Why Pfizer’s Covid Pill Isn’t A Miracle Medicine

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At the end of last year, it appeared that the key to “living with Covid” had finally been found. Pfizer’s antiviral Paxlovid has been approved, offering people infected with the coronavirus the option of taking a pill to combat their symptoms, reducing hospitalizations and other harmful effects of the disease.

But new studies raise significant doubts about a drug that was even mentioned by US President Joe Biden in his annual State of the Union address.

Among those questions are how well Paxlovid works with lower-risk patients, why some patients experience a “rebound” of Covid — their symptoms resurface after they stop taking the drug — and the possibility that the virus can develop resistance. to him.

Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said Paxlovid works well for higher-risk patients, but there is still a lot of uncertainty around how it should be used.

“At first there was hope that it would be not exactly a miracle drug, but the solution to Covid,” he said. “But I don’t think that’s going to happen.”

With the effectiveness of vaccines waning in the face of the arrival of new variants, antivirals — which reduce a virus’s ability to replicate — are key to protecting new waves of patients. As the United States abandoned its pandemic quarantines, the government promoted the use of Paxlovid. Since the spring, prescriptions for the drug have continued to increase, and last week the rules were changed to allow patients to buy Paxlovid from pharmacies, without the need for a prescription.

The antiviral is being used much less in other countries, but the governments of France and Germany are looking to encourage its adoption, and Australia has relaxed the criteria that qualify patients to use it.

Paxlovid has indeed had impressive results in its late-stage clinical trials, reducing the risk of hospitalization by 89%. It was much better than its only rival, Merck’s antiviral Lagevrio (molnupiravir), taken by mouth, which reduced the risk of hospitalization by about 30%. Paxlovid’s effectiveness translates into impressive sales: Pfizer predicts sales of $22 billion this year, while Merck’s forecast for Lagevrio is between $5 billion and $5.5 billion.

But clinical trials had limitations. One of them was the fact that it was done with unvaccinated people, and most people who take Paxlovid today are vaccinated.

In addition, the trials focused on high-risk patients, such as those with comorbidities. Pfizer only announced data on medium-risk patients last month, when it halted a trial because an internal review showed Paxlovid was not effective at reducing symptoms. The drug reduced hospital admissions, but the study was not large enough to allow a statistically significant conclusion on this point.

Another problem is that Paxlovid is inappropriate for some patients because it must be taken with ritonavir, a drug used to treat HIV that interacts with some common drugs.

Even so, the US government is strongly encouraging its use.

Gellad said management likes to cite statistics to show it is fighting the pandemic, but added: “The number of prescriptions you dispense is not a good criterion of success in dealing with Covid.”

Infectologist Davey Smith of the University of California at San Diego said that, in practice, doctors are prescribing Paxlovid widely. “Everyone who gets Covid wants to be treated with the drug, whether it’s high risk or not, so the demand for it is high.”

But he added that another important question is whether Paxlovid works equally well against the omicron, given that it was mostly studied when the delta variety was dominant. Pfizer said that, in laboratory studies, the drug demonstrates antiviral activity against the BA.1 and BA.2 omicron subvariants, and that its structure means it is likely to fight BA.4 and BA.5 subvariants equally well.

Smith analyzed one of the problems that took some of the shine out of Paxlovid. Some patients (including the president’s chief medical adviser Anthony Fauci) reportedly experienced a “rebound”, testing positive for the virus days after tests indicated they had outgrown the virus.

Pfizer said this rebound is unusual and that it also occurred among participants in its trials who took a placebo, suggesting that this occurs with some patients, whether they take Paxlovid or not.

But Michael Mina, a former professor at Harvard and now the medical director of the testing company eMed, suspects that this may occur in between 20% and 30% of patients. He is starting a trial to investigate how often it occurs in patients who have taken Paxlovid.

“It’s very important for us to know that frequency. If people are stopping taking Paxlovid after five days, following CDC guidelines, and then going back out into the world, but 12 days later they’re highly infectious, we need to know.” he said.

It is very important for us to know this frequency. If people are stopping taking Paxlovid after five days, following CDC guidelines, and then going back out into the world, but 12 days later are highly infectious, we need to know.

A positive sign is that, in Smith’s case study, the patients who experienced the rebound did not transmit Covid to their acquaintances. After examining how the rebound works, Smith suspects it is a problem with the dosage of the drug: maybe Paxlovid needs to be taken for more than five days, or maybe the dose needs to be higher.

Fortunately, he found no evidence that the rebound was being caused by a resistance that the virus was acquiring to the drug. However, viruses often adapt to stop an antiviral from working, and two recent studies have shown how Paxlovid can put pressure on the virus to mutate.

In a study led by Belgian virologist Dirk Jochmans, the virus underwent mutations that left it 20% less susceptible to the drug. In another study, this one led by virologist Judith Margarete Gottwein of the University of Copenhagen, he developed two mutations that made him 80% less susceptible.

Gottwein said the resulting virus was very effective. “It’s very scary. It would probably persist after treatment is over and spread.”

The studies put Paxlovid under a kind of pressure that would be very unusual in the real world, and Pfizer noted that it has so far not seen any such mutations outside the lab.

But the studies serve as a warning about what can happen if, for example, the antiviral drug does not eliminate the virus in an immunocompromised patient, where the virus would already have an easier time persisting and evolving. Gottwein believes that for this reason antivirals should never be taken alone.

David Ho, a virologist at Columbia University, thinks the sheer number of people taking Paxlovid in the United States could create a future problem. “The more we use the drug, the more likely we are to encounter resistance,” he explained.

There are other antivirals that are being developed: Miami-based pharmaceutical company Veru, a maker of oncology products, recently published positive results for its drug, which is both antiviral and anti-inflammatory, showing that it reduced deaths in hospitalized participants by 55%. with severe Covid.

More likely, Paxlovid will end up being used in combination with another drug or replaced with another. An oral antiviral made by Chinese company Shanghai Junshi Biosciences performed better than Paxlovid in clinical trials, reducing the average recovery time for patients. But it still needs to complete an international phase 3 trial.

Japanese pharmaceutical company Shionogi has had promising results for its own oral antiviral, which quickly cleared the virus in a largely vaccinated population. Takeki Uehara, vice president of Shionogi’s clinical research department, said his drug’s different structure means it stays in the body much longer and doesn’t need to be taken together with ritonavir. This, he says, can reduce the risk of rebounds.

Results of Shionogi’s final phase trial in Asia will be released on strike, and a larger international trial, conducted in collaboration with the US National Institutes of Health, is expected to have its results announced in October.

But as we head into yet another wave of Covid-19, Paxlovid is still by far the dominant antiviral. Analyst Akash Tewari of financial services firm Jefferies said that despite concerns raised by recent studies, Paxlovid’s ability to protect high-risk patients is a big plus in its favor.

Translation by Clara Allain

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