NEJM Publishes Shionogi Phase 3 SCORPIO-PEP Study Showing Ensitrelvir Significantly Reduces COVID-19 Risk After Exposure
Shionogi & Co., Ltd. announced that results from its global Phase 3 clinical trial, SCORPIO-PEP, evaluating the investigational oral antiviral ensitrelvir for post-exposure prophylaxis (PEP) of COVID-19, have been published in the New England Journal of Medicine (NEJM), marking a significant milestone in the development of preventive antiviral therapies for SARS-CoV-2.
The study is the first and only Phase 3 clinical trial of an oral antiviral to successfully meet its primary endpoint of preventing symptomatic COVID-19 following exposure to an infected household contact.
First Phase 3 Success for Oral COVID-19 Post-Exposure Prevention
The SCORPIO-PEP trial demonstrated that a five-day oral course of ensitrelvir significantly reduced the risk of developing symptomatic COVID-19 when administered shortly after exposure. According to study results, participants who received ensitrelvir experienced a 67% reduction in risk of symptomatic infection through Day 10 compared with placebo.
In the primary analysis population of 2,041 participants who had a confirmed negative SARS-CoV-2 test at baseline and no symptoms at enrollment, 2.9% of individuals treated with ensitrelvir developed symptomatic COVID-19, compared to 9.0% in the placebo group. This corresponds to a risk ratio of 0.33 (95% confidence interval [CI]: 0.22–0.49; p<0.0001), indicating a statistically significant reduction in infection risk.
The trial results were consistent across multiple analyses, reinforcing the antiviral’s protective effect in a real-world high-risk exposure setting, particularly within households where transmission risk is known to be elevated.
Stronger Protection in High-Risk Populations
A prespecified subgroup analysis of participants with one or more risk factors for severe COVID-19 showed even greater benefit. In this group, ensitrelvir reduced the risk of symptomatic infection by 76% compared to placebo.
Among participants with underlying risk factors, 2.4% of those receiving ensitrelvir developed symptomatic COVID-19, compared to 9.9% in the placebo group (risk ratio: 0.24; 95% CI: 0.12–0.49). These findings suggest that the antiviral may offer enhanced protection for individuals most vulnerable to severe outcomes, including older adults and those with comorbid conditions.
Mechanism of Action: Blocking Viral Replication Early
Ensitrelvir is a SARS-CoV-2 main protease inhibitor designed to interfere with a critical enzyme required for viral replication. By inhibiting the viral main protease, ensitrelvir prevents the virus from multiplying effectively in the early stages of infection.
Researchers suggest that this mechanism is particularly important in the post-exposure window, when viral replication begins before symptom onset. By interrupting this process, the drug may reduce or prevent progression to symptomatic disease.
Experts involved in the trial emphasized that early antiviral intervention represents a promising strategy for limiting disease spread and reducing clinical burden, particularly in household and community exposure settings.
Expert Commentary on Clinical Impact
Frederick Hayden, MD, Professor Emeritus of Clinical Virology and Medicine at the University of Virginia School of Medicine, highlighted the significance of the findings.
He noted that individuals who began ensitrelvir within 72 hours of exposure were approximately three times less likely to develop COVID-19 compared with those receiving placebo.
According to Hayden, these results represent the first clearly positive Phase 3 findings for an oral antiviral used in post-exposure prevention. He further emphasized that the data support ensitrelvir’s potential to protect a broad range of individuals, including those at increased risk of severe disease.
He also suggested that the findings may have implications beyond household exposure scenarios, potentially extending to other high-risk environments where rapid transmission occurs.
Safety and Tolerability Profile
The SCORPIO-PEP study reported that ensitrelvir was generally well tolerated, with safety outcomes comparable to placebo. Adverse events occurred in 15.1% of participants in the ensitrelvir group (n=1,190) and 15.5% in the placebo group (n=1,187), indicating no significant increase in overall adverse event frequency.
