FDA approves ensitrelvir for post-exposure prevention of COVID-19 in adolescents and adults

The FDA has approved XOCOVA (ensitrelvir) for post-exposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older following contact with an individual who has COVID-19, according to an announcement from Shionogi. The decision makes ensitrelvir the first oral antiviral approved in the United States to help prevent COVID-19 after exposure.¹

The approval was based on findings from the phase 3 SCORPIO-PEP trial, recently published in the New England Journal of Medicine, which evaluated ensitrelvir among household contacts of individuals with symptomatic COVID-19. The study enrolled participants who tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and initiated treatment within 72 hours after symptom onset in the infected household member.²

For pediatricians, the approval introduces a potential new option for adolescents aged 12 years and older who are exposed to COVID-19 in household settings. Although severe outcomes remain less common in children and adolescents than in older adults, COVID-19 continues to contribute to outpatient visits, hospitalizations, and disruptions to school and family activities.

^{Phase 3 trial demonstrates reduction in symptomatic infection}

The randomized, double-blind, placebo-controlled study included 2,041 participants in the modified intention-to-treat population, including adolescents and adults who had laboratory-confirmed negative SARS-CoV-2 tests at baseline. Participants were randomly assigned to receive ensitrelvir or placebo for 5 days.

Investigators reported that symptomatic COVID-19 developed in 2.9% of participants receiving ensitrelvir compared with 9.0% of those receiving placebo by day 10. This corresponded to a risk ratio of 0.33 (95% CI, 0.22-0.49; P < .001), representing a 67% relative reduction in the risk of symptomatic COVID-19.

The mean participant age was 42.4 years, and approximately 71% were enrolled within 48 hours of symptom onset in the index patient. More than one-third of participants had at least 1 risk factor for severe COVID-19. No COVID-19-related hospitalizations or deaths occurred during the trial.

According to the company, SCORPIO-PEP is the first phase 3 study of an oral antiviral agent to meet its primary endpoint for prevention of symptomatic COVID-19 following exposure to an infected individual.

^{Safety findings support use after exposure}

Safety outcomes were similar between groups. Adverse events occurred in 15.1% of participants receiving ensitrelvir and 15.5% of those receiving placebo. Serious adverse events were reported in 0.2% of participants in each group.

The most frequently reported adverse events occurring in at least 1% of participants receiving ensitrelvir and more commonly than placebo were headache, diarrhea, and cough. Investigators reported no cases of altered taste attributed to the medication during the study.

“The FDA approval of XOCOVA provides an important new approach to preventing COVID-19, which continues to impact lives. COVID-19 can become severe and even when mild or moderate, it can worsen or exacerbate chronic conditions or trigger new ones, including long COVID,” said Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine at the University of Virginia School of Medicine.

“Ensitrelvir inhibits viral replication, helping protect people who have been exposed to COVID-19 from developing illness. The PEP strategy has the potential to benefit anyone who does not want to get COVID-19. It could be useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities and following travel-related exposures.”

Nathan McCutcheon, president and CEO of Shionogi Inc., said the approval expands options for individuals exposed to SARS-CoV-2.

“The FDA approval of XOCOVA is an exciting new chapter in the Shionogi antiviral story, which includes innovative medicines that have changed the way we manage other viruses including HIV and influenza,” McCutcheon said.

“XOCOVA is the first and only oral option clinically proven to help prevent symptomatic COVID-19 after exposure among study participants regardless of vaccination status or baseline immunity from prior infection. With XOCOVA, people who are exposed to COVID-19 can act early to help protect themselves.”

References

1. Shionogi. Shionogi Announces FDA Approval of XOCOVA® (ensitrelvir), thJe First and Only Oral Option to Help Prevent COVID-19 Following Exposure. Shionogi. June 1, 2026. Accessd June 2, 2026. https://www.shionogi.com/global/en/news/2026/06/20260601.html..html

2. Ikematsu H, Hayashi K, Kaku N, et al. Ensitrelvir for postexposure prophylaxis of Covid-19. N Engl J Med. 2026;395. doi:10.1056/NEJMoa2602453.