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Japan is home to an untold number of conveniences and delights that American consumers regularly go without: Faster public transit! Better sunscreen! Lychee KitKats! But as we head into sick season, one Japanese invention would be especially welcome on the U.S. market: an antiviral pill that appears to shorten COVID symptoms, might protect against chronic disease, and doesn’t taste like soapy grapefruit.
Ensitrelvir, a drug made by the Osaka-based pharmaceutical company Shionogi, was conditionally approved in Japan last November. Like Paxlovid, ensitrelvir works by blocking an enzyme that the SARS-CoV-2 virus uses to clone itself inside the human body. But for the millions of Americans who will likely get COVID in the coming months, the new drug is almost certain to be out of reach. In 2021, Pfizer waited just five weeks for Paxlovid to receive its emergency use authorization. But ensitrelvir is still sitting in the approval pipeline, stuck in another round of clinical trials that may run well into 2024.
Existing data (not all of which have been peer-reviewed) show that people with COVID who promptly take ensitrelvir, marketed as Xocova in Japan, test negative about 36 hours faster than people who take a placebo. Fever, congestion, sore throat, cough, and fatigue disappear about a day earlier too. Even smell and taste loss appear to resolve more quickly. The company also has some tentative evidence suggesting that the drug can help protect patients from developing long COVID.
These findings were not enough for the FDA, but they are extremely encouraging, says Michael Lin, a bioengineering professor at Stanford University who works on drugs for treating coronavirus infections. Xocova “looked as good or a little bit better than Paxlovid,” he says. For instance, Pfizer’s clinical trials failed to show that Paxlovid clears symptoms any faster than a placebo in people who aren’t at high risk of developing severe COVID. Shionogi’s did just that.
Reshma Ramachandran, a family physician at Yale, told me that if the early Xocova results hold up in additional trials, she’d be inclined to prescribe it to her vaccinated patients in place of Paxlovid, simply because the evidence supporting its use is more direct. She said she’d be especially keen to give Xocova if the long-COVID finding can be reproduced.
No lab or pharmaceutical company has yet published a study that pits Xocova against Paxlovid head-to-head in treating COVID, so it’s impossible to say with certainty which one is better. You can’t draw conclusions just by comparing Pfizer’s clinical-trial results with Shionogi’s: Their drugs were tested in different populations with different levels of immunity at different points in the pandemic when different variants were circulating. Shionogi also required clinical-trial participants to start taking Xocova within three days of feeling sick, whereas patients in the Paxlovid trials began their treatment up to five days after symptoms started. Daniel Griffin, an infectious-disease specialist at Columbia University, told me that timing is everything when it comes to antivirals: In general, the sooner a patient starts taking a drug, the better it works.
A Pfizer spokesperson told me that the efficacy and adverse-event rates of Paxlovid and Xocova cannot directly be compared, and emphasized Paxlovid’s power to stave off hospitalization and death. (Xocova’s clinical trials were not able to provide meaningful data on those outcomes, which are now much rarer than they were in 2021.) “Since the beginning of the pandemic, we’ve known it will take multiple treatment options and preventative measures for the world to overcome the challenges of COVID-19,” he said in an email.
Even if Xocova turns out to be no more effective than Paxlovid, it still has several practical advantages. For one thing, it is literally easier to swallow. Paxlovid must be taken twice a day for five days, and each time you have to gulp down three pills: two containing nirmatrelvir (which actively combats the virus), plus one containing ritonavir (which slows the metabolism of nirmatrelvir, keeping it in your system longer). Xocova is taken just once a day for five days, and after the first three-pill dose, it’s one pill at a time. Paxlovid can also cause dysgeusia, a.k.a. Paxlovid mouth—a sour, metallic, taste that may last for hours after swallowing. Xocova seems to taste just fine.
Experts hope that Xocova will be more widely accessible than Paxlovid, too. Pfizer announced last week that the price of Paxlovid will soon rise from $529 to $1,390 when the drug enters the commercial market. Shionogi hasn’t decided on Xocova’s price in the U.S. market, but there’s reason to think it will be cheaper. In Japan, the only market where both drugs are currently available, a course of Xocova costs 51,851 yen (about $346), and Paxlovid is nearly double the price, at 99,027 yen (about $661). And whereas Japanese health authorities—like those in the U.S.—have recommended Paxlovid for use by patients at high risk of severe COVID, Xocova has been shown to benefit people with infections regardless of their risk status. Finally, whereas Paxlovid’s reach is limited by its many harmful interactions with other drugs, Xocova might pose fewer problems because it doesn’t contain ritonavir, Lin told me. The newer drug’s interaction profile is still being ironed out, but a company spokesperson pointed me to a running list from the University of Liverpool. (According to that source, you should avoid taking Paxlovid and Adderall at the same time—but going on Xocova is fine.)
Xocova may also sidestep one of patients’ most commonly voiced concerns about Paxlovid: that it will make their COVID go away and then return. One recent observational study of COVID patients found that symptoms rebounded among 19 percent of Paxlovid takers, versus 7 percent of nontakers. By contrast, Shionogi has reported that symptom rebound was vanishingly rare in its clinical trials of Xocova.
Neither Shionogi nor the FDA would give me an estimate of Xocova’s approval timeline in the U.S., but earlier this year, the company’s CEO estimated that it might get the nod in late 2024. This past spring, the FDA gave the drug “fast track” status, which means Xocova will be eligible for an expedited review process once the company submits its application. (The FDA declined to comment on Xocova’s prospects for approval, citing federal disclosure laws.) Until then, it’s running more clinical trials in the U.S. and abroad. One of them, conducted in partnership with the National Institutes of Health, will evaluate the drug’s performance in hospitalized patients. Another will evaluate its efficacy against long COVID, among other things.
To some experts, Xocova’s track is not nearly fast enough. David Boulware, an infectious-disease specialist at the University of Minnesota, told me that the FDA appears to be “slow walking” the approval process. Lin, too, would like to see more action. But it’s not clear how, exactly, that would happen. “I think the FDA is doing all that they can,” Ramachandran said; an emergency use authorization for Xocova isn’t a realistic option, given that the COVID public-health emergency has expired. Plus, Griffin said, caution is prudent when dealing with new drugs. “We want to make sure it’s safe. We want to make sure it’s effective,” he told me. “We also don’t want to fall into the trap we fell in with molnupiravir,” an earlier antiviral that looked promising at first, but ultimately offered disappointing benefits to COVID patients (though a surprising utility for cats).
If the FDA were to approve Xocova tomorrow, demand for Paxlovid likely wouldn’t disappear, experts told me. Lin said the two drugs might compete for users, like Motrin and Aleve. People who are in danger of being hospitalized or dying from COVID could still opt for Paxlovid. “But there’s a much larger group of people who just feel crummy, and they just want to feel better,” Griffin told me. For them, Xocova could make more sense. They just won’t have a choice until the FDA approves it.
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Rachel Gutman-Wei
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