Ensitrelvir, known commercially as Xocova in some regions, is an investigational oral antiviral developed by the Japanese pharmaceutical company Shionogi. This once-daily medication is currently being studied as a potential treatment and prophylactic option for COVID-19. The drug has faced a complex and evolving path toward authorization in the United States, which centers on the rigorous data requirements set by the Food and Drug Administration (FDA).
Defining Ensitrelvir and Its Purpose
Ensitrelvir is a small-molecule oral antiviral designed to treat mild-to-moderate COVID-19 infection. The drug belongs to the class of 3C-like (3CL) protease inhibitors, which target a specific enzyme within the SARS-CoV-2 virus. The 3CL protease is a non-structural protein that acts as a molecular scissor, essential for cleaving the viral polyprotein into functional components needed for replication.
By selectively inhibiting this enzyme, Ensitrelvir blocks the final stages of viral assembly and propagation. This targeted mechanism is intended to reduce the viral load in infected individuals, potentially leading to faster recovery and reduced symptom severity. The standard treatment course involves a five-day regimen, and it does not require co-administration with a booster like ritonavir.
The Current US Regulatory Status
Ensitrelvir has not received full approval or an Emergency Use Authorization (EUA) from the FDA for the treatment of COVID-19 symptoms. Initial efforts to secure authorization stalled due to insufficient evidence of a definitive clinical benefit, particularly regarding the time to sustained symptom resolution. While some data showed that the drug effectively reduced the SARS-CoV-2 viral load, the impact on patient symptoms did not meet the FDA’s high standard for a statistically significant improvement over placebo in the global Phase 3 SCORPIO-HR trial. This outcome highlighted the US agency’s focus on clear, demonstrable symptomatic benefit rather than solely on virological data. Consequently, the drug remains an investigational product for the treatment of active infection within the United States.
However, the regulatory landscape for Ensitrelvir is currently focused on a different application: post-exposure prophylaxis (PEP). The manufacturer has submitted a New Drug Application (NDA) to the FDA for the prevention of COVID-19 following exposure to an infected individual. This NDA is based on a separate Phase 3 trial that studied the drug’s ability to prevent infection. The FDA has accepted this application for review and has set a Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026, for a decision on the PEP indication.
International Authorization and Use
In contrast to the US status, Ensitrelvir has been authorized for use in several other countries. Japan, the home country of the manufacturer, granted the drug emergency regulatory approval in November 2022 under the brand name Xocova. This initial step was later followed by full, standard approval in March 2024 for the treatment of SARS-CoV-2 infection. This rapid authorization in Japan was based on data from the SCORPIO-SR trial, which demonstrated clinical symptomatic efficacy by showing a faster resolution of five typical Omicron-related symptoms. Furthermore, the drug has been made available in other regions, such as Singapore, where it received authorization for treatment through a Special Access Route application in 2023.
Regulatory Path Forward
For the currently pending application, the NDA for post-exposure prophylaxis, the company is relying on the results of the SCORPIO-PEP Phase 3 trial. This trial must provide compelling evidence that Ensitrelvir significantly reduces the risk of developing COVID-19 after a close exposure. For the original treatment indication, the path to a New Drug Application will require additional, well-controlled Phase 3 trials focused on hard clinical endpoints. These endpoints must address the initial concerns by providing definitive proof of reduced hospitalizations, decreased mortality, or a statistically significant and clinically meaningful reduction in the time to sustained symptom resolution. Meeting the full NDA standard is a higher evidentiary bar than an EUA, demanding extensive and conclusive safety and efficacy data across a broad patient population.