The most commonly reported treatment-emergent adverse events (≥1%) included headache, diarrhea, nasopharyngitis, cough, fatigue, and influenza-like symptoms. Importantly, no cases of dysgeusia (altered taste), a side effect commonly associated with other antiviral therapies, were attributed to ensitrelvir in the trial.
Overall, the safety profile supports the feasibility of short-course oral administration in outpatient or post-exposure settings.
Study Design and Population
SCORPIO-PEP was a global, double-blind, randomized, placebo-controlled Phase 3 clinical trial designed to evaluate both the safety and efficacy of ensitrelvir as a post-exposure prophylactic treatment.
The study enrolled 2,387 participants aged 12 years and older who were household contacts of individuals with symptomatic COVID-19. All participants tested negative for SARS-CoV-2 at screening and were asymptomatic at enrollment.
Participants were randomized in a 1:1 ratio to receive either ensitrelvir or placebo. Treatment was initiated within 72 hours of the index case developing symptoms, and participants received a five-day oral regimen consisting of 375 mg on Day 1 followed by 125 mg daily on Days 2 through 5.
The primary analysis population included 2,041 participants with confirmed negative baseline testing conducted by a central laboratory.
Notably, more than 98% of participants had evidence of prior SARS-CoV-2 infection or vaccination, reflecting a real-world population with hybrid immunity, which adds relevance to current epidemiological conditions.
Clinical Significance in the Post-Pandemic Era
Although COVID-19 has transitioned into an endemic phase in many regions, the risk of outbreaks and variant-driven surges remains a concern. New and evolving variants continue to challenge public health systems, and household transmission remains one of the most common routes of infection.
Shionogi researchers emphasized that COVID-19 can still lead to significant health consequences, including severe illness in vulnerable populations and long-term complications such as post-acute sequelae of SARS-CoV-2 infection (commonly known as long COVID). Even mild infections may exacerbate pre-existing conditions or contribute to chronic health issues.
Currently, there are no widely approved therapies specifically indicated for post-exposure prevention of COVID-19, leaving a gap in preventive care strategies following known exposure.
Potential Role of Post-Exposure Antivirals
The SCORPIO-PEP results highlight the potential value of antiviral therapies that can be administered immediately after exposure to prevent infection before it establishes itself in the body.
Unlike therapeutic antivirals used after symptom onset, post-exposure prophylaxis aims to intervene during the incubation period, when viral replication is beginning but immune activation and clinical disease have not yet fully developed.
Researchers argue that such an approach could significantly reduce transmission within households, healthcare settings, and other high-risk environments, while also lowering the burden on healthcare systems during seasonal or variant-driven surges.
Regulatory Status and Global Development
Ensitrelvir is currently under review by the U.S. Food and Drug Administration (FDA) for post-exposure prophylaxis of COVID-19. The application has been assigned a Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026.
In Japan, ensitrelvir—marketed under the brand name XOCOVA®—has already received regulatory approval for COVID-19 treatment and more recently for post-exposure prevention following household exposure. Additional regulatory submissions are ongoing in other global markets, including Taiwan.
It is important to note that outside Japan, ensitrelvir remains an investigational therapy and has not yet received regulatory approval for clinical use.
Shionogi & Co., Ltd. is a Japan-based, research-driven pharmaceutical company with a long-standing focus on infectious diseases and unmet medical needs. With more than 148 years of history, the company is engaged in the development of therapies across multiple therapeutic areas, including infectious diseases, central nervous system disorders, oncology, pain management, and rare diseases.
The company’s stated mission is to provide high-quality medicines that improve patient health and well-being globally, with a strong emphasis on innovation in antiviral therapies.
About Shionogi & Co., Ltd.
Shionogi & Co., Ltd. is a 148-year-old global, research-driven pharmaceutical company headquartered in Osaka, Japan, that is dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” The company currently markets products in several therapeutic areas including anti-infectives, pain, CNS disorders and cardiovascular diseases. Shionogi’s research and development currently targets two therapeutic areas: infectious diseases and diseases with unmet medical needs in pain/CNS, including Alzheimer’s disease, oncology, rare diseases, and sleep apnea.
