Ensitrelvir Shows No Day 60 Clinical Benefit in Hospitalized COVID-19

Key Takeaways

• No day 60 clinical recovery benefit was observed with ensitrelvir in the randomized comparison.
• Detectable viral antigen in plasma at day 5 was lower with ensitrelvir.
• Secondary clinical outcomes and prespecified safety outcomes were similar overall, while mortality and hemorrhagic event frequencies were numerically higher with ensitrelvir.

This international phase 3 randomized placebo-controlled study evaluated ensitrelvir, an oral 3CL protease inhibitor, in adults hospitalized for COVID-19 who received blinded study treatment with standard of care. Across sites from 2023 to 2025, 589 participants received treatment, with 293 assigned to ensitrelvir and 296 assigned to placebo. The enrolled cohort had a median age of 69 years; 49% were female and 68% were White. Corticosteroids and remdesivir were common components of standard of care in both groups. The primary endpoint was clinical recovery assessed by the days to recovery scale through day 60.

Recovery categories through day 60 were similar between groups, with a median DRS-60 category of 6 with ensitrelvir and 5.5 with placebo at the prespecified primary assessment. Interquartile ranges were 3 to 15 and 3 to 12, respectively, showing substantial overlap between study arms. At day 5, detectable viral antigen in plasma was reported in 13.4% of ensitrelvir recipients and 25.1% of placebo recipients, with P < .001. Secondary clinical outcomes also did not differ, leaving the early virologic separation without a parallel signal in overall recovery measures.

Prespecified safety outcomes were similar overall, although mortality and hemorrhagic event frequencies were higher with ensitrelvir than with placebo. Mortality was 6.1% with ensitrelvir and 4.4% with placebo, while hemorrhagic events occurred in 3.4% and 0.3%, respectively.

The authors concluded that ensitrelvir did not improve clinical recovery when added to standard of care for hospitalized adults. They suggested that lower illness severity in the Omicron era and frequent remdesivir and corticosteroid use may have contributed to the absence of clinical benefit.