Ensitrelvir Demonstrates Effectiveness in Preventing COVID-19 as Post-Exposure Prophylaxis: Results from the SCORPIO-PEP Phase 3 Trial
SCORPIO-PEP Phase 3: Ensitrelvir First Oral Antiviral to Prevent COVID-19 as Post-Exposure Prophylaxis
At the Conference on Retroviruses and Opportunistic Infections 2025, Shionogi & Co., Ltd. presented late-breaking scientific results from its global Phase 3 study, SCORPIO-PEP (Stopping COVID-19 pRogression with early Protease InhibitOr treatment – Post-Exposure Prophylaxis). The study evaluated the use of ensitrelvir, an oral small-molecule protease inhibitor, as a post-exposure prophylaxis (PEP) for preventing symptomatic COVID-19 in individuals exposed to the virus. Ensitrelvir is the first and only oral antiviral to show effectiveness in preventing COVID-19 in a Phase 3 trial, marking a significant advancement in post-exposure prevention strategies.
The SCORPIO-PEP Trial: Study Design and Results
The SCORPIO-PEP study was a double-blind, randomized, placebo-controlled clinical trial that assessed the impact of ensitrelvir as a post-exposure treatment for COVID-19. It involved 2,041 participants who were household contacts of individuals with symptomatic COVID-19 and had a negative screening for SARS-CoV-2 infection at the start of the trial. The participants were randomly assigned to receive either ensitrelvir (125 mg) or a placebo once daily for five days, starting within three days of exposure to the infected household member.
The study met both its primary and key secondary endpoints, demonstrating that ensitrelvir significantly reduced the incidence of symptomatic COVID-19. In the primary analysis population, only 2.9% of participants treated with ensitrelvir developed symptomatic COVID-19 by Day 10, compared to 9.0% in the placebo group. This resulted in a 67% relative risk reduction (risk ratio: 0.33; 95% CI: 0.22-0.49; p<0.0001).
The secondary analysis population, which included 2,387 participants, also showed promising results. In this group, 4.4% of those who received ensitrelvir developed symptomatic COVID-19, compared to 10.2% in the placebo group, reflecting a 57% relative risk reduction (risk ratio: 0.43; 95% CI: 0.32-0.59; p<0.0001).
SCORPIO-PEP Phase 3: Ensitrelvir First Oral Antiviral to Prevent COVID-19 as Post-Exposure Prophylaxis
A Valuable Tool in the Fight Against COVID-19
Dr. Frederick Hayden, Professor Emeritus of Clinical Virology at the University of Virginia School of Medicine, commented on the significance of the results: “COVID-19 remains a major public health threat. In addition to vaccination, post-exposure prophylaxis with timely oral antivirals could be an invaluable strategy to prevent illness in individuals who have been exposed to the virus, particularly those at high risk for severe disease.”
Ensitrelvir, marketed as Xocova® in countries where it has received approval, has already been granted emergency regulatory approval in Japan in 2022 and full approval in March 2024 for the treatment of COVID-19. In 2023, it became available in Singapore via a Special Access Route application and is currently undergoing regulatory review in Taiwan. In 2025, the U.S. Food and Drug Administration (FDA) granted ensitrelvir Fast Track designation for use as post-exposure prophylaxis following contact with someone who has COVID-19, as well as for the treatment of COVID-19.
Ensitrelvir’s Tolerability and Safety Profile
Ensitrelvir was generally well tolerated in the SCORPIO-PEP study, with adverse events occurring in 15.1% of participants in the ensitrelvir group compared to 15.5% in the placebo group. Notably, there were no hospitalizations or deaths related to COVID-19 during the trial, underscoring the safety profile of the drug.
Dr. Simon Portsmouth, Senior Vice President and Head of Clinical Development at Shionogi, emphasized the importance of these findings: “SARS-CoV-2 continues to circulate globally, leading to thousands of hospitalizations and hundreds of deaths each week. By reducing the risk of infection in individuals exposed to the virus, we address an important unmet medical need. Oral antivirals like ensitrelvir offer a promising tool for the prevention of COVID-19, similar to how antivirals have transformed the management of other infectious diseases like influenza and HIV.”
