Shionogi Initiates New Drug Application Submission for Ensitrelvir for Post-Exposure Prophylaxis with the U.S. Food and Drug Administration

OSAKA, Japan, March 31, 2025 – Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced that it has initiated the rolling submission of a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) for its investigational oral antiviral ensitrelvir (Generic name: ensitrelvir fumaric acid, Code No.: S-217622, hereafter “ensitrelvir”). The rolling submission of ensitrelvir for Post-Exposure Prophylaxis is being made based on the positive results from the Global Phase 3 Study, Stopping COVID-19 pRogression with early Protease InhibitOr treatment – Post-Exposure Prophylaxis (SCORPIO-PEP).¹

COVID-19 continues to pose a health risk for many people and remains a public health threat, with thousands of hospitalizations and hundreds of deaths each week in the U.S.^2,3,4 It can impact quality of life, lead to absence from work, cause long COVID, and progress to severe disease, hospitalization and death.^2,3,4 With continually decreasing vaccination rates, waning immunity after vaccination, and the potential for new variants to emerge, additional treatment and preventive options for COVID-19 are needed.^5,6 If this application is approved, ensitrelvir is expected to be the first orally-administered option for the post-exposure prophylaxis of COVID-19.

Ensitrelvir 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 and was granted Fast Track designation by the FDA in 2023 for the treatment of COVID-19. Shionogi is also in discussions with FDA regarding the treatment indication for COVID-19 with ensitrelvir.

Ensitrelvir, known as Xocova^® in countries where it is approved, received emergency regulatory approval in Japan in November 2022 and full approval in March 2024 for the treatment of COVID-19. In 2025, based on the favorable outcomes of the SCORPIO-PEP trial, a global Phase 3 post-exposure prevention study, an application was submitted in Japan to include additional benefits and efficacy related to the prevention of COVID-19. Shionogi submitted a supplemental New Drug Application for ensitrelvir in Japan for the post-exposure prophylaxis of COVID-19 in 2025. It became available in Singapore via a Special Access Route application in 2023, and it is currently under regulatory review in Taiwan. Ensitrelvir is an investigational drug outside of Japan and Singapore. In addition, the brand name Xocova^® has not been approved for use outside of Japan and Singapore and pertains only to the approved drug in Japan and Singapore.

Ensitrelvir is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus.⁷ Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting the 3CL protease.⁷

Shionogi evaluated the safety and efficacy of ensitrelvir through SCORPIO-SR, a Phase 3 study conducted in Asia, during the Omicron-dominant phase of the epidemic.⁸ In this study, ensitrelvir showed both clinical symptomatic efficacy (symptom resolution sustained for at least 24 hours) for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in a predominantly vaccinated population of patients with mild-to-moderate SARS-CoV-2 infection, regardless of risk factors.⁸ Regarding safety, most adverse events were mild in severity and no deaths were seen in the study.⁸ Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies.⁸ The data from this study were published in JAMA Network Open.

Additionally, the Phase 3 SCORPIO-HR study assessed ensitrelvir in a broad range of symptomatic, non-hospitalized participants with COVID-19, regardless of past SARS-CoV-2 infection. The study did not meet its primary endpoint of a statistically significant reduction in time to sustained resolution (symptom resolution sustained for at least 48 hours) of 15 common COVID-19 related symptoms for once-daily ensitrelvir compared to placebo.⁹ No new safety concerns were identified in the study, and treatment with ensitrelvir was well tolerated, with a similar adverse event profile as placebo.⁹

Shionogi recently announced that its global, double-blind, randomized, placebo-controlled Phase 3 study (SCORPIO-PEP) assessing ensitrelvir as oral post-exposure prophylaxis met the primary endpoint of preventing symptomatic COVID-19 through day 10.¹ SCORPIO-PEP is the first and only Phase 3 study of a COVID-19 oral antiviral as a post-exposure prophylaxis to meet the primary endpoint of preventing COVID-19.*

