FDA Approves Oral Ensitrelvir for COVID-19 Postexposure Prophylaxis

The FDA recently approved ensitrelvir (Xocova; Shionogi), an anti–SARS-CoV-2 oral drug for postexposure prophylaxis (PEP) of COVID-19, for adults and adolescents 12 years of age and older.¹ Ensitrelvir is now approved in the US and Japan for PEP against COVID-19 for individuals in this age group who have had contact with someone who has COVID-19.

The approval was based on evidence from the global phase 3 clinical trial SCORPIO-PEP (NCT05897541), which demonstrated favorable safety and efficacy in uninfected pediatric and adult patients who had been exposed to an infected individual, reducing the risk of symptomatic COVID-19 by 67%. The agent, which was also approved in Japan in March 2024 to treat COVID-19 based on results from the SCORPIO-SR phase 3 study, is now the first and only oral PEP option for COVID-19 and could help combat declining vaccination rates, waning immunity, and emerging strains of COVID-19.

The manufacturer, Shionogi, submitted a supplemental New Drug Application in Japan in July 2025 to extend the approved dosage and administration of ensitrelvir to include treatment for pediatric patients 6 years and older weighing 20 kg or more.^1,2

Ensitrelvir is a 3CL protease inhibitor that suppresses the replication of SARS-CoV-2 by inhibiting the 3CL protease. The SCORPIO-PEP trial met its primary end point of preventing COVID-19 following exposure to an infected individual. The primary efficacy end point was a confirmed COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test within 10 days of drug or placebo administration in participants who were negative at baseline.¹

“The PEP strategy has the potential to benefit anyone who does not want to get COVID-19,” Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine, said in a press release. “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.”

The trial was conducted from June 10, 2023, to September 2024.

A total of 2387 patients who tested negative for COVID-19 but had been exposed to someone in their household with symptomatic COVID-19 were randomly assigned 1:1 to once-daily ensitrelvir (375 mg on day 1 and 125 mg on days 2-5; n = 1030) or a placebo (n = 1011) within 72 hours of when the household member with COVID-19 began showing symptoms.

Nasopharyngeal swabs were obtained from participants on days 1, 3, 6, 10, 15, 21, and 28 for RT-PCR detection of SARS-CoV-2. Study participants kept a log of 14 symptoms associated with COVID-19.

There was a significant difference in the primary end point between the ensitrelvir group and the placebo group. Ensitrelvir reduced the risk of symptomatic COVID-19 by 67% in uninfected individuals following exposure to an infected individual through day 10 when compared with the placebo.

The trial also met its secondary end point, with the ensitrelvir group having a lower rate of symptomatic, laboratory-confirmed SARS-CoV-2 infection in a household contact within 10 days after administration of the trial drug or placebo in patients who were either RT-PCR positive or negative at baseline.

Ensitrelvir was well tolerated overall, as there were similar rates of adverse events across the ensitrelvir group (15.1%) and the placebo group (15.5%). The most common adverse events that occurred in at least 1% or more of participants in the ensitrelvir group were headache, diarrhea, and cough.

“[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,” Nathan McCutcheon, president and CEO of Shionogi, said in a press release. “With [ensitrelvir], people who are exposed to COVID-19 can act early to help protect themselves.”

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. June 1, 2026. Accessed June 1, 2026. https://www.shionogi.com/global/en/news/2026/06/20260601.html

2. Shionogi announces approval in Japan of a supplemental indication for Xocova (ensitrelvir fumaric acid) for the post-exposure prophylaxis of COVID-19. News release. Shionogi. March 23, 2024. Accessed May 14, 2026. https://www.shionogi.com/global/en/news/2026/03/20260323_1.html

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