An experimental antiviral pill developed by Pfizer reduced the risk of death and hospitalization by 89% in patients who were newly diagnosed with Covid-19 in a large study, the company said Friday.
The development of oral medicines that can be used to treat Covid early on could blunt the impact of the pandemic.
Nahid Bhadelia, the founding director of the Center for Emerging Infectious Diseases Policy & Research at Boston University, called oral antiviral pills “incredibly important” because existing treatments such as monoclonal antibodies must be given intravenously or as shots.
“With an oral antiviral, patients have more time and greater access to a treatment that will keep them out of the hospital,” Bhadelia said. “But the promise of oral antivirals will only be recognized if they’re available at your local pharmacy, and you can afford it, and you can get the test that tells you that you’re positive for Covid, so you can actually take advantage of this drug. So, the promise is there, but the rest of the pieces need to come together.”
The Pfizer result is the second success for an oral pill that prevents Covid patients from becoming hospitalized or dying. Merck and partner Ridgeback Therapeutics announced Oct. 1 that their pill, molnupiravir, reduced hospitalization and death by 50%. That pill also prevented death, and was granted conditional approval Thursday by the United Kingdom’s top medical regulators.
Outside experts contacted by STAT said the Pfizer results, which were issued in a press release and have not been peer reviewed or submitted to regulators, appear very promising. They also worried about whether the new pill will be made broadly available. Merck has made patents to molnupiravir available to manufacturers who can help make the drug available to nations that are less wealthy. In its press release, Pfizer said it plans to make the drug available using a “tiered pricing approach” based on the income level of each country.
The Pfizer medicine, known by the code name PF-07321332 or simply ’332, reduced hospitalization by 89% compared to placebo when given with the HIV drug ritonavir within three days of symptom onset. The medicine also reduced the chance that patients would die. There were 7 deaths out of 385 patients in the placebo group, and none in the 389-patient group that received the medicines. Pfizer plans to market ‘332 under the brand name Paxlovid.
When Pfizer reported earnings on Tuesday, the company told investors that news on ’332 might not arrive until the beginning of next year. That’s because the study, which was originally set to enroll 3,000 patients who would receive either placebo or the combination of ’332 and ritonavir, would stop at different timepoints depending on how effective the medicines proved to be. A more effective treatment requires fewer patients — and therefore less time.
An outside data safety monitoring board stopped the study early when 774 patients had been treated for 28 days. In that time frame, 27, or 7%, of those on placebo were hospitalized or died compared to three who received ’332 and ritonavir. That translates into an 89% reduction between the groups. The study also allowed patients to start taking the treatment (or placebo) within five days after symptoms appeared, not three. In that group of 1,219, there were 41 patients who were hospitalized or died in the placebo group compared to 6 who received the medicines, an 85% reduction.
Mikael Dolsten, Pfizer’s chief scientific officer, said he first heard about the results Wednesday night in a telephone call from Jim Rusnak, a Pfizer senior vice president. He said he jumped out of his chair and cheered at the positive result.
“I’m hoping certainly when the news breaks it will be another sigh of relief for those who are living in areas with a lot of SARS-Cov-2 around them and full hospitals,” Dolsten told STAT in an interview.Related: Merck’s Covid-19 antiviral pill receives first authorization in U.K.
Pfizer has two more studies of the drug ongoing. This study was in patients with risk factors for severe Covid who were unvaccinated. A second study is testing the drug in lower-risk patients and those who have been vaccinated, potentially making it an option for treating breakthrough infections, Dolsten said. A third will test whether the drug can prevent infection in people who are likely to be exposed to the virus.
Researchers were quick to make early comparisons between the Merck and Pfizer drugs, even though data from both have only been made available in press releases. “The numbers look impressive when you compare it to Merck’s molnupiravir,” said Celine Gounder, an infectious disease expert and the CEO and founder of Just Human Productions, a non-profit multimedia organization. Merck reported that its medicine reduced hospitalizations 50%, a lower headline figure than seen here.