SCORPIO-PEP assessed 2,387 study participants aged 12 years and older with a negative screening test for SARS-CoV-2 infection and no symptoms at the time of enrollment, who were exposed to a person living in their household with symptomatic COVID-19. Study participants were randomly assigned in a 1:1 ratio to receive ensitrelvir (125 mg) or placebo, once daily, and began treatment within three days of when the household member with COVID-19 began showing symptoms. Participants then continued ensitrelvir or placebo for five days. Overall, ensitrelvir was generally well tolerated, with similar rates of adverse events in the ensitrelvir group and the placebo group (15.1% and 15.5%, respectively).¹ There were no COVID-19 related hospitalizations or deaths.

An investigator-initiated research study with ensitrelvir is ongoing in hospitalized patients for the management of COVID-19 as part of the Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) platform protocol. STRIVE was developed under the auspices of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.

Shionogi also recently released preliminary results from a multicenter, randomized, double-blind, placebo-controlled trial of ensitrelvir in mild to moderate COVID-19 patients aged 6 to under 12 years in Japan. The study confirmed safety and tolerability and found the pharmacokinetics of ensitrelvir in this age group similar to adults.¹⁰

For Further Information, Contact:
SHIONOGI Website Inquiry Form: https://www.shionogi.com/global/en/contact.html

U.S. Media: ShionogiCommunications@shionogi.com
SEU Press Office: pressoffice@shionogi.eu

*Literature search conducted December 2024.

1. Hayden F. Ensitrelvir to Prevent COVID-19 in Households: SCORPIO-PEP Phase III Placebo-Controlled Trial Results. Abstract 200. Presented at CROI 2025, San Francisco, CA: March 9-12, 2025.

 

2. Trends in United States COVID-19 Deaths, Emergency Department (ED) Visits, and Test Positivity by Geographic Area. The Centers for Disease Control and Prevention. Accessed March 26, 2025. Available at: https://covid.cdc.gov/covid-data-tracker/#trends_weeklydeaths_select_00

 

3. Long COVID Basics. Centers for Disease Control and Prevention. Accessed February 24, 2025. Available at: https://www.cdc.gov/covid/long-term effects/?CDC_AAref_Val=https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html.

 

4. COVID-NET Laboratory-confirmed COVID-19 hospitalizations. The Centers for Disease Control and Prevention. Accessed March 26, 2025. Available at: https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalization-network

 

5. Carabelli AM, Peacock TP, Thorne LG, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nature Reviews Microbiology. 18 Jan 2023;21:162–177. doi:10.1038/s41579-022-00841-7.

 

6. Kriss JL, Black CL, Razzaghi H, et al. Influenza, COVID-19, and Respiratory Syncytial Virus Vaccination Coverage Among Adults — United States, Fall 2024. MMWR Morb Mortal Wkly Rep. 21 Nov 2024;73:1044–1051. doi:10.15585/mmwr.mm7346a1.

 

7. Unoh Y, et al. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. Journal of Medicinal Chemistry. 30 Mar 2022;65:9,6499-6512. doi:10.1021/acs.jmedchem.2c00117.

 

8. Yotsuyanagi H, et al. Efficacy and safety of 5-day oral Ensitrelvir for patients with mild to moderate COVID-19. JAMA Netw Open. 9 Feb 2024;7(2):e2354991. doi:10.1001/jamanetworkopen.2023.54991.

 

9. Luetkemeyer A, et al. Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial, Clinical Infectious Diseases, 2025;, ciaf029, https://doi.org/10.1093/cid/ciaf029.

 

10. 3^rd Quarter of Fiscal 2024 Financial Results. January 31, 2025. Page 20. Accessed March 5, 2025. Available at: https://www.shionogi.com/content/dam/shionogi/jp/investors/ir-library/presentation-materials/fy2024/%EF%BC%93q/E_FY2024_3Q%20financial%20results_.pdf.