Drug Update · Infectious Disease

FDA Approves Ensitrelvir for COVID-19 Postexposure Prophylaxis: 67% Reduction in SCORPIO-PEP

July 11, 2026

Primary endpoint result (mITT)

2.9% vs. 9.0% (risk ratio 0.33; 95% CI 0.22-0.49) [1][12]

ITT endpoint result

4.4% vs. 10.2% (risk ratio 0.43; 95% CI 0.32-0.59) [12]

mITT population

Ensitrelvir n=1,030; Placebo n=1,011 (total mITT N=2,041) [1][12]

Randomized

2,387 subjects randomized [12]

Dose

375 mg on Day 1; 125 mg daily on Days 2-5 [12]

Approval date

FDA original approval date: 2026-05-29; label effective 2026-06-03 [12]

Clinical Perspective

This approval affects clinicians managing adults and adolescents 12 years of age and older who are household contacts of patients with COVID-19 and who test SARS-CoV-2–negative at baseline. The source-confirmed trial data support initiating ensitrelvir within 72 hours after contact (the trial enrolled contacts within 72 hours after symptom onset in the index patient) using the FDA-recommended 5-day regimen to reduce the risk of developing symptomatic infection ^[1]^[2]. Which patient subgroups (for example, persons with differing baseline serostatus or a broader population of immunocompromised contacts) derive similar preventive benefit remains an open question?

Dr. Simran Kohli · Infectious Diseases

Ensitrelvir (XOCOVA) was approved by the FDA for post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. The approval was supported by the randomized, double-blind, placebo-controlled SCORPIO-PEP trial, which showed a 67% reduction in confirmed symptomatic COVID-19 by day 10 in the modified intention-to-treat population (risk ratio, 0.33; 95% CI, 0.22-0.49) ^[1]^[2].

Clinical Context

Ensitrelvir is an oral inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like (main) protease (Mpro) developed by Shionogi. The agent had prior regulatory approval in Japan for treatment of mild-to-moderate COVID-19; the current FDA approval is for post-exposure prophylaxis in household contacts of a patient with COVID-19 who are SARS-CoV-2–negative at baseline. The SCORPIO-PEP trial enrolled household contacts and tested a short course regimen started within 72 hours after symptom onset in the index patient. The approval provides a new oral antiviral option specifically for post-exposure prophylaxis in household contacts, an indication for which no antiviral had been previously approved ^[1]^[2].

Key Findings

The SCORPIO-PEP trial showed ensitrelvir reduced the risk of confirmed symptomatic COVID-19 by 67% versus placebo (risk ratio, 0.33; 95% CI, 0.22-0.49) in the modified intention-to-treat population (ensitrelvir n=1,030; placebo n=1,011) by day 10 ^[1]^[2].
In the intention-to-treat analysis (all randomized subjects), ensitrelvir reduced the risk of confirmed symptomatic COVID-19 by 57% versus placebo (risk ratio, 0.43; 95% CI, 0.32-0.59) through day 10 ^[2].
The mITT population included 2,041 household contacts who were SARS-CoV-2–negative at baseline by central laboratory RT-PCR; 71.1% of participants underwent randomization within 48 hours after symptom onset in the index patient and 37.0% had at least one risk factor for severe COVID-19 ^[1].

Safety & Tolerability

The incidence of adverse events during the trial was similar in the ensitrelvir and placebo groups (15.1% in the ensitrelvir group and 15.5% in the placebo group) ^[1].
The incidence of serious adverse events was 0.2% in each group ^[1].
No COVID-19–related hospitalizations or deaths were reported in either trial arm ^[1].

Study Design

SCORPIO-PEP was a randomized, double-blind, placebo-controlled, multinational post-exposure prophylaxis trial. Persons who were SARS-CoV-2–negative on local testing and were household contacts of a patient with COVID-19 were randomized to receive ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or matching placebo within 72 hours after symptom onset in the index patient. Clinicians should consult current prescribing information for full dosing guidance. The primary endpoint was COVID-19 (central laboratory RT-PCR–confirmed SARS-CoV-2 infection plus ≥1 prespecified symptom lasting ≥48 hours) by day 10 in the modified intention-to-treat population ^[1]^[2]. A total of 2,387 subjects were randomized, and the mITT population included 1,030 in the ensitrelvir group and 1,011 in the placebo group ^[1]^[2].

FAQ

Q1 What is ensitrelvir (XOCOVA) approved for?

Ensitrelvir (XOCOVA) is approved by the FDA for post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. The approval is based on the SCORPIO-PEP randomized trial demonstrating reduced incidence of RT-PCR–confirmed symptomatic COVID-19 through day 10 when the drug was started within 72 hours after symptom onset in the index patient. Clinicians should consult current prescribing information for full dosing guidance.

Q2 How does ensitrelvir work?

Ensitrelvir is an oral inhibitor of the SARS-CoV-2 3C-like (main) protease (Mpro), an enzyme required for viral polyprotein processing and replication. The drug’s mechanism targets viral protease activity to inhibit replication. This mechanism and the clinical efficacy data supporting post-exposure prophylaxis are described in the prescribing information and the SCORPIO-PEP trial publication.

Q3 What is the recommended dose of ensitrelvir for post-exposure prophylaxis?

The FDA-recommended regimen for post-exposure prophylaxis in adults and adolescents 12 years and older is 375 mg (three 125-mg tablets) orally on Day 1 followed by 125 mg (one 125-mg tablet) orally on Days 2 through 5, taken with or without food, and initiated as soon as possible and within 72 hours following contact with an individual who has COVID-19. Verify pregnancy status of females of reproductive potential prior to initiating therapy per the prescribing information. Clinicians should consult current prescribing information for full dosing guidance.

Q4 What are the most common side effects of ensitrelvir?

In the SCORPIO-PEP trial the overall incidence of adverse events was similar between ensitrelvir and placebo (15.1% vs 15.5%), and serious adverse events occurred in 0.2% of participants in each group. No COVID-19–related hospitalizations or deaths were reported in either arm. For complete safety details and postmarketing information consult the full prescribing information and the trial publication.

Clinicians should consult current prescribing information for full dosing guidance.

FDA Approves Ensitrelvir for COVID-19 Postexposure Prophylaxis: 67% Reduction in SCORPIO-PEP

FDA Approves Ensitrelvir for COVID-19 Postexposure Prophylaxis: 67% Reduction in SCORPIO-PEP

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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