Ensitrelvir First Oral Antiviral Proven for COVID-19 Prevention in Phase 3 Trial

Shionogi & Co., Ltd., located in Osaka, Japan, presented groundbreaking findings at the Conference of Retroviruses and Opportunistic Infections (CROI) 2025, focusing on its Phase 3 study named SCORPIO-PEP. This study evaluated ensitrelvir as an oral post-exposure prophylaxis against COVID-19, marking a significant milestone as it is the first such study to successfully achieve its primary goal of preventing the disease.

The SCORPIO-PEP study involved a total of 2,041 household contacts screened negative for SARS-CoV-2, where ensitrelvir was found to significantly reduce the risk of developing symptomatic COVID-19. Participants treated with the drug showed a 67% reduction in relative risk compared to those receiving a placebo, with only 2.9% developing symptoms versus 9.0% in the placebo group. The findings were reinforced through secondary analyses involving a broader group of 2,387 participants, which similarly demonstrated a decrease in symptomatic cases among those treated with ensitrelvir.

Dr. Frederick Hayden from the University of Virginia highlighted the importance of prophylactic measures in combatting COVID-19, particularly for high-risk individuals. He noted that oral antivirals like ensitrelvir could significantly aid in preventing the onset of illness following exposure to the virus, especially alongside vaccination efforts.

Ensitrelvir, marketed as Xocova® in approved regions, received emergency approval in Japan back in 2022 and gained full approval by March 2024. It became accessible in Singapore through a Special Access Route application in 2023, while currently undergoing regulatory review in Taiwan. The U.S. Food and Drug Administration (FDA) granted it Fast Track designation for use as a post-exposure prophylaxis in 2025.

The SCORPIO-PEP study recruited participants aged 12 and older who were asymptomatic at enrollment but had been exposed to COVID-19 within their household. Participants were randomized to receive either ensitrelvir or a placebo within three days following symptom onset in the household member with COVID-19. Treatment continued for five days, showing favorable tolerance and no significant differences in adverse events between the two groups.

Dr. Simon Portsmouth emphasized the significance of oral antivirals in potentially transforming COVID-19 prevention and treatment, drawing parallels with their impact on diseases like influenza and HIV. He pointed out the persistent threat posed by the virus and the importance of minimizing infection risks to address a critical medical need.

Post-exposure prophylaxis (PEP) is crucial for individuals with close exposure to COVID-19, especially those vulnerable to severe illness due to factors such as age, underlying health conditions, or compromised immunity. PEP could play a pivotal role in settings such as hospitals and nursing homes, helping mitigate the clinical and economic burdens of COVID-19. It is also vital to consider PEP amidst emerging variants that might evade existing immunity from vaccines or previous infections.

Ensitrelvir, a 3CL protease inhibitor developed in partnership with Hokkaido University, targets the 3CL protease enzyme essential for SARS-CoV-2 replication. It demonstrated efficacy in reducing symptoms during the Omicron phase in Asia, with most adverse events being mild and transient.

Complementing the findings from SCORPIO-PEP, ongoing research includes studies like STRIVE, focusing on hospitalized patients, and recent trials concerning safety and pharmacokinetics in younger patients aged 6 to under 12 in Japan. These studies continue to affirm ensitrelvir's potential in managing COVID-19 across various demographics and conditions.