Ensitrelvir Reduced Symptomatic COVID-19 Risk After Exposure in Phase 3 Trial

A 5-day course of the investigational oral antiviral ensitrelvir reduced the risk of symptomatic COVID-19 after household exposure to an infected individual, according to findings from the phase 3 SCORPIO-PEP clinical trial published in The New England Journal of Medicine.¹

“Ensitrelvir works to inhibit viral replication, helping protect people who have been exposed to COVID-19 from becoming sick. In this study, people taking ensitrelvir within 72 hours after household exposure were three times less likely to develop COVID-19 compared with those given placebo,” first study author Frederick Hayden, MD, Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine, said in a press release. “These first, clearly positive results with an oral antiviral underscore ensitrelvir’s potential to protect a range of individuals from COVID-19, including those at higher risk of severe disease and potentially in other settings.”²

The global, double-blind, randomized, placebo-controlled trial evaluated ensitrelvir as postexposure prophylaxis in individuals aged 12 years and older who had a negative local screening test for SARS-CoV-2 infection, no symptoms at enrollment, and household exposure to a person with symptomatic COVID-19. In the primary analysis population of 2041 household contacts with centrally confirmed negative SARS-CoV-2 tests, symptomatic COVID-19 through day 10 occurred in 2.9% of participants treated with ensitrelvir vs 9.0% of those assigned to placebo, corresponding to a 67% relative risk reduction (risk ratio, 0.33; 95% CI, 0.22-0.49; P < .001).¹

Ensitrelvir is an oral SARS-CoV-2 main protease inhibitor that suppresses viral replication by selectively inhibiting the main protease required for replication. In SCORPIO-PEP, participants were randomly assigned 1:1 to ensitrelvir or placebo and began treatment within 72 hours of symptom onset in the household index patient. Ensitrelvir was administered as 375 mg on day 1 followed by 125 mg once daily on days 2 through 5.^1,2

The trial included 2387 participants overall and was conducted from June 2023 through September 2024. More than 98% of household contacts had evidence of prior SARS-CoV-2 infection, vaccination, or both, based on positivity for SARS-CoV-2 N and/or S antibodies.¹

A prespecified subgroup analysis of participants with at least 1 risk factor for severe disease also favored ensitrelvir. In that group, symptomatic COVID-19 through day 10 occurred in 2.4% of participants who received ensitrelvir compared with 9.9% of those who received placebo, representing a 76% relative risk reduction (risk ratio, 0.24; 95% CI, 0.12-0.49).¹

Ensitrelvir was generally well tolerated, with similar adverse event rates in the ensitrelvir and placebo groups, at 15.1% and 15.5%, respectively. The most common treatment-emergent adverse events, reported in at least 1% of participants, were headache, diarrhea, nasopharyngitis, cough, fatigue, and influenza. No altered taste, or dysgeusia, was attributed to ensitrelvir in the trial.¹

Ensitrelvir is under FDA review for postexposure prophylaxis of COVID-19, with a Prescription Drug User Fee Act action date of June 16, 2026. The agent is approved in Japan, where it is known as Xocova, but remains investigational outside Japan.²

References:

1. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. Published online May 13, 2026. doi:10.1056/NEJMoa2509306
2. Shionogi. New England Journal of Medicine Publishes Shionogi Study Demonstrating Ensitrelvir Prevents COVID-19 Following Exposure. News release. May 13, 2026. Accessed May 15, 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