Shionogi Wins FDA Approval for First Oral XOCOVA to Prevent COVID-19 After Exposure

The U.S. Food and Drug Administration (FDA) has approved Shionogi’s XOCOVA (ensitrelvir) for post-exposure prophylaxis (PEP) of COVID-19 in adults and adolescents aged 12 years and older, making it the first oral antiviral authorized in the United States to prevent symptomatic COVID-19 following exposure.

The approval came ahead of the June 16, 2026 PDUFA target date and introduces the first and only oral option for COVID-19 prevention after a known exposure.

Expanding Role of Ensitrelvir

XOCOVA is a SARS-CoV-2 main protease inhibitor developed through a collaboration between Shionogi and Hokkaido University. By blocking a viral enzyme essential for replication, the drug helps prevent infection from progressing after exposure.

The approval expands ensitrelvir’s role beyond treatment and addresses a remaining prevention gap as COVID-19 continues to cause substantial illness, hospitalizations, and long-term health complications despite widespread immunity from vaccination and prior infection.

Phase 3 SCORPIO-PEP Trial

The FDA’s decision was supported by SCORPIO-PEP (NCT05897541), a global Phase 3, randomized, double-blind, placebo-controlled study evaluating XOCOVA in household contacts of individuals with symptomatic COVID-19.

The trial enrolled 2,387 participants aged 12 years and older who tested negative and were asymptomatic at baseline. The primary analysis included 2,041 participants with laboratory-confirmed negative SARS-CoV-2 tests. Treatment began within 72 hours of symptom onset in the infected household member. Participants received a 375 mg loading dose on day one followed by 125 mg once daily on days two through five.

Efficacy and Safety

XOCOVA met its primary endpoint, reducing the risk of symptomatic COVID-19 by 67% through Day 10 compared with placebo among uninfected household contacts exposed to an infected individual. The benefit was observed regardless of vaccination status or prior infection.

The study marks the first Phase 3 trial to show that an oral antiviral can prevent symptomatic COVID-19 after exposure, supporting the potential role of antiviral prophylaxis in outbreak control and high-risk settings.

Safety outcomes were comparable between groups. Adverse events occurred in 15.1% of participants receiving XOCOVA and 15.5% of those receiving placebo. The most common adverse events were headache, diarrhea, and cough. Investigators reported no cases of XOCOVA-associated dysgeusia. Results from SCORPIO-PEP were published in the New England Journal of Medicine in May 2026.

Expert and Industry Perspective

Clinical virologist Frederick Hayden highlighted the approval as an important addition to COVID-19 prevention strategies, particularly in households, healthcare facilities, and long-term care settings where exposure risk remains elevated.

Shionogi noted that XOCOVA demonstrated efficacy regardless of baseline immunity, supporting its potential use across a broad population following exposure.

Future Development Plans

The approval establishes a new category within COVID-19 prevention and gives Shionogi an opportunity to expand the role of antiviral prophylaxis in outbreak management. The company plans a focused U.S. commercial rollout while evaluating broader use in high-risk exposure settings.

XOCOVA is already approved in Japan for both the treatment and prevention of COVID-19. In the United States, its current approval is limited to post-exposure prophylaxis.

 Reference

Shionogi Announces FDA Approval of XOCOVA® (ensitrelvir), the First and Only Oral Option to Help Prevent COVID-19 Following Exposure| Shionogi Inc.