Post-Exposure Prophylaxis: A Critical Need in the Ongoing COVID-19 Pandemic
COVID-19 remains a global health threat, with ongoing risks to public health, quality of life, and economic stability. The virus can lead to severe disease, hospitalization, long COVID, and even death, particularly in vulnerable populations. As variants of concern continue to emerge, and with the waning immunity from vaccines over time, additional preventive measures are critical.
Post-exposure prophylaxis (PEP) is particularly vital for individuals who have had close contact with someone infected with SARS-CoV-2. This group includes individuals at high risk of severe illness, such as the elderly, those with compromised immune systems, and individuals with chronic health conditions. In high-risk settings, such as healthcare facilities and long-term care homes, PEP could help protect both vulnerable populations and healthcare workers.
Dr. Portsmouth highlighted the broader benefits of PEP, saying, “As new variants emerge, which may partially evade vaccine-induced immunity, and given the challenges associated with low vaccination rates and declining immunity in the population, additional preventive options are necessary. Post-exposure prophylaxis can help fill this gap, particularly as part of a comprehensive strategy to control the spread of COVID-19.”
The Future of Ensitrelvir in COVID-19 Prevention
As COVID-19 continues to affect communities worldwide, there is a clear need for effective preventive treatments, particularly for individuals who are exposed to the virus but have not yet developed symptoms. Ensitrelvir’s success in the SCORPIO-PEP trial represents a significant step forward in addressing this need, providing an oral antiviral that can be used post-exposure to prevent the onset of symptomatic COVID-19.
Looking forward, the availability of ensitrelvir as a post-exposure prophylactic treatment could significantly impact how COVID-19 is managed, particularly in high-risk environments. If ensitrelvir receives full regulatory approval, it may become an essential part of COVID-19 prevention strategies, alongside vaccination and other preventive measures.
Conclusion: A Step Forward in COVID-19 Prevention
The results from the SCORPIO-PEP Phase 3 trial provide compelling evidence for the use of ensitrelvir as an oral post-exposure prophylaxis to prevent symptomatic COVID-19. As a first-of-its-kind treatment, ensitrelvir offers a new, effective option for individuals at risk of contracting the virus, particularly in the face of new variants and declining immunity. Shionogi’s continued commitment to the development of this promising antiviral provides hope for better management and prevention of COVID-19 moving forward.
About ensitrelvir
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 the replication of the virus.12 Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting the 3CL protease.12
Shionogi evaluated the safety and efficacy of ensitrelvir through SCORPIO-SR, a Phase 3 study conducted in Asia, during the Omicron-dominant phase of the epidemic.13 In this study, ensitrelvir showed both clinical symptomatic efficacy (symptom resolution sustained for at least 24 hours) for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in a predominantly vaccinated population of patients with mild-to-moderate SARS-CoV-2 infection, regardless of risk factors.13
Regarding safety, most adverse events were mild in severity and no deaths were seen in the study.13 Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies.13 The data from this study were published in JAMA Network Open.
Additionally, the Phase 3 SCORPIO-HR study assessed ensitrelvir in a broad range of symptomatic, non-hospitalized participants with COVID-19, regardless of past SARS-CoV-2 infection. The study did not meet its primary endpoint of a statistically significant reduction in time to sustained resolution (symptom resolution sustained for at least 48 hours) of 15 common COVID-19 related symptoms for once-daily ensitrelvir compared to placebo.14 No new safety concerns were identified in the study, and treatment with ensitrelvir was well tolerated, with a similar adverse event profile as placebo.14
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. STRIVE was developed under the auspices of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.
Shionogi also recently released preliminary results from a multicenter, randomized, double-blind, placebo-controlled trial of ensitrelvir in mild to moderate COVID-19 patients aged 6 to under 12 years in Japan. The study confirmed safety and tolerability and found the pharmacokinetics of ensitrelvir in this age group similar to adults.15
