So far, the world has looked to vaccines for prevention and, in rich countries, to expensive IV infusions of drugs called antibodies that block the virus. With pills in blister packs that you can pick up at midnight at the pharmacy with a prescription, there will be what the doctor and social media pundit Eric Topol calls “a whole new approach to tackling the virus.”
“You get a prescription, you go to the CVS, and that’s it.”
Crucially, the protease is, in the jargon of biologists, a “highly conserved” molecule. That means that even as the virus evolves, this part rarely changes. So while the coronavirus has been mutating quickly to evade vaccines, so far it looks as though Paxlovid will work just as well against any variant—whether it’s omicron or whatever comes next.
In fact, laboratory tests run by Pfizer suggest Paxlovid will work against all coronaviruses, maybe even one still lurking in a bat cave somewhere. If so, it means the company has hit on a potential defense against the next outbreak, too. “It has the potential to be a pan-coronavirus agent and stockpiled against future pandemics,” says Owen, the Pfizer chemist. “But it’s here for this pandemic, because we did it super fast.”
Pfizer’s drug isn’t the only antiviral to show promise. In late 2020, a drug called remdesivir was the first chemical approved in the US to treat covid-19. But remdesivir has to be given through an IV drip, five days in a row. That has limited its impact. In contrast, Pfizer’s chemists tweaked their antiviral chemical so you could swallow it.
“I feel that Paxlovid is the big step we were working for this pandemic,” says Kris White, a researcher at the Icahn School of Medicine in New York, who was recruited by Pfizer to give the drugs to mice in 2020. “I believe it is going to be the treatment for covid.”
As he says, “You get a prescription, you go to the CVS, and that’s it.”
Cautious optimism
Despite the early excitement, Pfizer’s pill still remains in short supply.
Desperate to end the pandemic, the Biden administration immediately spent $5.3 billion to pre-purchase 10 million courses of Paxlovid in December and doubled the amount a few weeks later. But those 20 million courses won’t all become available until midyear, mostly too late to deal with the current omicron surge.
And some medical researchers suspect Pfizer’s spectacular test results could be too rosy. The human trial that led to its authorization was relatively small, involving about 2,000 people, which means the true effectiveness of the drug could turn out to be less stellar in the real world. “We should not jump to conclusions about its miraculous efficacy,” says Thomas Agoritsas, a doctor specializing in medical evidence at the Geneva University Hospitals.
NICO ORTEGA
Another drawback is that Paxlovid should be given within five days of the start of symptoms. Pfizer’s own internal models identify that as a challenge. An August 2021 study in the Annals of Emergency Medicine found that, on average, people have symptoms for five or six days before they turn up at a hospital. By that time, those with serious cases are gasping for air and face deadly lung problems due not to the virus, but to their body’s immune reaction against it. At that point, the pill can’t help.
That raises questions about whether Paxlovid will actually ease the pandemic. Even when patients are not that sick, there’s often a time lag while their infection is confirmed. For this reason, Pfizer has floated the idea of offering the drug to people while they wait for test results.
“The name of the game is speed,” says Myoung Cha, president of home-based care at Carbon Health, which operates walk-in medical clinics in the US. “Even if we had oral drugs available today, the testing debacle would prevent many people from getting treated.”
Pfizer is also running a study to see if the pills help people who’ve only been exposed to covid-19, as a sort of prophylactic treatment.
“It’s a tight window: two days to get tested and another two to get the drug.”
For now, there isn’t enough Paxlovid to go around, so the drug is being rationed—and so far in a chaotic fashion. The US Food and Drug Administration authorized the pills for anyone with a confirmed covid-19 infection and one risk factor for developing serious illness. But which risk factors qualify—and which patients should get the drug—is still up for debate.
Bob Wachter, head of medicine at the University of California, San Francisco, announced on Twitter that his hospital would be reserving the pills for people with compromised immune systems, like kidney transplant or cancer patients. The state of New York suggested that it might prioritize Black and Hispanic residents, reasoning that they are at higher risk because of health inequities.
The most significant risk factor for serious covid-19 is being unvaccinated—and it was unvaccinated people whom Pfizer studied in its human trial. If avoiding the shots puts you near the head of the line for the pills, people could take that as reason to stay unvaccinated. However, David Boulware, a doctor who studies covid-19 treatments at the University of Minnesota, suspects that people who refuse the vaccine might not be seeking treatment in time to get Paxlovid. He says patients in his hospital’s ICU are mainly vaccinated people with abnormal immune systems, or unvaccinated people who turn up short of breath and are already in considerable distress. Some have already tried “random” home remedies or disputed treatments like the antiparasite drug ivermectin.
“It’s a tight window: two days to get tested and another two to get the drug,” he says. “If you are sitting at home and think covid is a hoax, will you get tested quick enough? Because by the time you’re in the hospital, your disease is being driven by the body’s inflammation response and by then the antivirals don’t have a big role.”
In a statement, the World Health Organization said it believes “prevention is better than cure” and that “these drugs will not be alternatives to vaccines.” The organization, based in Geneva, has yet to make a formal recommendation in favor of Paxlovid and says it wants to track whether side effects emerge.
“It’s going to be very hard to use Paxlovid on a wide scale, because people are going to have to be tested and treated very early,” says Robert Shafer, a professor of medicine at Stanford University. “It’s just not going to have the same impact that vaccines will, and it will be a very expensive solution in comparison.”
A different strategy
Maybe like that. But the pills are still an important addition to the anti-covid arsenal.
Early in the pandemic, international organizations plowed billions into vaccine programs. They also gave priority to “repurposing” existing drugs, essentially searching pharmacy shelves for anything that might help. But designing a new, customized chemical drug didn’t get the same kind of public support. “The world seemed to give up on new antivirals before they even started,” Annette von Delft, a researcher at the University of Oxford, wrote in Nature last year.
Von Delft is part of an organization called Covid Moonshot that says it struggled to find funding for new antiviral pills. That’s despite some big successes with other antivirals, like the pills that keep HIV in check and, more recently, those that conquered hepatitis C. The group says one reason is that health authorities believed designing a new chemical from the ground up would take too long .
It’s true that such an effort involves unavoidable rounds of trial and error. “You can’t give a computer an enzyme and say, ‘Design me a drug for this.’ It might give you 100 ideas, but then you have to synthesize those,” says Michael Lin, a researcher at Stanford University. Synthesizing a single drug can take several weeks, and then you still have to learn its key properties, like whether it’s absorbed in the gut or broken down in the liver. All that is done through real-life tests on animals.
What’s more, some large drug companies have shifted away from antiviral research in recent years. Despite the successes with HIV and hepatitis C, the list of viruses affecting rich countries—viruses for which there’s no vaccine and where a pill could make money—hasn’t been very long. Academics like Icahn’s White, who is a specialist in influenza drugs, saw their career prospects dimming. “People didn’t think there were any more profitable viruses to treat,” says White. “There was a period there where it was hard to stay in business.”
But, it turns out, the chemists knew a few tricks that proved invaluable against the covid virus.
SARS-CoV-2 causes illness by injecting a cell with genetic material that gets the cell to copy the proteins needed to manufacture even more virus copies. As it turns out, a number of those viral proteins are generated as one long piece—think of a chain of connected sausage links. The job of the protease chemists were targeting is to cut this big “polyprotein” into working parts, something it does using a special molecular notch.
