Supported by Phase 3 SCORPIO-PEP trial data, ensitrelvir could become the first oral therapy to prevent COVID-19 following exposure, with an FDA decision due June 16, 2026.
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The US Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for ensitrelvir, an investigational oral antiviral developed by Shionogi Inc, for the prevention of COVID-19 following exposure to an infected individual. The agency has set a Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026.1
The NDA is supported by results from SCORPIO-PEP, a global, double-blind, randomized, placebo-controlled Phase 3 trial and the first to meet its primary endpoint of preventing COVID-19 after exposure. If approved, ensitrelvir would become the first oral therapy available in the United States for post-exposure prophylaxis of COVID-19.1
At the 2025 Conference on Retroviruses and Opportunistic Infections (CROI), Shionogi reported that ensitrelvir significantly reduced the risk of symptomatic COVID-19 in exposed individuals. Among 2,041 household contacts with negative SARS-CoV-2 screening tests, 2.9% of participants receiving ensitrelvir developed symptomatic COVID-19 by day 10, compared with 9% in the placebo group (risk ratio, .33; 95% CI, .22–.49; P<.0001). This represents a 67% relative risk reduction.2
Results were consistent in a broader analysis of 2,387 participants, with rates of 4.4% versus 10.2% in the ensitrelvir and placebo groups, respectively (risk ratio, .43; 95% CI, .32–.59; P<.0001).2
Ensitrelvir was well tolerated, with adverse events reported in 15.1% of the treatment group and 15.5% of the placebo group. No COVID-19–related hospitalizations or deaths occurred.2
COVID-19 remains highly transmissible, with up to 50% of individuals living with an infected household member developing infection. Current interventions include vaccines, which are administered before exposure, and antivirals such as nirmatrelvir-ritonavir, which are given after diagnosis once viral replication is established. No oral antivirals are currently approved to prevent infection after exposure.1
Ensitrelvir is a SARS-CoV-2 main protease (3-CL) inhibitor that blocks viral replication by selectively inhibiting this enzyme. The drug is marketed as Xocova in Japan and Singapore, where it has already received regulatory approval for treatment of COVID-19.1
The FDA has accepted Shionogi’s NDA for ensitrelvir, an investigational oral antiviral for COVID-19 prevention after exposure.
Phase 3 SCORPIO-PEP demonstrated significant reduction in infection risk compared with placebo.
Ensitrelvir, marketed as Xocova in Japan and Singapore, is also under regulatory review in Europe and Asia.
Data from SCORPIO-SR, a Phase 3 trial conducted in Asia during the Omicron-dominant phase, demonstrated symptomatic efficacy and antiviral activity in patients with mild-to-moderate COVID-19. The trial included predominantly vaccinated participants and showed faster symptom resolution for five common Omicron-related symptoms. Most adverse events were mild, with no deaths reported. Common laboratory findings included transient decreases in high-density lipoprotein and increases in triglycerides. Results from SCORPIO-SR were published in JAMA Network Open.1
Ensitrelvir received US FDA Fast Track designation in 2025 for post-exposure prophylaxis and remains under regulatory review in multiple regions, including the European Union and Taiwan. In 2025, Shionogi also submitted NDAs in Japan for post-exposure prophylaxis and for treatment in children aged 6–12 years. Pediatric trial data indicated that ensitrelvir was safe, well tolerated, and had pharmacokinetics similar to those observed in adults.1
Experts emphasized that post-exposure prophylaxis could be a critical tool for individuals at high risk of severe disease, including older adults, immunocompromised patients, and residents of congregate settings. If approved by the FDA, ensitrelvir would represent the first oral antiviral option for preventing COVID-19 infection following exposure, addressing a key gap in prophylactic care for SARS-CoV-2.1
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