Raphael Thys
In the early days of the pandemic, all eyes were on potential vaccines. In May 2020, the US announced Operation Warp Speed, a plan to spend billions on vaccine development. But mostly out of sight of the news media, quieter efforts to custom-design a covid-19 pill were moving forward with similar urgency and hope.
Chemists at Pfizer’s research facility in Connecticut dusted off some ideas the company had developed during the SARS outbreak in 2003. Even back then, an obvious line of attack had been to block a well-understood component of the virus life cycle involving a key protease, a protein that orchestrates how the virus copies itself. Find a chemical that is able to stick tightly enough to that protein, and it would stop the virus from replicating in the body, lessening the chances that a patient would become seriously ill.
Right away, researchers got a lucky break. When Pfizer checked, it found that none of the thousands of proteins in the human body shared the same bit of molecular structure they planned to interfere with in SARS-CoV-2. That meant they could hit the virus hard and not expect any major side effects. Nature had provided the scientists with a big bull’s-eye. “This is the most solid biological target I have ever worked on,” says Pfizer chemist Dafydd Owen.
Pfizer sped the drug forward by testing hundreds of chemicals in parallel and then making big batches of the most promising one. Even as the first covid vaccines were authorized in the US in December 2020, animal studies were underway on the drug that would later be named Paxlovid. Human trials began in March 2021.
By the fall of 2021, Pfizer was ready to declare success. A monitoring board decided to stop the human study because covid-19 patients on Paxlovid weren’t dying—but those given the dummy drug were. “It was an incredible moment,” says Charlotte Allerton, Pfizer’s head of medicine design. Even though it trailed the vaccine development by nearly a year, Allerton believes Paxlovid still set a record—the fastest any drug company has ever moved from a synthesizing a new chemical to proving that it safely treats a disease.
A test in unvaccinated volunteers done by Pfizer had shown that the new pill cut the chance of a serious case of covid by 89%. And the results seemed to come at a perfect time. Infections and deaths were about to reach new heights. The new, fast-spreading omicron variant has infected millions of people each day just in the US. President Joe Biden, whose administration authorized the pill’s sale on December 22, 2021, touted it as “a game changer.”
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.
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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.
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 so. 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.
The next act for messenger RNA could be bigger than covid vaccines
The researchers knew if they could stuff that opening with a chemical that sticks to it very strongly—so strongly it can’t be detached—the protease wouldn’t do its job and the virus wouldn’t multiply. “To create a protease inhibitor, it’s like milling a key to fit a lock,” says Lin. “You want a drug that fits in that pocket perfectly and makes it unavailable.”
By mid-2020, chemists including Lin were tossing out proposals for chemical shapes that might work. But making and testing chemicals in a hurry is where the limitless R&D funds of big companies come into play. Pfizer was able to synthesize 800 molecules in all, according to the company.
After identifying the most promising ones, in September 2020, the company moved quickly. At that point, a company would normally invest in small production amounts for testing. But Owen wanted enough drug on hand to start a human study right away if it worked in animals. He took the gamble of speeding up production.
By December 2020, some of the first supplies of the new compound had reached White in New York. All eyes were on the vaccines from Moderna and Pfizer, which were approved that month. But in White’s lab, he was clearing his schedule so that Pfizer’s antiviral drugs could be given to mice infected with SARS-CoV-2. “I was extremely busy when Pfizer emailed, but we set up a Zoom and I moved them to the head of the line,” he says.
The first compound from Pfizer he tried was a bust. The second, Paxlovid, was an obvious hit, reducing the amount of virus in the mice’s bodies by a factor of one thousand or more. Within a year, the drug had gained authorization from the FDA.
Cost effective
In purchasing 10 million courses of Paxlovid for $5.3 billion, the US established a price of around $530 per course of pills—six tablets a day for five days. Italy, Germany, and Belgium also placed orders. According to Pfizer CEO Albert Bourla, the price of the vaccine (around $30 for each dose) helped determine what the new drug should cost.
