Paxlovid tablets for the treatment of coronavirus disease (COVID-19) are seen in boxes at the Misericordia Hospital in Grosseto, Italy, February 8, 2022.
Jennifer Lorenzini | Reuters
The Food and Drug Administration’s independent panel of advisers recommended full approval of Pfizer’s Covid-19 antiviral pill Paxlovid for high-risk adults on Thursday, but noted potentially harmful drug interactions.
The treatment is recommended for people over 50 or those who suffer from medical conditions such as high blood pressure or diabetes that put them at higher risk of being hospitalized or dying from Covid.
The FDA first made Paxlovid available in December 2021 for emergency use in high-risk individuals age 12 and older. Pfizer filed for full approval of the drug in June 2022, but the FDA extended the review period for the application in December.
The Agency will normally follow the advice of its advisory committees, but is not required to do so. A final decision is expected to be made in May.
“I would say, other than oxygen, Paxlovid has probably been the most important treatment tool during this outbreak and continues to be,” said Richard Murphy, chief of infectious diseases at White River Junction Veterans Affairs Medical Center.
The panel, which voted 16-1 to recommend full approval, was based on three of Pfizer’s mid-to-late-stage clinical trials of Paxlovid, which enrolled more than 6,000 patients in 21 countries.
A ‘clinically relevant’ reduction in risk
One study, called EPIC-HR, looked at high-risk adults who had not been vaccinated and had no previous Covid infection. The study found that Paxlovid reduced the risk of hospitalization or death by 86% in adults treated within five days of symptom onset and 89% in those treated within three days of symptom onset, according to an FDA review of company data.
“I thought the efficacy data were clear and convincing,” said Dr. Sankar Swaminathan, chief of the Division of Infectious Diseases at the University of Utah School of Medicine.
Dr. Adaora Adimora, a professor in the department of infectious diseases at the University of North Carolina School of Medicine, called the reduction in risk in the Pfizer trials “clinically meaningful” for most people and the broader population at a time when the U.S. still has thousands of Covid cases every week. About 200,000 cases of Covid are reported each week nationwide, according to the Centers for Disease Control and Prevention.
But advisers agreed that serious side effects due to interactions between Paxlovid and other drugs were a key 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 point in Guangzhou, south China’s Guangdong province. About a third of people with Covid will experience a return of their symptoms regardless of whether they were treated with the antiviral Paxlovid, according to a study published online on Tuesday.
street | Afp | Getty Images
“I would just like to emphasize that we emphasize the importance of risk reduction for the prescriber, the primary care physician, the physician and other prescribers regarding drug interactions,” said Dr. David Hardy, assistant clinical professor of medicine at the University of Southern California.
“That’s where I think we can get into trouble, I have to say, they’re going to get into trouble prescribing this drug without really knowing what ritonavir is [one of the medications in Paxlovid] does with other drugs,” he said.
More than half of Paxlovid-eligible Medicare and Veterans Affairs patients are on drugs that have drug interactions with Paxlovid, according to an FDA review of safety monitoring data. Approximately 74 percent of Paxlovid prescriptions were from senior primary care physicians who may not have experience managing potential adverse drug interactions, the FDA review added.
The FDA said its Office of Surveillance and Epidemiology had 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 drugs causing problems are immunosuppressants, which are often used to treat HIV and organ transplant patients, the FDA said.
But Swaminathan noted that drug interactions should be “addressable and minimized.” FDA staff said earlier in the meeting that interactions could potentially be managed by adjusting the dosage of certain drugs, increasing patient monitoring and ensuring that product labeling informs prescribers and patients of potential drug interactions.
Paxlovid consists of two drugs: nirmatrelvir, which blocks a key enzyme that the Covid virus needs to replicate, and ritonavir, which increases the first drug’s ability to fight infection.
Patients take Paxlovid within five days of the onset of Covid symptoms to reduce the risk of hospitalization or death. To complete a full course of the drug, patients must take three Paxlovid pills twice daily for five days.
More than 12 million courses of Paxlovid have been delivered to U.S. pharmacies, and 1.3 million doses are available nationwide, according to federal data. About 10 million patients in the U.S. and 14 million worldwide have been treated with the drug, according to Jim Rusnak, Pfizer’s chief internal medicine officer.
Sales of Paxlovid jumped to $18.9 billion in 2022, the first year it was available, but Pfizer expects that revenue to fall 58% to $8 billion in 2023.
The only vote against Paxlovid was from Terry Gillespie, a patient advocate from Plainfield, Illinois. Gillespie raised concerns about doctors not knowing when to prescribe the drug, noting that they had a Covid infection four to five times “but not once” were they offered Paxlovid.
“I don’t think doctors really know how to use it,” Gillespie said.
After the vote, Swaminathan said there was an “alarmingly large number of patients” whose doctors had dissuaded them from taking Paxlovid because of fears of reoccurrence of Covid. Patients then see their Covid symptoms return or test positive after initially recovering.
“I am concerned that there is not a good understanding in the medical community and a real disincentive for patients to take an effective drug that could save their lives,” he said.
Reports of these cases emerged shortly after Paxlovid hit the market in 2021, with President Joe Biden and his former chief medical adviser, Dr Anthony Fauci, appearing to have recovered from Covid after taking the antiviral cocktail before testing positive again result.
Swaminathan said there was a “dramatic acceptance” among the media that Paxlovid caused rebound cases and that they were “potentially worse” than patients had before taking the drug, despite a lack of data to support that belief.
Dr. Lindsey Baden, chair of the group and director of Brigham and Women’s Hospital, added that emerging data show that Paxlovid-induced rebound cases “are not the biology of what’s going on.”
“Until very recently, and even some of the data shared today helped me understand what that means.” So we see real-time data that is systematic and informative,” Baden said.
An FDA review of Pfizer’s clinical trials found that overall recovery rates ranged from 10% to 16%, “with no evidence of a higher rate of symptom recovery or moderate symptom recovery” in patients who received Paxlovid, in compared to patients who received a placebo. It is also independent of patients’ risk of severe disease or whether the omicron variant or an earlier strain is dominant, according to agency staff.
More data are needed in immunocompromised patients
Before the panel’s vote, FDA officials said more data are needed to determine whether immunocompromised people need a longer course of Paxlovid that goes beyond the traditional five days. They cited a complete lack of clinical trial data on the use of Paxlovid in these people, noting that only 13 of more than 2,000 patients in the EPIC-HR study had weakened immune systems.
FDA staff said immunocompromised people may benefit more from longer courses of Paxlovid because they are more likely to have prolonged Covid infections. The Centers for Disease Control and Prevention says that immunocompromised patients can remain infectious after 20 days from the onset of symptoms and recommends that these patients isolate themselves for at least 20 days. Approximately 7 million U.S. adults are immunocompromised, the CDC estimates.
Pfizer officials emphasized the company’s ongoing efforts to study the use of Paxlovid in immunocompromised patients. In September, the company began enrolling these patients in a clinical trial examining different course lengths of Paxlovid, including 10- and 15-day courses.
Dr. Paula Carvalho, a professor at the University of Washington, said she was “quite happy” with the company’s plan, but noted that she hoped the HIV population would be included in the clinical trials.
“I hope the studies can be done in a timely manner because we need this information pretty badly,” Carvalho said.