New Antivirals Show Promise for Preventing and Treating COVID-19

An antiviral pill has, for the first time, been shown to prevent COVID-19 in people exposed to the SARS-CoV-2 virus at home, according to trial results published today in the New England Journal of Medicine. The drug, called ensitrelvir, is made by the Japanese pharmaceutical company Shionogi. It blocks an enzyme that coronaviruses need to make new copies of themselves, hitting the same target as one of the two active ingredients in Pfizer’s antiviral Paxlovid. The drug could be a lifeline for those who still face real danger from the virus, such as care-home residents or transplant recipients on immune-suppressing medication.

In an international study of more than 2,000 household contacts conducted from June 2023 to September 2024, about 9% of people who got a placebo within 72 hours of a housemate developing symptoms became symptomatic themselves, compared with only about 3% of those who got a five-day course of ensitrelvir. Confirmed infections, symptomatic or not, turned up in only 14.0% of those who received the drug, compared with 21.5% of those who got a placebo. The therapy generally proved tolerable, without the taste-related side effects often seen with Paxlovid.

Japan’s health ministry approved ensitrelvir, marketed as Xocova, in March for post-exposure use on the strength of these trial data. Regulators in the United States, Europe and elsewhere are considering whether to follow suit, with a US decision expected in the next month or so. The advance arrives years after the peak of the COVID-19 pandemic, so the real-world impact might be felt by only a narrow band of individuals. The success of ensitrelvir lands in a field marked by repeated setbacks: Paxlovid is the closest a pill has come to demonstrating post-exposure protection, cutting infections by roughly 30% compared with placebo in a household-prevention trial, but the effect fell short of statistical significance. Other antivirals and antibody infusions have likewise come up short.

In a separate development, researchers have redesigned the hepatitis C drug boceprevir to create a more effective treatment for COVID-19. Some virus variants no longer respond well to current therapies, like Paxlovid, due to mutations in the main COVID-19 virus protease (Mpro), a key enzyme the virus uses to replicate. Using X-ray crystal structures, scientists refined boceprevir atom by atom to improve how the drug binds within key pockets of the enzyme. The resulting compound, ML2006a4, binds more tightly and durably than earlier drugs and shows superior protection in preclinical animal studies. It binds covalently to Mpro and retains strong activity even against variants harboring resistance-associated mutations. The research was published in Science Translational Medicine.

COVID-19 still causes tens of thousands of deaths and hundreds of thousands of hospitalizations each year in the United States alone.