For Pfizer, easy-to-take covid-19 pills could become another blockbuster. “It’s a license to make money. As much of it as they can make, they can sell to governments,” says Boulware. “Demand will outstrip supply, and that is going to be the case for the foreseeable future.”
But even at around $500 per person, Paxlovid could be a bargain. If Pfizer’s trial numbers stand up, doctors who give the drug to the patients at greatest risk could save about one person for every 100 they treat. That’s $50,000 for a life. Medical economists say the drugs even have the chance of being “cost negative”—that is, they’ll save money if they keep enough people out of the hospital, since each hospitalization costs thousands of dollars.
One area where antiviral pills have an edge is as an insurance policy against new variants—or even different coronaviruses that are yet to be discovered. Covid-19 has surprised scientists again and again by mutating in ways that allow it to spread faster or even evade immunity. Of the antibody drugs authorized to treat covid-19, several, such as the one sold by biotech company Regeneron, no longer work against omicron.
Resistance like that occurs because the virus continually changes its “spike”—the molecule it uses to get into cells, and the one targeted by vaccines and antibodies. Being able to shape-shift the spike gene, which is the most exposed part of the virus, is probably an evolutionary survival strategy—one that lets coronaviruses adapt to new species and dodge immune reactions. But researchers don’t think the virus can so easily evolve ways of dodging Paxlovid. That’s because the protease is very finely tuned for its job, so much so that even distantly related viruses have proteases that look very similar.
Could a Paxlovid-resistant form of covid-19 appear? It could—the protease could conceivably evolve enough to dodge the drug. But such a variant might be less good at copying itself and probably wouldn’t spread very far. “I don’t think that resistance is a big concern,” says Shafer, who maintains a database of drug-resistant types of HIV at Stanford University. “Changes to the protease are bad for the virus.” A treatment that lasts just five days also doesn’t give much time for the virus to evolve resistance, he says.
The less changeable nature of the protease gene—even among cousin germs—is also why Pfizer’s drug might prove useful against viruses we haven’t encountered yet. Laboratory tests run by the company show that in addition to blocking the growth of SARS-CoV-2 in cells, it also inhibits half a dozen other coronaviruses. These include MERS, a dangerous germ spread by camels that kills a third of the people who get it; the original SARS virus from 2003; and a handful of coronaviruses that cause only colds.
And although Paxlovid is the most promising antiviral out there for covid-19 right now, more than a dozen new antivirals are now in development; the next generation could be even better. That’s what happened with HIV. There are now so many effective HIV drugs on the market that the original protease inhibitors have been relegated to second-line treatment.
New pills for other viral diseases could be on the way too. In June 2021, the US finally turned its attention back to antivirals in a big way, announcing it would spend $3 billion on a major search for next-generation drugs. About half that money will pay to establish eight to 10 new antiviral research centers that will each work on covid-19 and another germ of their choice, like Ebola or the common cold.
“The espoused goal is to have something that’s off the shelf the next time one of these major public health threats emerges—actually, we want to have many things,” says Matthew Frieman, a coronavirus specialist at the University of Maryland School of Medicine, who is among those applying for the funds. According to Frieman, the idea is that coronaviruses could one day be treated with a combination of antiviral drugs, similar to the “cocktails” used to control HIV. “It’s the same idea: the more drugs in combination, the better,” he says. “And you protect against mutant viruses, because it’s harder to escape from two drugs than one. I think we need a suite of antivirals that target this virus.”
It may even be possible to find drugs that work against nearly any virus, even ones as different as Ebola and influenza. Frieman says he’s found some compounds that may do that by acting on the human body, rather than on parts of the virus. “We’re hoping there are a whole new spectrum of ways to target viruses,” he says. “We just need to find them. In the past, we had no funding because no one cared. I think we have only scratched the surface.”
