FDA Approves oral antiviral for Post-Exposure Prevention of COVID-19

The U.S. FDA has approved ensitrelvir (Xocova), an oral antiviral developed by Shionogi, to help prevent COVID-19 in individuals aged 12 years and older following exposure to the SARS-CoV-2 virus. The approval makes Xocova the first and only oral medication authorized for post-exposure prevention of COVID-19, providing a convenient treatment option for reducing the risk of infection after known exposure.

This approval introduces the first and only oral option to help prevent COVID-19 after exposure in the current therapeutic landscape, addressing a critical gap in prevention. XOCOVA is a five-day oral regimen with three tablets taken on day one and one tablet taken on days two through five. The approval occurred ahead of the Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026.

“The FDA approval of XOCOVA provides an important new approach to preventing COVID-19, which continues to impact lives. COVID-19 can become severe and even when mild or moderate, it can worsen or exacerbate chronic conditions or trigger new ones, including long COVID,” said Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine. “Ensitrelvir inhibits viral replication, helping protect people who have been exposed to COVID-19 from developing illness. The PEP strategy has the potential to benefit anyone who does not want to get COVID-19. It could be useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities and following travel-related exposures.”

The approval is based on positive results from SCORPIO-PEP, the only Phase 3 study of an oral antiviral to meet the primary endpoint of preventing symptomatic COVID-19 following exposure to an infected individual.* XOCOVA significantly reduced the risk of symptomatic COVID-19 by 67% in uninfected individuals following exposure to an infected individual through Day 10 compared with placebo (ensitrelvir n=1,030; placebo n=1,011).3,4 Overall, XOCOVA was generally well tolerated, with similar rates of adverse events across groups (15.1% in the XOCOVA group (n=1,190) and 15.5% in the placebo group (n=1,187)).4 The most common adverse events (regardless of causality) occurring in greater than or equal to 1% of the XOCOVA group and at a greater frequency compared to placebo were headache, diarrhea, and cough.3 There were no reports of altered taste (dysgeusia) attributed to XOCOVA in the trial.4,5 Results from the SCORPIO-PEP trial were published in the New England Journal of Medicine on May 14, 2026.

“The FDA approval of XOCOVA is an exciting new chapter in the Shionogi antiviral story, which includes innovative medicines that have changed the way we manage other viruses including HIV and influenza,” said Nathan McCutcheon, President and CEO, Shionogi Inc. “XOCOVA is the first and only oral option clinically proven to help prevent symptomatic COVID-19 after exposure among study participants regardless of vaccination status or baseline immunity from prior infection. With XOCOVA, people who are exposed to COVID-19 can act early to help protect themselves.”

The Ongoing Impact of COVID-19

COVID-19 remains highly transmissible, driven by Omicron and its subvariants, and up to 47% of people living with an infected individual may develop COVID-19.6 The U.S. Centers for Disease and Control estimates that between October 1, 2025 and May 23, 2026 there were 3.8-12.4 million new cases in the U.S., resulting in 800,000 – 2.3 million outpatient visits, 120,000 – 240,000 hospitalizations and 13,000 - 42,000 deaths.7

Beyond acute infection, COVID-19 can have lasting impacts. People diagnosed with COVID-19 had increased rates of both new and worsening neurologic, cardiovascular, respiratory, and renal conditions during the year following infection.8-17 COVID-19 also disproportionately affects older adults with greater risk for severe illness and death in close-community settings, such as long-term care facilities.18

About SCORPIO-PEP

The global, double-blind, randomized, placebo-controlled Phase 3 study, SCORPIO-PEP, assessed the safety and efficacy of XOCOVA as post-exposure prophylaxis for COVID-19. The study included 2,387 study participants aged 12 years and older with a negative local 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. The primary analysis included 2,041 household contact participants with a central laboratory-confirmed negative SARS-CoV-2 test at baseline.

The trial was conducted from June 2023–September 2024. More than 99% of household contacts tested positive for antibodies against SARS-CoV-2 N (nucleocapsid) or S (spike) proteins, indicating that nearly all had evidence of previous SARS-CoV-2 infection or vaccination, or both.

Study participants were randomly assigned at a 1:1 ratio to receive XOCOVA (375 mg on day 1 and 125 mg on days 2-5) or placebo, once daily, and began treatment within 72 hours of when the household member with COVID-19 began showing symptoms. Participants then continued XOCOVA (125 mg) or placebo for five days. SCORPIO-PEP is the first and only Phase 3 study of an oral antiviral to meet the primary endpoint of preventing COVID-19 following exposure to an infected individual.

Reference:

Frederick G. Hayden, Masaharu Shinkai, Tristan W. Clark,  Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts, N Engl J Med, DOI: 10.1056/NEJMoa2509306