New Oral Antiviral Slashes COVID-19 Risk After Exposure, Phase 3 Trial Finds

In a major development for pandemic management, a new oral antiviral has demonstrated the ability to significantly prevent symptomatic COVID-19 in individuals recently exposed to the virus. Data from the phase 3 SCORPIO-PEP study, published in the New England Journal of Medicine, show that Shionogi’s investigational drug, ensitrelvir, reduced the risk of developing the disease by 67% compared to a placebo.

The study marks a milestone in infectious disease research as the first and only phase 3 trial of an oral antiviral to successfully meet its primary end point for post-exposure prophylaxis (PEP). Currently, there are no FDA-approved oral therapies specifically designed to prevent COVID-19 after a person has been exposed but before they become ill.

Targeting the Replication Window

Ensitrelvir works by selectively inhibiting the SARS-CoV-2 main protease, an enzyme essential for viral replication. By blocking this process during the critical window between exposure and the onset of symptoms, the drug aims to stop the infection before it can take hold.

The global, double-blind trial involved 2041 household contacts who initially tested negative for the virus and showed no symptoms. Participants began a 5-day course of either ensitrelvir or a placebo within 72 hours of a household member becoming symptomatic. By Day 10, only 2.9% of those taking ensitrelvir developed symptomatic COVID-19, compared to 9.0% in the placebo group.

“People taking ensitrelvir within 72 hours after household exposure were three times less likely to develop COVID-19,” noted Frederick Hayden, MD, Professor Emeritus at the University of Virginia School of Medicine, in a news release. He emphasized that these results underscore the drug’s potential to protect individuals in high-risk settings.

Enhanced Protection for High-Risk Groups

The data were even more striking for vulnerable populations. In a prespecified subgroup analysis of participants with 1 or more risk factors for severe disease—such as obesity or chronic illness—ensitrelvir provided a 76% reduction in the relative risk of developing symptomatic disease.

Safety data from the trial were equally encouraging. Ensitrelvir was generally well-tolerated, with adverse event rates nearly identical to the placebo group (15.1% vs 15.5%). Common adverse effects included headache and fatigue, but notably, there were no reports of altered taste (dysgeusia), a side effect often associated with other COVID-19 treatments.

A New Tool Against Emerging Variants

The timing of these results is critical as public health officials monitor new SARS-CoV-2 variants, including the heavily mutated Omicron subvariant BA.3.2, nicknamed “Cicada,” which is currently circulating in dozens of US states.

Aeron Hurt, PhD, Vice President at Shionogi, pointed out that preventing the initial infection does more than just stop a cough; it may also help patients avoid long COVID or the exacerbation of pre-existing chronic conditions. "Ensitrelvir cuts the chances of developing COVID-19 by two-thirds, which is substantial, particularly in households where the risk of spread is high," Hurt said.

The drug, already approved in Japan under the brand name Xocova, is currently under priority review by the FDA. A final decision is expected by June 16, 2026. If approved, ensitrelvir could become the first oral antiviral available to Americans as a preventative measure following exposure to the virus.

REFERENCE

New England Journal of Medicine Publishes Shionogi Study Demonstrating Ensitrelvir Prevents COVID-19 Following Exposure. News release. Shionogi. May 13, 2026. Accessed May 13, 2026. https://www.shionogi.com/us/en/news/2026/05/new-england-journal-of-medicine-publishes-shionogi-study-demonstrating-ensitrelvir-prevents-covid-19-following-exposure.html