Late last year it looked like a key to “living with Covid” had finally been found. Pfizer’s antiviral drug Paxlovid had been approved, giving the newly infected the option of popping a pill to tackle their symptoms, cutting hospitalisations and other damaging effects of the disease.
But new studies have raised significant questions about a drug that was even mentioned by US president Joe Biden in his annual state of the union address.
These include how well it works in lower-risk patients, why some suffer Covid-19 “rebound” — symptoms returning after they stop taking the drug — and whether the virus could become resistant to it.
Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said the drug works well for higher-risk patients, but there is still a lot of uncertainty about how it should be used.
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“Initially there was hope that it would be, not a miracle drug, but it would be the solution to Covid,” he said. “But I don’t think it is going to turn out to be.”
With vaccine efficacy fading in the face of new variants, antivirals — which reduce the ability of a virus to replicate — are a key to protecting new waves of patients. As the US has opened up, the government has rolled out Paxlovid. Prescriptions have soared since the spring, and last week, rules were changed so patients can get the drug from pharmacists without visiting a doctor.
Uptake in other countries is much lower but the French and German governments are trying to encourage it and Australia has expanded the criteria qualifying patients for the drug. The drug is available in Ireland but, to date, its use has been sparing.
Paxlovid certainly did post impressive late-stage clinical trial results, reducing the risk of hospitalisation by 89 per cent. This was far higher than its only rival, oral antiviral Merck’s Lagevrio, which cut the risk by about 30 per cent. The efficacy rate has proved a huge selling point: Pfizer expects $22 billion (€21.9 billion) of Paxlovid sales this year, compared to Merck’s forecast for $5 billion to $5.5 billion for Lagevrio.
But the trial had limitations. One was that it was in unvaccinated people, while the majority of recipients of the drug are now vaccinated.
It also focused on high-risk patients, such as those with underlying conditions. Pfizer did not report data on standard-risk patients until last month, when it stopped a trial because an interim analysis showed it was not effective in reducing symptoms. Paxlovid did reduce hospitalisations — but the study was not large enough for a statistically significant conclusion on that point.
It is also inappropriate for some patients because it must be taken with ritonavir, a drug used to treat HIV that interacts with some common medications.
Yet the US government is pushing it fairly hard.
Dr Gellad said the administration likes to quote figures to show it is tackling the pandemic but added: “The number of prescriptions you give out is not a good measure of success in dealing with Covid.”
Davey Smith, an infectious disease specialist at the University of California San Diego, said in practice doctors are prescribing it widely. “Everybody who gets Covid wants to be treated with the drug, whether or not they are high risk: there is a very big demand for it.”
But he added that another important question was whether the drug works as well against Omicron, given it was mainly studied when the Delta variant was dominant. Pfizer said the drug shows antiviral activity against Omicron subvariants BA.1 and BA.2 in lab studies, and its structure means it is likely to be able to tackle the BA.4 and 5 subvariants as well.
Dr Smith has looked into one of the problems that has taken the shine off Paxlovid. Some patients, including the president’s chief medical adviser Anthony Fauci, have suffered “rebound”, testing positive for the virus only days after tests showed they had cleared it.
Pfizer said rebound is “uncommon” and also occurred in the placebo arm of its trial, suggesting it happens to some patients regardless of whether they take the drug.
But Michael Mina, a former Harvard professor who is now chief medical officer at testing company eMed, suspects it could happen in 20 to 30 per cent of patients. He is launching a trial to investigate how often it occurs in Paxlovid patients.
“It is very important for us to know how frequent it is. If people are finishing Paxlovid after five days and following CDC [Centres for Disease Control] guidance and going back into the world, yet 12 days later they are highly infectious, we have to know,” he said.
One good sign is that in Dr Smith’s case study, the patients suffering rebound did not spread Covid-19 to their contacts. After examining how rebound worked, he suspects it is a dosing problem: perhaps the five-day course of Paxlovid needs to be longer, or the dose higher.
Mutating virus
Fortunately, he did not find evidence that rebound was caused by the virus becoming resistant to the drug. However, viruses frequently adapt to stop an antiviral working and two recent studies showed how Paxlovid could put pressure on the virus to mutate.
In a study led by Belgian virologist Dirk Jochmans, the virus evolved mutations that made it 20 per cent less susceptible to the drug, while in another by Judith Margarete Gottwein, a virologist at the University of Copenhagen, it evolved two changes that made it 80 per cent less susceptible.
Dr Gottwein said the resulting virus was “very fit”. “It is very scary, it would probably persist after the end of treatment and spread.”
The studies put Paxlovid under the kind of pressure that would be very unusual in the real world and Pfizer stressed it has not observed any such mutations outside the lab.
But they serve as a warning about what could happen if, for example, the antiviral did not clear the virus in an immunocompromised patient where it is already easier for it to persist and evolve. Dr Gottwein believes for this reason antivirals should never be taken alone.
David Ho, a virologist at Columbia University, believes the large numbers taking Paxlovid in the US could cause a problem down the line. “The more we use it, the more we are likely to encounter resistance,” he said.
There are other antivirals in development: Miami-based oncology company Veru recently published positive results for its drug, which is both antiviral and anti-inflammatory, showing it reduced deaths in hospitalised participants with severe Covid-19 by 55 per cent.
It is likely in the end that Paxlovid will be used in combination with or be replaced by another drug. In trials, an oral antiviral made by Chinese company Shanghai Junshi Biosciences outperformed Paxlovid, cutting the median time to recovery. But it still needs to complete an international phase 3 trial.
Japanese drugmaker Shionogi has also shown promising results for its oral antiviral, which rapidly cleared the virus in a mainly vaccinated population. Takeki Uehara, vice-president of Shionogi’s clinical research department, said its different structure means it stays in the body for much longer and does not need to be taken with ritonavir. This could reduce the risk of rebound, he said.
Results from Shionogi’s late-stage trial in Asia will come out soon, and a broader international trial, in collaboration with the US National Institutes of Health, is set to report results in October.
But as we head into another Covid-19 wave, Paxlovid is still the dominant antiviral by far. Akash Tewari, an analyst at Jefferies, said that despite the concerns raised in recent studies, the drug’s ability to protect high-risk patients was a “win no matter what”. - Copyright The Financial Times Limited 2022
