Ensitrelvir PEP Eases Symptom Severity in COVID-19 Breakthrough Cases

Exploratory analyses of the phase 3 SCORPIO-PEP trial evaluated ensitrelvir (Xocova; Shionogi) in household contacts with breakthrough COVID-19 or infection present at baseline, according to data being presented at IDWeek 2026, held October 21-24 in Washington, DC.¹ Participants receiving ensitrelvir had lower peak viral RNA levels and numerically fewer severe symptoms than placebo recipients.²

The FDA approved ensitrelvir in May 2026 for post-exposure prophylaxis (PEP) of COVID-19 in adults and adolescents 12 years and older following contact with an infected individual.¹ The new analyses describe viral and symptom outcomes among participants who became infected despite prophylaxis, a subgroup not captured by the primary end point.²

SCORPIO-PEP (NCT05897541) was a global, double-blind, randomized, placebo-controlled trial enrolling 2,387 household contacts 12 years and older with a negative local screening test and no symptoms.^1,3 Participants received ensitrelvir 375 mg on Day 1 and 125 mg on Days 2 through 5, or placebo, within 72 hours of symptom onset in the index patient.³ In the primary analysis, ensitrelvir reduced the risk of symptomatic COVID-19 through Day 10 by 67% vs placebo (n = 1,030 vs n = 1,011).¹,³

Among breakthrough infections defined by RT-PCR positivity regardless of symptoms, mean maximum viral RNA was 3.1 log₁₀ copies/mL with ensitrelvir vs 4.3 log₁₀ copies/mL with placebo (144 vs 217 cases).Among symptomatic breakthrough cases, severe symptoms occurred in 28.6% (8/28) of ensitrelvir recipients vs 53.9% (48/89) of placebo recipients. Mean maximum total symptom scores were 6.6 and 8.9, respectively.²

Investigators also evaluated 237 household contacts with SARS-CoV-2 detected by baseline central RT-PCR despite a negative local screening test and no symptoms. Ensitrelvir recipients in this group had numerically lower mean viral RNA levels on Days 3 and 6. Severe symptoms developed in 11.1% (2/18) of ensitrelvir recipients vs 37.5% (9/24) of placebo recipients.²

Ensitrelvir Reduces Infectious SARS-CoV-2 Titers in Phase 3 Analysis

In a separate poster, investigators reported a post hoc pooled analysis of the phase 3 SCORPIO-SR and SCORPIO-HR trials in patients with confirmed COVID-19.⁴ The analysis measured infectious virus titers, which reflect replication-competent virus rather than residual viral RNA detected by RT-PCR.¹,⁴ By Day 4, ensitrelvir recipients (n = 484) had numerically greater reductions in infectious virus titers than placebo recipients (n = 487), with a least-squares mean difference of 0.21 log₁₀ TCID₅₀/mL.⁴

Undetectable infectious virus on Day 4 was observed in 95.7% (463/484) of the ensitrelvir group vs 72.1% (351/487) of the placebo group.⁴ Results were consistent across subgroups defined by age, vaccination status, and risk factors for severe COVID-19.¹ Findings from both IDWeek analyses are exploratory.¹

In SCORPIO-PEP, adverse events occurred in 15.1% of ensitrelvir recipients (n = 1,190) and 15.5% of placebo recipients (n = 1,187).³ Headache, diarrhea, and cough were the most common adverse events occurring more often with ensitrelvir, and no dysgeusia attributed to ensitrelvir was reported.^1,3 Prescribing information lists several contraindicated coadministered agents, including carbamazepine, colchicine, rifampin, and simvastatin.¹

“Timing is indeed key, and as many people know, with antivirals, the earlier the better,” said Florin Draica, MD, CMD, MBA, senior vice president of US medical affairs at Shionogi Inc. “So it's pretty much as early as you can get.”

Draica said patients with chronic conditions stand to gain the most from prophylaxis. “Patients who tend to benefit most are patients with underlying chronic conditions whose health may be impacted by COVID-19,” he said. “COVID-19, even mild to moderate, can lead to exacerbations or worsening or relapse of these conditions.”

Ensitrelvir is approved in the US, Japan, and the European Union for COVID-19 PEP in individuals 12 years and older.¹ It is not approved for the treatment of COVID-19 in the US.¹

REFERENCES

1. Shionogi & Co, Ltd. IDWeek 2026: new exploratory analyses evaluate Xocova (ensitrelvir) following COVID-19 exposure, including breakthrough infections and infection present at baseline. News release. October 21, 2026. Accessed October 24, 2026. https://www.shionogi.com/us/en/news/2026/10/idweek-2026-new-exploratory-analyses-evaluate-xocova-ensitrelvir-following-covid-19-exposure-including-breakthrough-infections-and-infection-present-at-baseline.html

2. Fukushi A, Nobori H, Sakaguchi H, et al. Early pre-symptomatic treatment with ensitrelvir among PCR-positive, SARS-CoV-2-exposed and infected household contacts: SCORPIO-PEP subpopulation analysis. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC.

3. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306

4. Hurt AC, Nobori H, Sakaguchi H, et al. Reduction of infectious SARS-CoV-2 and viral RNA with ensitrelvir: a pooled analysis of SCORPIO-SR and SCORPIO-HR trials. Poster presented at: IDWeek 2026; October 21-24, 2026; Washington, DC.