Study Results Position Ensitrelvir as Potential First Oral Antiviral for COVID-19 Post-Exposure Prevention

Results from the phase 3 SCORPIO-PEP trial published in the New England Journal of Medicine highlight the potential of ensitrelvir as the first oral antiviral designed to prevent COVID-19 after exposure. Developed by Shionogi & Co., the five-day oral treatment reduced the risk of symptomatic COVID-19 by 67% compared with placebo in individuals exposed to an infected household member.

Among more than 2,000 participants in the primary analysis population, only 2.9% of those receiving ensitrelvir developed symptomatic disease by Day 10, compared with 9.0% in the placebo arm. The benefit was even greater in individuals with risk factors for severe illness, where the therapy demonstrated a 76% relative risk reduction. Investigators say the findings are especially important because no approved antiviral therapy currently exists for post-exposure prevention of COVID-19.

Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine, noted that participants treated within 72 hours of household exposure were three times less likely to develop COVID-19 than those receiving placebo, underscoring the drug’s potential in high-risk settings. The study also found ensitrelvir to be generally well tolerated, with adverse event rates similar to placebo and no reports of treatment-related altered taste. Shionogi leaders said the antiviral could represent a major advance in pandemic preparedness as new variants continue to emerge and COVID-19 remains capable of triggering severe disease or worsening chronic health conditions.

Contagion recently spoke to Hayden about the study results.

Contagion: How do the SCORPIO-PEP Phase 3 results position ensitrelvir as a potential first-in-class oral antiviral for post-exposure prevention of COVID-19, and what populations could benefit most from this approach?

Hayden: Currently, there is no FDA-approved antiviral for preventing COVID-19 after exposure to the virus. As we well know, COVID-19 can become severe, and even if mild or moderate, it can exacerbate or worsen chronic conditions or lead to the onset of new ones, including long COVID. Yet, there is very little that can be done following exposure to an infected individual, so a clear unmet need exists for an easily administered oral antiviral that is effective for post-exposure prophylaxis (PEP).

To date, SCORPIO-PEP is the first Phase 3 study of an oral antiviral to meet the primary endpoint of preventing COVID-19 after exposure. When started within 72 hours after exposure to a household member with COVID-19, a 5-day course of ensitrelvir significantly reduced the risk of COVID-19 by 67% in uninfected household contacts (mITT population) through Day 10 compared to placebo (2.9% versus 9.0%). In a pre-specified subgroup analysis of participants with one or more risk factors for severe disease, a 76% risk reduction for COVID-19 was observed with ensitrelvir through Day 10 vs placebo.

The SCORPIO-PEP study included household contacts with (37%) and without high-risk conditions. As such, COVID-19 prevention could benefit large categories of people who want to avoid the disease and its potential consequences.

Contagion: The study showed a 67% reduction in symptomatic COVID-19 overall and a 76% reduction among higher-risk participants. What do these findings suggest about the potential role of ensitrelvir in protecting vulnerable populations and reducing downstream complications such as long COVID?

Hayden: If approved by the FDA, ensitrelvir PEP could play an important role in helping protect against COVID-19 in persons exposed to SARS-CoV-2, particularly in those at higher risk for complications. Thus, oral ensitrelvir PEP could prove useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities, or in travel groups. Preventing COVID-19 in these settings is important because outbreaks can potentially lead to very poor clinical and economic outcomes.

The current study did not capture longer term data on development of Long COVID, but it is reasonable to think that preventing acute COVID-19 would considerably reduce its likelihood.

Contagion: With no currently approved therapies for preventing COVID-19 after exposure, how could ensitrelvir change current public health and clinical strategies for managing household transmission and future variant-driven surges?

Hayden:The availability of oral ensitrelvir PEP would add an important new strategy to protect against COVID-19 and its complications. It would also help shift management from our primarily reactive approach at present, i.e., testing and treating after symptoms develop, toward earlier intervention that reduces the risk of COVID-19 development in the first place. This is increasingly relevant as SARS-CoV-2 vaccine uptake, even in high-risk persons, continues to wane and new SARS-CoV variants emerge with the potential to cause surges in disease incidence.

The future impact of SARS-CoV-2 is unpredictable, with the potential for surges and new variants. Ensitrelvir targets a highly conserved part of the virus that has not changed significantly as the virus has evolved. This is supported by previous ensitrelvir clinical and in vitro studies, where the drug was shown to be active against prior and current variants of COVID-19, including Omicron subvariants.

Reference
New England Journal of Medicine Publishes Shionogi Study Demonstrating Ensitrelvir Prevents COVID-19 Following Exposure. Shionogi press release. May 13, 2026. Accessed May 16, 2026.
https://www.shionogi.com/us/en/news/2026/05/new-england-journal-of-medicine-publishes-shionogi-study-demonstrating-ensitrelvir-prevents-covid-19-following-exposure.html