SCORPIO-PEP Phase 3: Ensitrelvir First Oral Antiviral to Prevent COVID-19 Post-Exposure
Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) presented late-breaking scientific findings at the Conference of Retroviruses and Opportunistic Infections (CROI) 2025. The presentation included new data from its global, double-blind, randomized, placebo-controlled Phase 3 study, Stopping COVID-19 pRogression with early Protease InhibitOr treatment – Post-Exposure Prophylaxis (SCORPIO-PEP). This trial assessed ensitrelvir (Generic name: ensitrelvir fumaric acid, Code No.: S-217622, hereafter “ensitrelvir”) as an oral post-exposure prophylaxis. SCORPIO-PEP is the first and only Phase 3 study of a COVID-19 oral antiviral as post-exposure prophylaxis to meet its primary endpoint of preventing COVID-19 infection.
The study successfully met both its primary and key secondary endpoints. The primary analysis population included 2,041 household contact participants with a negative screening SARS-CoV-2 test, excluding those who were already positive by PCR at the central laboratory. Among those treated with ensitrelvir, 2.9% developed symptomatic COVID-19 compared to 9.0% in the placebo group (risk ratio: 0.33; 95% CI: 0.22-0.49; p<0.0001) at Day 10.
This result represents a 67% relative risk reduction. A secondary analysis included 2,387 household contacts who had a negative local test for SARS-CoV-2 but were not excluded based on central laboratory PCR results. The findings were similar, with 4.4% of participants treated with ensitrelvir developing symptomatic COVID-19 compared to 10.2% in the placebo group (risk ratio: 0.43; 95% CI: 0.32-0.59; p<0.0001).
Dr. Frederick Hayden, Professor Emeritus of Clinical Virology and Medicine at the University of Virginia School of Medicine, emphasized the importance of post-exposure prophylaxis. “COVID-19 remains a major threat to public health, and the best way to avoid serious complications is to reduce the risk of infection in the first place,” he stated. “In addition to vaccination, timely use of an oral antiviral as post-exposure prophylaxis could help prevent COVID-19, particularly in high-risk individuals.”
Ensitrelvir, branded as Xocova® in countries where it is approved, first received emergency regulatory approval in Japan in 2022, followed by full approval in March 2024 for COVID-19 treatment. It became available in Singapore through a Special Access Route application in 2023 and is currently under regulatory review in Taiwan. In 2025, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to ensitrelvir for post-exposure prophylaxis following COVID-19 exposure. Additionally, the FDA had granted Fast Track designation in 2023 for its use in treating COVID-19. Ensitrelvir remains an investigational drug outside of Japan and Singapore, and the Xocova® brand name has not been approved for use elsewhere.
SCORPIO-PEP enrolled 2,387 participants aged 12 and older who tested negative for SARS-CoV-2 and were asymptomatic at enrollment but had been exposed to a household member with symptomatic COVID-19. Participants were randomly assigned in a 1:1 ratio to receive ensitrelvir (125 mg) or placebo once daily, with treatment initiated within three days of symptom onset in the infected household member. Treatment continued for five days. The study demonstrated that ensitrelvir was generally well tolerated, with similar adverse event rates in the treatment and placebo groups (15.1% vs. 15.5%, respectively). Notably, no participants experienced COVID-19-related hospitalizations or deaths.
Dr. Simon Portsmouth, Senior Vice President and Head of Clinical Development at Shionogi, underscored the significance of these findings. “SARS-CoV-2 continues to circulate, leading to thousands of hospitalizations and hundreds of COVID-19 deaths weekly. Reducing infection risk in exposed individuals addresses a critical unmet medical need. Oral antivirals have transformed treatment and prevention strategies for infectious diseases such as influenza and HIV. Ensitrelvir presents a similar opportunity for COVID-19,” he stated.
COVID-19 remains a persistent public health threat, impacting quality of life, workplace productivity, and overall well-being. It can cause long-term complications such as long COVID, progress to severe illness, and lead to hospitalizations or fatalities. Additional preventive measures are required for individuals with close contact with COVID-19 cases, particularly those at high risk of severe disease.
Post-exposure prophylaxis (PEP) is essential for mitigating infection risk following exposure, especially among vulnerable populations such as the immunocompromised, elderly, or individuals with chronic health conditions. In healthcare settings, nursing homes, and long-term care facilities, PEP could play a vital role in reducing transmission and minimizing clinical and economic impacts. By decreasing the likelihood of acute infection, PEP may also help prevent long COVID, a condition associated with prolonged symptoms and functional impairment.
With the continuous emergence of new SARS-CoV-2 variants, PEP serves as a crucial preventive measure, particularly as some variants may evade immunity acquired through vaccination or prior infection. Furthermore, declining vaccination rates and waning post-vaccination immunity necessitate additional protective options to curb the spread of COVID-19. The integration of oral antivirals like ensitrelvir into prevention strategies may provide a critical tool in combating COVID-19 on a broader scale.
Shionogi remains committed to developing innovative solutions to address infectious diseases and public health challenges. The findings from SCORPIO-PEP represent a significant step toward expanding COVID-19 prevention efforts and offering effective post-exposure prophylaxis options for at-risk populations. Further regulatory evaluations and potential approvals worldwide could enable broader access to ensitrelvir as a vital tool in the ongoing fight against COVID-19.
