Ensitrelvir Effective as Oral Antiviral for Postexposure Prophylaxis Against COVID-19

Ensitrelvir (Xocova; Shionogi), an oral antiviral treatment approved in Japan to treat mild to moderate COVID-19, the illness caused by SARS-CoV-2, has demonstrated efficacy in preventing illness in uninfected people with household exposure to the virus, indicating the potential for a convenient postexposure prophylaxis (PEP) option to prevent a serious disease course.^1,2

Preventing serious COVID-19 illness before the virus spreads remains a major unmet need. | Image Credit: © JeromeCronenberger - stock.adobe.com

The data, presented in a late-breaking oral presentation at the Conference of Retroviruses and Opportunistic Infections (CROI) 2025, were gathered throughout the phase 3 SCORPIO-PEP study. The global, double-blind, randomized, placebo-controlled clinical trial assessed ensitrelvir as oral PEP, becoming the first and only phase 3 study of such an antiviral to meet the primary study end point of preventing COVID-19, in addition to key secondary end points.¹

“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,” Frederick G Hayden, MD, trial designer and presenter at CROI, said in a news release accompanying the data. “In addition to vaccination, PEP 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.”²

The trial included a primary analysis population of 2041 household contact participants 12 years and older that had a negative screening SARS-CoV-2 test and excluded patients who were already positive through a polymerase chain reaction (PCR) test. Patients must have been exposed to a person living in their household with symptomatic COVID-19. Enrollees were randomly assigned 1:1 to receive ensitrelvir 125 mg or placebo, once daily, and were instructed to begin treatment within 3 days of the household member with COVID-19 being symptomatic. Following treatment initiation, enrollees continued ensitrelvir or placebo for 5 days, the study authors wrote.¹

According to the investigators, 2.9% of participants treated with ensitrelvir developed symptomatic COVID-19, compared with 9.0% of participants treated with placebo at day 10 (risk ratio (RR): 0.33; 95% CI, 0.22-0.49; P < .0001), demonstrating a 67% risk reduction. Importantly, the treatment was generally well-tolerated among participants, with similar adverse event rates in the ensitrelvir group (15.1%) and placebo group (15.5%) and no COVID-19-related hospitalizations or deaths reported.¹

Participants in the secondary analysis population—which included 2387 household contact participants with a negative local test for SARS-CoV-2, not excluding those with a positive SARS-CoV-2 PCR result at baseline—had similar results to the primary analysis group. In this cohort, 4.4% of individuals treated with ensitrelvir developed symptomatic COVID-19, compared with 10.2% of participants treated with placebo (RR: 0.43; 95% CI, 0.32-0.59; P < .0001), according to the study authors. The results from each of the end point populations indicate major potential to not just treat mild to moderate COVID-19 but prevent illnesses from occurring in the first place—even when a person in the same household is infected.^1,2

In a critical point, 37% of participants in the trial presented with at least 1 risk factor for developing life-threatening complications for COVID-19. The inclusion of these patients signifies that ensitrelvir is effective in patients with comorbidities that put them at higher risk for serious illness, a population that continues to face a lack of effective treatments and no approved PEP options. Ensitrelvir, a 3CL protease inhibitor, was granted fast track designation by the FDA in 2023 for the treatment of COVID-19 illness, and in 2025 for COVID-19 PEP following contact with a patient who harbors the illness.¹

“This is the first clinical trial of an oral antiviral drug to show significant protection against COVID-19,” Hayden said. “If approved by the FDA for this purpose, it would be an important addition to current preventive strategies.”²

REFERENCES

1. Shionogi. Late-breaking at CROI 2025: SCORPIO-PEP phase 3 trial: Ensitrelvir is the first and only COVID-19 oral antiviral to demonstrate prevention of COVID-19 as postexposure prophylaxis. News Release. Released March 13, 2025. Accessed March 17, 2025. https://www.shionogi.com/global/en/news/2025/03/20250313.html#:~:text=Ensitrelvir%20demonstrated%20a%20statistically%20significant,to%20placebo%20at%20day%2010.

2. UVA Health Newsroom. Drug can help prevent household COVID-19 spread. News Release. Released March 12, 2025. Accessed March 17, 2025. https://newsroom.uvahealth.com/2025/03/12/drug-can-help-prevent-household-covid-19-spread/