FDA Accepts Shionogi’s Ensitrelvir NDA for Review as the First Oral Therapy for the Prevention of COVID-19 Following Exposure

Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced the U.S. Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) from Shionogi Inc., a New Jersey-based subsidiary of Shionogi, for ensitrelvir (Generic name: ensitrelvir fumaric acid, Code No.: S-217622), an investigational oral antiviral for the prevention of COVID-19 following exposure to an infected individual. The FDA has set an action date of June 16, 2026 under the Prescription Drug User Fee Act (PDUFA).

The NDA is supported by results from the global, double-blind, randomized, placebo-controlled Phase 3 study, SCORPIO-PEP, which studied ensitrelvir as post-exposure prophylaxis (PEP). If approved, ensitrelvir would be the first and only oral therapy for the prevention of COVID-19 following exposure to an infected individual.1,2

SARS-CoV-2 remains highly transmissible and up to half of people living with an infected individual may develop COVID-19.3,4 The virus is constantly evolving, with novel symptoms reported.5,6 COVID-19 continues to impact daily life and may lead to absences from school and work, may cause long COVID, and in some cases, may progress to severe disease.7-12 Even patients with mild COVID-19 may experience worsening of preexisting chronic conditions.13-17

Following exposure to COVID-19, the best way to avoid its potentially serious and long-term complications is to stop viral replication, which prevents the development of the disease.1,2 There are currently no approved antiviral therapies proven to prevent COVID-19 following exposure.1,2,18 COVID-19 vaccines are received before exposure, and they do not stop viral replication.19,20 Other COVID-19 antivirals are taken following exposure and diagnosis, after viral replication has occurred and disease is already established.21

“Shionogi has a long history of innovation in infectious disease treatment and prevention. Our dedication to this field has led to significant breakthroughs in the development of novel antimicrobials and antivirals for HIV/AIDS, influenza and COVID-19. If approved, ensitrelvir will be the first and only oral therapy to help protect people in the U.S. from COVID-19 following exposure," said Nathan McCutcheon, MBA, President and CEO, Shionogi Inc.

About ensitrelvir

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

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 based on results from SCORPIO-SR, a Phase 3 study conducted in Asia, during the Omicron-dominant phase of the pandemic.

In SCORPIO-SR, 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. Most adverse events were mild in severity and no deaths were seen in the study. Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies. Results from this study were published in JAMA Network Open.

In 2025, Shionogi submitted two new drug applications in Japan for post-exposure prophylaxis of COVID-19 and for COVID-19 treatment in pediatric patients aged six to under 12 years. The pediatric submission is based on a multicenter, randomized, double-blind, placebo-controlled trial of ensitrelvir in mild-to-moderate COVID-19 patients aged 6 to 12 years in Japan. The study confirmed safety and tolerability and found the pharmacokinetics of ensitrelvir in this age group to be similar to that in adults.

Ensitrelvir became available in Singapore for the treatment of COVID-19 via a Special Access Route application in 2023, and it is currently under regulatory review in Taiwan for the treatment of COVID-19. Ensitrelvir is also under regulatory review with the European Medicines Agency for COVID-19 post-exposure prophylaxis and treatment.22

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.

FDA Accepts Shionogi’s Ensitrelvir NDA for Review as the First Oral Therapy for the Prevention of COVID-19 Following Exposure

Researchers identify three drugs as possible therapeutics for COVID-19

In continuation of my update on Amodiaquine and nebivolol

amodiaquine

Zuclopenthixol

Nebivolol

Based on virtual and in vitro antiviral screening that began in the earlier months of the COVID-19 pandemic, the researchers led at UTHSC by Colleen Jonsson, PhD, identified zuclopenthixol, nebivolol, and amodiaquine as promising therapeutics for the virus in its early stages.

Dr. Jonsson is a professor and the Endowed Van Vleet Chair of Excellence in Virology in the College of Medicine at UTHSC. She also directs the UTHSC Regional Biocontainment Laboratory (RBL), where this research was conducted. The university's RBL is one of roughly a dozen federally funded labs authorized to safely study contagious pathogens.

In a paper published in ACS Pharmacology & Translational Science, the researchers propose the drugs as possible candidates for testing in future clinical trials to improve immune response to the virus. Amodiaquine is an older antimalarial, zuclopenthixol is an antipsychotic, and nebivolol is a blood pressure medication.

"Particularly in the context of this pandemic, there is a stringent need for high-quality studies that can provide critical knowledge concerning the COVID-19 disease and reliable treatment proposals," the paper states. "With these caveats in mind, we conceived a computational workflow that included independent in vitro validation, followed by assessing emerging candidates in the context of available clinical pharmacology data with the aim of proposing suitable candidates for clinical studies for early stage (incubation and symptomatic phases) patients infected by SARS-CoV-2."

"Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection," the researchers wrote.

Comparing the drugs to hydroxychloroquine, the anti-malarial drug most-frequently studied in clinical trials for use as a COVID-19 therapeutic, the researchers examined 4,000 approved drugs and found these three to act similarly to the hydroxychloroquine, and in some cases, more safely. The research indicates they may also improve efficacy when combined in lower doses with remdesivir, an anti-viral given an emergency use authorization by the United States Food and Drug Administration as a therapeutic for COVID-19.

"Think of it as a whack-a-mole game," said Tudor Oprea, MD, PhD, professor of Medicine and Pharmaceutical Sciences, chief of the UNM Division of Translational Informatics, and corresponding author on the paper. "Instead of having one hammer, you have two hammers, which is more effective. We're trying to give the scientific community two hammers, instead of one."

Dr. Jonsson added, "This is a very exciting discovery and we are following up on the potential use of zuclopenthixol, nebivolol, and amodiaquine in additional research studies."

https://en.wikipedia.org/wiki/Amodiaquine

https://en.wikipedia.org/wiki/Zuclopenthixol

https://en.wikipedia.org/wiki/Nebivolol

Researchers identify three drugs as possible therapeutics for COVID-19