Pfizer’s Paxlovid study fails to answer key questions over benefit for broader populations

Pfizer said Tuesday that a much-watched study of its antiviral Paxlovid in patients who have Covid but don’t have risk factors for severe disease failed to show a benefit in speeding alleviation of Covid symptoms, but did seem to prevent doctor’s visits and hospitalizations.

Additionally, because of the small number of hospitalizations overall in the study, it failed to produce a statistically significant finding on whether patients who had previously been vaccinated against Covid were hospitalized less often if they received Paxlovid.

The data in no way invalidate earlier results that show that Paxlovid prevents hospitalizations and saves lives in patients at high risk of severe Covid. But the results, published in a press release, are likely to take time for experts to digest and understand.

“I think this is one where you have to say it’s hard to make conclusions based on a press release but these data appear to be intriguing but not convincing,” said Andy Pavia, the chief of the division of pediatric infectious diseases at the University of Utah Hospital.

The results are likely to spur debates on how careful doctors should be in prescribing Paxlovid. Pfizer’s profound early results came from a group of high-risk, unvaccinated patients. But the Food and Drug Administration authorized it for anyone with at least one risk factor such as diabetes or high blood pressure; anecdotally, doctors report that the drug is largely being used in high-risk vaccinated patients, especially amid a big push by the U.S. government to make sure the drug reaches all people indicated to get it.

Still, there was little data for how well the drug worked in these high-risk vaccinated patients and open questions about whether it might also be useful in patients who have no risk factors.

“This reinforces that Paxlovid is not going to have a big role in vaccinated people except in people who are maybe at highest risk,” said Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “Maybe in a bigger trial, it would be statistically significant, but the effect is small.”

In a statement, Pfizer CEO Albert Bourla said: “With up to 40-50% of people around the world estimated to be high risk, we believe there remains a significant unmet need for treatment options to help combat this disease, and we will continue to prioritize efforts to advance the development of Paxlovid.”

But Gellad argued that the data suggest it’s crucial to find the subset of patients who are at highest risk, especially as the drug comes with side effects and the small potential for rebound.

“We really need to understand who is really at high risk, and we need to know who is being hospitalized,” he said.

Real world studies in largely — but not entirely — vaccinated populations in Hong Kong and Israel have also suggested Paxlovid provides some benefit for lower risk patients, with a recent Israeli study finding the drug reduced the risk of severe disease or death by 46% among patients covered by the largest local healthcare provider.

The Israeli study suggested the drug had the biggest benefit for patients with a neurological disease, a malignancy or who are on immunosuppressive drugs.

Real world studies in largely — but not entirely — vaccinated populations in Hong Kong and Israel have also suggested Paxlovid provides some benefit for lower risk patients, with a recent Israeli study finding the drug reduced the risk of hospitalization by 46% among patients covered by the largest local health care provider.

The Israeli study suggested the drug had the biggest benefit for patients with a neurological disease, a malignancy, or who are on immunosuppressive drugs.

Pfizer announced in December that an early look at the study did not look likely to meet its main goal of showing alleviation of Covid symptoms at four days, but that patients who received Paxlovid appeared less likely to need medical care than those who received placebo.

In an updated analysis from 1,153 patients enrolled in the study through December 2021, there was a 51% difference in the need for medical care — that’s five patients who needed it in the treatment arm, compared to 10 on placebo — but the result was not statistically significant.

The results were similar, however, in patients who had previously been vaccinated. Originally, the study included volunteers who were fully vaccinated but were at high risk of Covid symptoms. After Paxlovid was authorized for those people, they could no longer be enrolled in the study. Pfizer changed the entry criteria to include people whose last vaccination occurred at least 12 months before enrollment.

A sub-group analysis of 721 vaccinated adults with at least one risk factor for progression to severe Covid indicated those who received Paxlovid were 57% less likely to be hospitalized or die, but the result was not statistically significant. There were three patients who were hospitalized or died in the Paxlovid group compared to seven in the placebo group.

Davey Smith, an infectious disease expert at the University of California, San Diego, said he viewed the data as supportive of giving Paxlovid to those who have been vaccinated and have caught Covid and who have at least one high risk factor.

“It answers a question that’s been open for a while: Whether or not vaccinated people with high-risk conditions should be treated. Myself and other doctors have been doing so. But it’s good to have some assurance.”

Even without statistical significance, he said, “I think everything is pointing in the right direction.”

Pavia said that one big question regarding whether people who are at lower risk should receive Paxlovid will not be study results, but whether or not strains of the SARS-CoV-2 virus develop resistance to the drug as it becomes more widely used. If little resistance develops, doctors may use the medicine broadly. But if there is a risk of resistance, they will likely keep it in reserve for patients at higher risk.