Why Pfizer May Be Holding Paxlovid Close to the Chest

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Reportedly, Pfizer is holding its COVID-19 antiviral therapy Paxlovid under tight control. This is a disappointment to numerous investigators who want to test the antiviral combination therapy with other drugs in case the virus develops resistance to the combo. 

Per a review of the clinicaltrials.gov database conducted by Bloomberg, Pfizer apparently has not begun any combination trials in humans, and no reported human tests are using the drug in combination with other therapies.

So far, Paxlovid has been authorized for less than half a year and has only been granted emergency use authorization (EUA), not full approval. The regimen is a combination of ritonavir, an antiretroviral typically used to treat HIV, and the company's nirmatrelvir. Nirmatrelvir is a novel main protease inhibitor engineered to block the activity of the main protease of SARS-CoV-2. It was authorized in the U.S. in late December 2021 for patients at high risk of progression to severe COVID-19, including hospitalization or death.

There are also reports of Pfizer resisting requests to use Paxlovid in combination studies. Drugs for Neglected Diseases Initiative (DNDi), a nonprofit, reported that the company rejected a request in January to provide Paxlovid for combination studies with an inhaled steroid in Africa. 

The idea was to develop a new treatment that could be initiated more than five days after symptoms appear. According to Bloomberg, DNDi North American regional director Rachel Cohen said Pfizer's answer was "a categorical no. I don't know why it's been so difficult for them to at the very least provide some study drug."

It's possible that the fact it's two different antiviral drugs will decrease the likelihood of SARS-CoV-2 developing resistance to it. However, Derek Lowe, Ph.D., who writes the "In The Pipeline" column for Science, says it's "likely just a matter of time." He also expressed surprise that combination trials weren't already underway, saying, "From where I stand, it looks like a natural thing to try."

A Pfizer spokesperson told Bloomberg it is considering combination studies, but none are underway.

Reshma Ramachandran, Ph.D., a postdoctoral fellow in Yale University's National Clinician Scholars Program who focuses on transparency in drug company trials, said, "It's all very puzzling. It really makes me wonder what's going on."

However, Carl Dieffenbach, Ph.D., director of the division of AIDS in the National Institute of Allergy and Infectious Diseases, who headed the Biden administration's antiviral efforts against COVID-19, thinks the EUA may be part of the issue, which can add extra red tape to studying combinations. "The company has to approve of how the drug is being used. And a lot of companies aren't necessarily keen on having their agent combined with others."

RNA viruses mutate, such as HIV, which has demonstrated fast resistance to antivirals. For that matter, SARS-CoV-2, with its numerous variants, has proven to evolve and mutate very quickly. Columbia University virologist David Ho, Ph.D., says resistance to Paxlovid "is easy to generate in the lab."

Pfizer is arguing that the short treatment duration and high concentrations used for Paxlovid minimize the risk of resistance. It is also assessing mutations in patients and in the laboratory, which it will use to design second-generation drugs.

Still, researchers point out that combinations are important to deal with likely resistance.

In a May 3 interview, Pfizer's CEO Albert Bourla said that combination studies may make sense eventually, but it isn't "right now in a hurry to do something like that." Meanwhile, the company is expecting the drug to bring in $22 billion alone this year. And it is focused on decreasing Paxlovid's six daily pills for five days and working to decrease its negative interactions with other common drugs.

Merck and Ridgeback Biotherapeutics also developed a COVID-19 antiviral, molnupiravir. It would make sense to try molnupiravir and Paxlovid in a combination study. Reportedly, Merck and Pfizer conducted preliminary conversations in 2021 about the combination. However, Dr. Nicholas Kartsonis, M.D., senior vice president of clinical research at Merck, indicated that laboratory assays would have to be conducted to rule out undesirable interactions before human trials could run.

Meanwhile, one of the peculiarities of Paxlovid is rare cases of rebound symptoms. In clinical trials, the drug reduced COVID-19-related hospitalization and death by 89% in a group of outpatient adults. But there have been cases of people who received the drug and completed the five-day regimen who then had a rebound of symptoms. 

Initially, Bourla shrugged it off, saying, "Paxlovid does what it has to do: It reduces the viral load. Then your body is supposed to do the job." And if the virus levels rebound, "then you give a second course, like you do with antibiotics, and that's it."

The Food and Drug Administration came back quickly, with Dr. John Farley, M.D., director of the FDA's Office of Infectious Diseases, saying, "There is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the 5 days recommended in the Provider Fact Sheet for paxlovid) or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course."