What Happened to Paxlovid?

The COVID antiviral arrived too late for the Omicron wave, but it remains a powerful weapon.

Photo-Illustration: Intelligencer
Photo-Illustration: Intelligencer

Paxlovid, the COVID antiviral developed by Pfizer, was hailed as a miracle drug against COVID-19 when it was approved for use by the FDA in December. But it was nowhere to be found during the Omicron wave that followed and now is little discussed and underused, with doses reportedly piling up on pharmacy shelves. Has Paxlovid failed to live up to the hype as a pandemic game changer, or is it another effective defense against COVID that’s been unjustly snubbed by a misinformed public?

For a frontline view I turned to my brother-in-law, John Emy, a doctor of internal medicine who practices with CareMount Medical in Manhattan and has been prescribing Paxlovid to his patients with COVID. He said he’s a fan — with qualifications. “I think it’s a great drug. It’s certainly very effective. It starts working pretty quickly,” he told me over the phone while walking to work. “Usually within 24 hours, the symptoms start to improve.” He wondered how badly it was really needed, though. “It’s probably wasted on the mildly ill,” he said. “Before we had Paxlovid, plenty of people who had mild symptoms would get over it and they were fine.”

Five hours later, he texted me that he’d thought of another argument for taking Paxlovid. “By reducing viral load quickly it could reduce contagiousness,” he wrote, before dropping the lede: “I woke up feeling not great, but then much worse on the subway after I spoke with you. I have COVID.”

He was on the fence about taking Paxlovid. His symptoms were mild. He felt feverish and mentally fuzzy but his temperature was normal. As an extremely healthy marathon-runner who’s fully vaxxed, he wasn’t particularly worried about getting seriously ill. On the other hand, he’s got asthma, which is a risk factor for severe COVID. In the end, a talk with a colleague helped push him toward a decision. “I think I’d be fine without an antiviral,” he texted, “but I’m going to take it with the hope of getting back to work more quickly.”

The story of Paxlovid starts back in 2003, when the first SARS outbreak took place in Asia. Looking to develop a medication that could stop its spread, Pfizer started researching drugs that could block the action of a viral protein called a protease, which is necessary for the virus to replicate itself inside the host cell. One advantage of a medication like this, compared to a vaccine, is that it attacks a vulnerability of the virus that doesn’t mutate in the same way that the spike proteins targeted by vaccines do. That means it’s likely to be equally effective against all variants.

Pfizer’s preliminary research didn’t get too far before SARS petered out. But when SARS-CoV-2 popped up, they put the idea back on the fast track, ultimately trying out more than 600 candidate compounds in test tubes. The most promising were then tested in animals before being winnowed down once more for human trials.

Pfizer started testing Paxlovid in September 2021, enrolling patients who were suffering from mild to moderate symptoms — meaning they hadn’t been hospitalized yet — and were at high risk of their symptoms turning severe, either due to being over 65 or having comorbidities like obesity or diabetes. Pfizer expected the study to last into 2022, but was able to end the trial early because the results were so spectacular. It reduced hospitalizations in those who caught COVID by 90 percent and eliminated deaths entirely. Among the thousand or so trial participants who took the drug, none died, versus seven people in the control group.

Pfizer applied for emergency-use authorization in November and was approved five weeks later. At a time when vaccination rates had stalled out and Omicron infections were soaring, it seemed Paxlovid could prevent the deaths of a lot of Americans. “This anti-COVID pill has all the features of a breakthrough intervention at the time when we absolutely need it,” wrote Scripps’ Eric Topol in The Guardian.

But as the Omicron wave hit in the weeks that followed, there were very few doses of Paxlovid available, and by the time production ramped up enough to produce significant quantities, caseloads had fallen dramatically. Public demand was low.

To help things along, the Biden administration last month launched a program called “Test to Treat,” under which patients with COVID symptoms can go to a participating pharmacy, get a test, and immediately receive a five-day course of Paxlovid. The one-stop-shopping approach is designed to cut down on the time between the patient’s first symptoms and the time they take their first dose, because Paxlovid is meant to be taken within the first five days.

Judging by a website used to track the distribution and uptake of the drug, however, not many people are taking advantage of the offer. Of the 50 or so available sites listed in Manhattan, about half showed that their stocks are apparently untouched — even as case rates in the borough have risen some 400 percent since March 1.

There’s an obvious reason for that lack of interest, says epidemiologist Saad Omer, director of the Yale Institute for Global Health: Not enough people know that the program exists. “We need to have some meat-and-potatoes public-health information,” he says. “Any successful test-to-treat program is dependent on accurate, complete, timely information.”

It will also help if access to the program is expanded. For now, the emergency-use application only allows the drug to be prescribed to those with an increased risk of severe COVID, because that’s who took part in the trial. Other trials are currently underway to see if Paxlovid is safe and effective for children and for patients at a standard risk of severe symptoms — that is to say, the rest of the public. Pfizer is also testing Paxlovid on people who’ve potentially been exposed to COVID but haven’t yet tested positive. The latter study could yield results within the next few months, says Pfizer spokesman Kit Longley, while the other two “could have results by the end of the year.”

Another burning question is whether Paxlovid might be effective against long COVID. Last month, a team of researchers at Stanford published a preprint reporting the case of a previously healthy, double-dosed 47-year-old woman who came down with COVID and suffered symptoms for two days, then mostly felt better, but continued to feel fatigued and achy, with insomnia and cognitive difficulties — symptoms consistence with “Post-Acute Sequelae of SARS-CoV-2,” a.k.a. long COVID. Six months later, she was potentially exposed to COVID again, began experiencing symptoms, and was put on a course of Paxlovid. Soon after, “she reported being back to her normal, pre-COVID health status and function including working full-time and exercising rigorously.”

That’s encouraging, but not dispositive. “We have to be careful about reading too much into individual cases like this — they can’t by themselves prove anything, but they can suggest avenues for further research,” says Linda Geng, a professor of medicine at Stanford and the paper’s lead author. “There are some interesting hypotheses about how Paxlovid may be useful in the treatment of long COVID, but we’d need further investigation and clinical trials before coming to any conclusions.” To that, two Paxlovid trials are currently underway that will include a six-month follow of those taking part.

Regardless of how widely Paxlovid is rolled out, and how eagerly it’s taken up by the public, the most important thing to remember is that the best defense against COVID is to be fully vaxxed and boosted.

For his part, my brother-in-law, after deciding to take Paxlovid, wound up feeling much better the next morning. He gives most of the credit for that, though, to the mRNA jabs he’d gotten. “Thank God for the vaccines,” he texted. “I would probably have been much sicker had I not been vaccinated.”

What Happened to Paxlovid?