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.
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 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 end point of preventing COVID-19 after exposure. If approved, ensitrelvir would become the first oral therapy available in the United States for postexposure prophylaxis of COVID-19.1
Clinical Trial Evidence
At the 2025 Conference on Retroviruses and Opportunistic Infections,
Results were consistent in a broader analysis of 2387 participants, with rates of 4.4% and 10.2% in the ensitrelvir and placebo groups, respectively (risk ratio, 0.43; 95% CI, 0.32-0.59; 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
Background and Mechanism
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 (3CL) 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.
Prior Clinical Evidence
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 5 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 postexposure prophylaxis and remains under regulatory review in multiple regions, including the European Union and Taiwan. In 2025, Shionogi also submitted NDAs in Japan for postexposure prophylaxis and for treatment in children aged 6 to 12 years. Pediatric trial data indicated that ensitrelvir was safe, was well tolerated, and had pharmacokinetics similar to those observed in adults.1
Experts emphasized that postexposure 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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