FDA Approves Ensitrelvir for Post-Exposure Prophylaxis of COVID-19 in Adolescents and Adults

The FDA has approved the oral antiviral ensitrelvir (Xocova; Shionogi & Co, Ltd) for postexposure prophylaxis (PEP) of COVID-19 in adults and adolescents 12 years and older following contact with an individual who has COVID-19. This approval introduces the first and only oral option to help prevent COVID-19 after exposure in the current therapeutic landscape, addressing a critical gap in prevention.¹

“[Ensitrelvir] 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 [ensitrelvir], people who are exposed to COVID-19 can act early to help protect themselves,” Nathan McCutcheon, president and CEO of Shionogi Inc, said in the news release.¹

What is Ensitrelvir?

Ensitrelvir is a main protease inhibitor of SARS-CoV-2. The virus has an enzyme called the main protease, which is essential for viral replication, and ensitrelvir suppresses SARS-CoV-2 replication by selectively inhibiting the main protease. It is a 5-day oral regimen with 3 tablets taken on day 1, and 1 tablet taken on days 2 through 5.¹

According to the news release, the approval occurred ahead of the Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026. The drug is currently approved in the US and Japan.¹

“The FDA approval of [ensitrelvir] 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,” Frederick Hayden, MD, Stuart S. Richardson Professor Emeritus of Clinical Virology and professor emeritus of medicine, University of Virginia School of Medicine, said.¹

Clinical Data Supporting Ensitrelvir’s Approval

The treatment’s approval is supported by positive findings from the SCORPIO-PEP trial (NCT05897541), a randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety and efficacy of ensitrelvir in preventing symptomatic SARS-CoV-2 infection in household contacts of an individual with symptomatic COVID-19.^1,2

Enrolled patients were randomly assigned to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5; n = 1030) or placebo (n = 1011) within 72 hours after symptom onset in the index patient. SCORPIO-PEP’s primary end point was COVID-19 (defined by a central laboratory–confirmed positive reverse transcriptase–polymerase chain reaction [RT-PCR] assay and the presence of ≥ 1 of 14 prespecified COVID-19 symptoms lasting ≥ 48 hours) by day 10 in a household contact in the modified intention-to-treat population (all the participants who underwent randomization, had a central laboratory–confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least 1 dose of the trial drug or placebo). Findings were published in The New England Journal of Medicine.^2,3

The incidence of COVID-19 was lower in the ensitrelvir group (2.9%) than in the placebo group (9.0%; risk ratio, 0.33 [95% CI, 0.22-0.49]; P < .001). Notably, the incidence of adverse events (AEs) during the trial was similar in the 2 groups: approximately 15.1% of patients in the ensitrelvir group reported an AE compared with 15.5% in the placebo group. Approximately 0.2% of patients in each group experienced a serious AE. Importantly, no hospitalizations or deaths specifically related to COVID-19 were reported.³

“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,” Hayden said.¹

REFERENCES

1. Shionogi announces FDA approval of XOCOVA (ensitrelvir), the first and only oral option to help prevent COVID-19 following exposure. News release. Shionogi & Co, Ltd. June 1, 2026. Accessed June 2, 2026. https://www.shionogi.com/global/en/news/2026/06/20260601.html..html

2. Phase 3 study of S-217622 in prevention of symptomatic SARS-CoV-2 infection (SCORPIO-PEP). ClinicalTrials.gov. Updated August 6, 2025. Accessed June 2, 2026. https://clinicaltrials.gov/study/NCT05897541

3. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for Covid-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306