On June 1, Shionogi & Co., Ltd. of Japan announced that the U.S. FDA had approved its oral antiviral drug XOCOVA (ensitrelvir) for post-exposure prophylaxis against COVID-19. This is currently the first and only oral post-exposure prophylaxis drug approved in the U.S. market.

Ensitrelvir is a 3CL main protease inhibitor targeting SARS-CoV-2 , jointly developed by Hokkaido University and Shionogi & Co., Ltd. This drug selectively inhibits the activity of the main protease essential for viral replication, blocking viral amplification in the body. Ensitrelvir is administered orally as a single agent .

The FDA approval was based on the results of the global, multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial SCORPIO-PEP . The study enrolled nearly 2,400 household contacts living with COVID-19 patients in the United States, Argentina, Japan, South Africa, and Vietnam. Participants began taking medication within 72 hours of the index case developing symptoms.

Data from the primary analysis population (2041 individuals with negative baseline screening) showed that by day 10, the incidence of symptomatic COVID-19 was 2.9% in the enitrelvir group and 9.0% in the placebo group, representing a 67% reduction in relative risk (hazard ratio 0.33; 95% confidence interval: 0.22–0.49; p<0.0001). The secondary analysis population (2387 individuals, not excluding those with positive baseline central laboratory PCR) showed consistent results: the incidence of symptomatic COVID-19 was 4.4% in the enitrelvir group and 10.2% in the placebo group (hazard ratio 0.43; 95% confidence interval: 0.32–0.59; p<0.0001).

In terms of safety, the incidence of adverse events was similar in the ensitalvir group and the placebo group, at 15.1% and 15.5%, respectively. The most common adverse events (incidence ≥1% and higher than in the placebo group) were headache, diarrhea, and cough ; no COVID-related hospitalizations or deaths occurred during the entire trial.

Shionogi & Co. has a deep-rooted expertise in the antiviral field, with its COVID-19 research pipeline dating back to the early stages of the pandemic . XOCOVA (ensitrelvir) received emergency regulatory approval in Japan in November 2022, and in March 2024, based on the results of the SCORPIO-SR Phase 3 trial conducted during the Omicron epidemic in Asia, it received full approval for the treatment of mild to moderate COVID-19. In March 2026, the drug received further approval from the Japanese Ministry of Health, Labour and Welfare for a new indication: post-exposure prophylaxis, becoming the world's first oral 3CL protease inhibitor approved for this indication.

In the United States, Shionogi submitted a New Drug Application (NDA) to the FDA on September 2, 2025, and was granted Priority Review status, with a target action date of June 16, 2026. The FDA ultimately granted approval ahead of schedule on June 1. Currently, ensitrelvir is also under regulatory review in Europe .

In conclusion , Shionogi, a Japanese pharmaceutical company with a 148-year history, has once again demonstrated its R&D strength in the anti-infective field by expanding the indications of enstatrelvir from treatment to prevention. This FDA approval not only makes enstatrelvir the first oral post-exposure prophylaxis option for COVID-19 in the US market, but also adds an important pharmaceutical tool to global COVID-19 prevention and control strategies.

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