Oral Antiviral Demonstrates Prevention of COVID-19 in Phase 3 Study

Positive results have been announced from a phase 3 trial that evaluated the efficacy and safety of ensitrelvir for the prevention of symptomatic SARS-CoV-2, pharmaceutical company Shionogi announced in a release.¹ The data was presented during a presentation at the 2025 Conference of Retroviruses and Opportunistic Infections (CROI).

Results from the SCORPIO-PEP (NCT05897541) study showed that ensitrelvir met the primary endpoint of preventing COVID-19 in household contacts with a negative screening SARS-CoV-2 test through day 10. The therapy also met its key secondary endpoint of preventing COVID-19 in household contacts with a negative local test for SARS-CoV-2 and those with a central laboratory positive SARS-CoV-2 test through day 10.

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Ensitrelvir is an investigational oral antiviral that is approved for use in Japan and Singapore. It suppresses the replication of SARS-CoV-2 by selectively inhibiting the viral 3CL protease, which is critical for replication of the virus. The therapy was granted Fast Track designation by the FDA in 2025 for post-exposure prophylaxis of COVID-19 following contact with an individual who has COVID-19.

“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 Hayden, MD, Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine at the University of Virginia School of Medicine​, said in a release.¹ “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.”

SCORPIO-PEP was a randomized, double-blind, placebo-controlled phase 3 study that evaluated the efficacy and safety of ensitrelvir for the prevention of symptomatic SARS-CoV-2 infection in household contacts of an individual with symptomatic COVID-19. The study cohort included 2400 patients aged 12 years and older who were randomly assigned to receive ensitrelvir 125 mg or placebo once daily.

The study included 2 analyses. The first analysis included 2041 household contact patients with a negative screening SARS-CoV-2 test. Of the patients treated with ensitrelvir, 2.9% developed symptomatic COVID-19 compared to 9% in the placebo group at day 10. The second analysis included 2387 household contact patients who had a negative local test for SARS-CoV-2, but it did not exclude patients with a central laboratory positive SARS-CoV-2 test. Of the patients who were treated with ensitrelvir, 4.4% developed symptomatic COVID-19 compared to 10.2% in the placebo group.

The study also found that the therapy was generally well tolerated. Rates of adverse events were similar between the treatment and placebo groups, with no COVID-19 related deaths or hospitalizations.

“SARS-CoV-2 continues to circulate and there are still thousands of hospitalizations and hundreds of COVID-19 deaths each week,” Simon Portsmouth, MD, FRCP, senior vice president and head of clinical development at Shionogi, said in a release.¹ “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.”

READ MORE: COVID-19 Resource Center

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References

1. 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 Post Exposure Prophylaxis. News Release. Shionogi. March 12, 2025. Accessed March 12, 2025. https://www.businesswire.com/news/home/20250311777665/en/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-Post-Exposure-Prophylaxis