The Food and Drug Administration’s independent panel of advisors recommended full approval of Pfizer’s Covid-19 antiviral pill Paxlovid for high-risk adults on Thursday, while also highlighting potentially harmful drug interactions.
The treatment is recommended for individuals over 50 or those with medical conditions such as high blood pressure or diabetes, which increase the risk of hospitalization or death from Covid.
The FDA initially authorized Paxlovid for emergency use in December 2021 for high-risk individuals aged 12 and up. Pfizer submitted an application for full approval of the drug in June 2022, but the FDA extended its review period for the application in December.
The agency typically follows the advice of its advisory committees but is not obligated to do so. It is expected to make a final decision in May.
“I’d say besides oxygen, Paxlovid has probably been the single most important treatment tool during this epidemic and continues to be,” said Richard Murphy, chief of infectious diseases at the Veterans Affairs White River Junction Medical Center.
The panel, which voted 16-1 in favor of full approval, reviewed data from three of Pfizer’s mid- to late-stage clinical trials on Paxlovid, involving more than 6,000 patients across 21 countries.
One trial, called EPIC-HR, studied high-risk adults who were unvaccinated and had no prior Covid infection.
The trial found that Paxlovid reduced the risk of hospitalization or death by 86% in adults treated within five days of symptom onset and by 89% in those treated within three days of symptom onset, according to an FDA review of the company’s data.
“I thought that the efficacy data was clear and convincing,” said Dr. Sankar Swaminathan, chief of the division of infectious diseases at the University of Utah’s School of Medicine.
Dr. Adaora Adimora, a professor in the department of infectious diseases at the University of North Carolina School of Medicine, described the risk reduction in Pfizer’s trials as “clinically meaningful” for most individuals and the broader population, especially since the U.S. still reports thousands of Covid cases each week.
Approximately 200,000 Covid cases are reported weekly nationwide, according to the Centers for Disease Control and Prevention.
However, advisors acknowledged that serious adverse reactions due to drug interactions with Paxlovid are a significant safety concern.
This photo taken on July 31, 2022 shows a health worker taking a swab sample from a woman to be tested for the Covid-19 coronavirus at a swab collection site in Guangzhou, in China’s southern Guangdong province.
Around a third of people with Covid will experience a rebound of their symptoms, regardless of whether they’ve been treated with the antiviral Paxlovid, according to a study posted online Tuesday.
“I would just emphasize that we underscore the importance of risk mitigation to the prescriber, primary care, physician, and other prescribers in terms of drug-drug interactions,” said Dr. David Hardy, an adjunct clinical professor of medicine at the University of Southern California.
“That’s where I think we may get into trouble, I should say, where they would get into trouble with prescribing this medication without a good knowledge of what ritonavir [one of the medications in Paxlovid] does to other medications,” he said.
According to an FDA review of safety surveillance data, more than half of Paxlovid-eligible Medicare and Veterans Affairs patients are on medications that have interactions with Paxlovid.
Approximately 74% of Paxlovid prescriptions were from adult primary care practitioners who may not be experienced in managing the possible adverse drug interactions, the FDA review added.
The FDA reported that its office of surveillance and epidemiology recorded 271 reports of serious adverse events potentially related to drug interactions with Paxlovid, including 147 hospitalizations and six deaths as of late January.
The most common problematic drugs were immunosuppressants, which are often used to treat HIV and organ transplant patients.
However, Swaminathan noted that drug interactions should be “addressable and minimized.”
FDA staff suggested that interactions could be managed by adjusting the dose of certain drugs, increasing patient monitoring, and ensuring product labeling informs prescribers and patients of potential drug interactions.
Paxlovid comprises two medications: nirmatrelvir, which inhibits a key enzyme the Covid virus needs to replicate, and ritonavir, which enhances the effectiveness of the first medication.
Patients take Paxlovid within five days of developing Covid symptoms to reduce their risk of hospitalization or death. A full course of the drug involves taking three Paxlovid pills twice a day for five days.
More than 12 million courses of Paxlovid have been delivered to pharmacies across the U.S., and 1.3 million doses are available nationwide, according to federal data.
Approximately 10 million patients in the U.S. and 14 million worldwide have been treated with the drug, according to Jim Rusnak, Pfizer’s chief development officer for internal medicine.
Sales of Paxlovid surged to $18.9 billion in 2022, its first year of availability, but Pfizer expects that revenue to drop 58% to $8 billion in 2023.
The single vote against Paxlovid came from Terry Gillespie, a patient representative from Plainfield, Illinois, who expressed concerns about doctors’ understanding of when to prescribe the drug.
Gillespie noted having a Covid infection four to five times “but never once” being offered Paxlovid.
“I don’t feel that the doctors really know how to use it,” Gillespie said.
Following the vote, Swaminathan mentioned having a “distressingly large number of patients” whose doctors discouraged them from taking Paxlovid due to fears of rebound Covid cases, where patients experience a return of symptoms or test positive after initially recovering.
“I am concerned that there’s not a good understanding in the medical community and an actual dissuading of patients from taking an effective drug that could save their life,” he said.
Reports of rebound cases surfaced soon after Paxlovid entered the market in 2021, with President Joe Biden and his former chief medical advisor Dr. Anthony Fauci seemingly recovering from Covid after taking the antiviral cocktail, only to test positive again.
Swaminathan said there’s a “dramatic acceptance” among the media that Paxlovid causes rebound cases and that they are “potentially worse” than the initial symptoms, despite a lack of data supporting that belief.
Dr. Lindsey Baden, the chairperson of the panel and director of Brigham and Women’s Hospital, added that emerging data indicates Paxlovid-caused rebound cases are “not the biology of what is going on.”
“Up until very recently, and even some of the data shared today have helped me understand what it means. So we are seeing data in real time that are systematic and informative,” Baden said.
An FDA review of Pfizer’s clinical trials found rates of rebound ranged from 10% to 16%, “with no evidence of a higher rate of symptom rebound or moderate symptom rebound” in patients who received Paxlovid compared to those who received a placebo, regardless of patients’ risk of severe disease or the dominance of the omicron variant or an earlier strain, according to the agency’s staff.
Before the panel’s vote, FDA staff said more data is needed to determine if immunocompromised individuals require a longer course of Paxlovid beyond the traditional five days.
They noted a lack of clinical trial data on the use of Paxlovid in this population, highlighting that only 13 of the more than 2,000 patients in the EPIC-HR trial had weakened immune systems.
The FDA staff suggested that immunocompromised individuals might benefit more from extended courses of Paxlovid, as they are more likely to experience prolonged Covid infections.
The Centers for Disease Control and Prevention recommends that immunocompromised patients isolate for at least 20 days, as they may remain infectious beyond 20 days of symptom onset. Roughly 7 million U.S. adults are estimated to be immunocompromised.
Representatives from Pfizer emphasized the company’s ongoing efforts to research Paxlovid’s use in immunocompromised patients.
In September, the company began enrolling these patients in a clinical trial examining different durations of a Paxlovid course, including 10- and 15-day courses.
Dr. Paula Carvalho, a professor at the University of Washington, expressed satisfaction with Pfizer’s plan but emphasized the importance of including the HIV population in clinical trials.
“I hope that the studies can be done in a timely way, because we need this information pretty badly,” Carvalho said.
