Shionogi & Co., Ltd. announced groundbreaking results from its Phase 3 SCORPIO-PEP trial at the Conference of Retroviruses and Opportunistic Infections (CROI) 2025, demonstrating that ensitrelvir is the first and only COVID-19 oral antiviral to successfully prevent COVID-19 as post-exposure prophylaxis.
The global, double-blind, randomized, placebo-controlled study showed that ensitrelvir (generic name: ensitrelvir fumaric acid) reduced the risk of developing COVID-19 by 67% in uninfected individuals who had been exposed to the virus, compared to placebo. Currently, there are no approved medicines to prevent COVID-19 in people who have been exposed to SARS-CoV-2 infection.
Significant Reduction in COVID-19 Risk
The primary analysis population included 2,041 household contact participants with a negative screening SARS-CoV-2 test, excluding those found to already be positive by PCR at the central laboratory. Among participants treated with ensitrelvir, only 2.9% developed symptomatic COVID-19 compared to 9.0% of participants on placebo (risk ratio: 0.33; 95% CI: 0.22-0.49; p<0.0001) at Day 10, representing a statistically significant 67% relative risk reduction.
A secondary analysis population of 2,387 household contact participants who had a negative local test for SARS-CoV-2 (but not excluding those with a central laboratory positive SARS-CoV-2 PCR at baseline) showed similar results, with 4.4% of participants treated with ensitrelvir developing symptomatic COVID-19 compared to 10.2% of participants on placebo (risk ratio: 0.43; 95% CI: 0.32-0.59; p<0.0001).
"COVID-19 remains a major threat to public health, and the best way to avoid the serious and long-term complications associated with the virus is to reduce the risk of being infected in the first place," said Frederick Hayden, MD, Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine. "In addition to vaccination, post-exposure prophylaxis with timely use of an oral antiviral would be a valuable way to help prevent COVID-19 illness in people who have been exposed, especially people at high risk for severe disease."
Study Design and Safety Profile
The SCORPIO-PEP trial assessed 2,387 study participants aged 12 years and older with a negative screening test for SARS-CoV-2 infection and no symptoms at enrollment, who were exposed to a person living in their household with symptomatic COVID-19. Participants were randomly assigned in a 1:1 ratio to receive ensitrelvir (125 mg) or placebo once daily, beginning treatment within three days of when the household member with COVID-19 began showing symptoms and continuing for five days.
The drug was generally well tolerated, with similar rates of adverse events in the ensitrelvir group and the placebo group (15.1% and 15.5%, respectively). No COVID-19 related hospitalizations or deaths occurred during the study.
Mechanism of Action and Regulatory Status
Ensitrelvir is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for viral replication. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting this protease.
The drug, known as Xocova® in countries where it is approved, received emergency regulatory approval in Japan in 2022 and full approval in March 2024 for the treatment of COVID-19. It became available in Singapore via a Special Access Route application in 2023 and is currently under regulatory review in Taiwan.
Ensitrelvir was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) in 2025 for post-exposure prophylaxis of COVID-19 following contact with an individual who has COVID-19. It also received Fast Track designation in 2023 for the treatment of COVID-19. Shionogi plans to continue interacting with regulatory authorities worldwide.
Addressing an Unmet Medical Need
"SARS-CoV-2 continues to circulate and there are still thousands of hospitalizations and hundreds of COVID-19 deaths each week," said Simon Portsmouth, MD, FRCP, Senior Vice President, Head of Clinical Development. "If we can reduce the risk of infection among individuals who are exposed to SARS-CoV-2, this fulfills an important unmet medical need. Oral antivirals have changed the way we treat and prevent other infectious diseases, including influenza and HIV, and there is an opportunity to do the same with COVID-19."
COVID-19 continues to pose a health risk for many people and remains a public health threat. It can impact quality of life, lead to absence from work, cause long COVID, and can progress to severe disease, hospitalizations, and death. Additional protective options are needed for those who have close contact with people with COVID-19.
Importance of Post-Exposure Prophylaxis
Post-exposure prophylaxis (PEP) is particularly important for reducing the risk of developing COVID-19 after exposure, especially for those at high risk of developing severe illness, such as people with weakened immune systems, chronic health conditions, the elderly, or those who could transmit COVID-19 to high-risk populations.
In settings like hospitals, nursing homes, or long-term care facilities, PEP could help protect against COVID-19 and contain the potential clinical and economic impact. PEP may also help reduce the risk of developing acute COVID-19, thereby reducing the risk of developing long COVID.
Additionally, PEP is an important preventive option as new variants emerge, which may escape vaccine-induced or infection-acquired immunity. With low vaccination rates and waning immunity after vaccination, additional preventative measures are needed.
Previous Clinical Studies
Shionogi has evaluated ensitrelvir in multiple clinical trials. The SCORPIO-SR Phase 3 study, conducted in Asia during the Omicron-dominant phase of the epidemic, showed both clinical symptomatic efficacy and antiviral efficacy in a predominantly vaccinated population of patients with mild-to-moderate SARS-CoV-2 infection, regardless of risk factors.
The Phase 3 SCORPIO-HR study assessed ensitrelvir in symptomatic, non-hospitalized participants with COVID-19, regardless of past SARS-CoV-2 infection. While this study did not meet its primary endpoint of a statistically significant reduction in time to sustained resolution of 15 common COVID-19 related symptoms, no new safety concerns were identified, and treatment with ensitrelvir was well tolerated.
An investigator-initiated research study with ensitrelvir is ongoing in hospitalized patients for the management of COVID-19 as part of the Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) platform protocol. Shionogi also recently released preliminary results from a trial of ensitrelvir in mild to moderate COVID-19 patients aged 6 to under 12 years in Japan, confirming safety and tolerability with pharmacokinetics similar to adults.
