicine, Anti-infectives, and Hospital Global Product Development at Pfizer.

He noted a small subset of patients experienced COVID-19 viral load rebound, but it was very rare for patients to have a rebound of both viral load and symptoms. Rusnak cited a CDC Health Advisory that states a brief return of COVID-19 symptoms may be intrinsic to the virus in some persons.

“These reports show that COVID-19 rebound occurs in placebo-treated patients and also occurs amongst patients treated with other antiviral agents,” Rusnak said.

FDA clinical virology reviewer Patrick Harrington, PhD, concurred that rebound in COVID-19 (RNA or virus) shedding or symptoms “occurs in a subset of infections, is not clearly associated with Paxlovid treatment, is not associated with severe disease outcomes, and likely reflects natural COVID-19 disease progression.”

Benefit-risk assessment of Paxlovid was vital to take into consideration, and FDA clinical reviewer Stephanie Troy, MD, said that on a population level, benefit of Paxlovid outweighs risk, but on an individual level, the benefit may not outweigh risk in all high-risk patients.

Specifically, drug-drug interaction (DDI) must be taken into consideration. Providers should be certain patients are not on any contraindicated medications before prescribing Paxlovid.