Gounder said that she wanted to see more data on how monoclonal antibodies, another effective Covid treatment, were used in the study, and on what day after diagnosis patients started treatment.
Outside researchers have also raised questions about whether Merck’s drug could make changes to patients’ DNA, which could in theory lead to birth defects or a risk of cancer.
“This is a theoretical risk,” Gounder said. “We don’t know, and it’s not necessarily a bad drug. We just need to study it because there is that potential risk. But with a protease inhibitor, you don’t have that risk, and I didn’t see anything in Pfizer’s press release that was concerning regarding side effects.”
Merck has insisted that its drug, which will be reviewed by an expert panel convened by the Food and Drug Administration on Nov. 30, is not likely to cause such changes based on animal studies it has conducted.
“We’re very happy that it’s not mutagenic or genotoxic in the in vivo mammalian systems that we study,” said Dean Li, Merck’s head of research and development, in an interview last week. “We study it [in those systems] for longer and higher doses than in the human studies.”Related: Molnupiravir: another Covid-19 treatment, another opportunity to recognize inequity
Li also said that the drug’s benefit in preventing death, which it did in the company’s studies, would prove to be an important indicator of its efficacy for doctors and patients. “What many people will do is their eyes will immediately go to mortality because that’s something they understand,” Li said.
Dolsten made oblique references to the Merck drug, saying that Pfizer had decided to develop a protease inhibitor like ’332 because it would not do any damage to DNA. He also made a reference to Merck’s efficacy when talking about the decision to stop the company’s study early.
“Certainly if we were at 50% we would not have stopped the trial,” Dolsten said. “That was not what we were aiming for.”Related: CDC advisers endorse Pfizer’s Covid-19 vaccine for kids 5-11
Comparisons were less favorable, however, when it came to doctors’ expectations as to whether the drug would be made globally available.
Angie Rasmussen, a vaccine researcher at the Vaccine and Infectious Disease Organization-International Vaccine Centre in Saskatchewan, Canada, said that she raised her eyebrows at statements that Pfizer would make the drug available equitably around the world.
“That certainly has not been the case for accessing their vaccine,” Rasmussen said. “Without question, having new antivirals to add to the mix is a ‘game-changer,’ but the utility in the global efforts to halt the devastation of this pandemic remains to be seen.” She asked not only how much Pfizer planned to charge for its drug, but what the cost of ritonavir would be. (Pfizer does not make ritonavir.)
“It is Pfizer’s ambition to make this medicine accessible to as many patients as possible on the globe,” Dolsten said. “We’ll find the best way to do that.”Related: Pfizer will use a warranty to refund the cost of a lung cancer drug if it doesn’t work
Some have suggested combining the Merck and Pfizer pills to prevent viral resistance. Dolsten said that Pfizer’s studies have shown the protease inhibitor works on different strains of the virus and does not seem to lead to resistant strains, and that he thinks given the drug’s safety and efficacy it doesn’t make sense to combine it with another treatment.
The course of treatment is two ’332 pills and one ritonavir, twice a day for five days.
The drug was invented and tested at a speed that makes the normal pace of drug development, which can span decades, appear sluggish. The Pfizer pill was developed by the company starting in March 2020 by a team that included Annaliesa Anderson, chief scientist in the company’s vaccine development group, and Charlotte Allerton, its head of medicine design. In four months, they had hundreds of potential medicines. By March 2021, ’332 was ready to begin testing in humans, and a few months later, efficacy testing began. Pfizer started making the medicine in large quantities, and plans to have more than 50 million courses available in 2022.
One of the worries about effective antiviral pills is that they might increase vaccine hesitancy. But experts emphasized that this is not the case, and that the pills should represent an extra level of protection for society on top of vaccines, but not a replacement.
“Would you rather get stitches over wearing a seat belt?” said Bhadelia. “No. So why would you pick antivirals over a vaccine? You take a vaccine first for protection, and if you’re unfortunate to get a breakthrough infection and you’re high-risk, that’s where an antiviral helps.”