Ensitrelvir Did Not Improve Recovery in Hospitalized Adults With Covid-19

Key Takeaways

• Ensitrelvir plus standard of care was not associated with a significant improvement in clinical recovery through day 60 compared with placebo plus standard of care.
• Detectable plasma viral antigen at day 5 was lower with ensitrelvir, but this was not accompanied by better clinical recovery.
• Secondary clinical outcomes and prespecified safety outcomes were similar between groups, although mortality and hemorrhagic events were numerically higher with ensitrelvir.

In an international phase 3 randomized, placebo-controlled trial, ensitrelvir added to standard of care did not improve recovery in adults hospitalized with COVID-19, with an odds ratio of 0.82 for a better day 60 recovery category (95% CI, 0.62 to 1.09; p=0.19).

The trial enrolled 589 participants between 2023 and 2025, with 293 assigned to ensitrelvir and 296 assigned to placebo in a blinded comparison. Median age was 69 years, 49% of participants were female, and 68% were White. Ensitrelvir was an oral 3CL protease inhibitor with potent antiviral activity. Standard care commonly included corticosteroids in 61% versus 54% and remdesivir in 62% versus 60% of the ensitrelvir and placebo groups, respectively. The study tested whether the antiviral added measurable benefit on top of routine inpatient therapy.

The prespecified primary endpoint was clinical recovery on the Days to Recovery Scale through day 60, analyzed with a Van Elteren test. The median DRS-60 category was 6 in the ensitrelvir group and 5.5 in the placebo group. The odds ratio for a better DRS-60 category with ensitrelvir was 0.82, with a 95% confidence interval of 0.62 to 1.09 and p=0.19. Those results showed no significant improvement in the main clinical recovery measure.

Detectable plasma viral antigen at day 5 was lower with ensitrelvir than with placebo, at 13.4% versus 25.1% (p<0.001). Secondary clinical outcomes did not differ between groups. The antiviral effect on this laboratory measure was not matched by better recovery outcomes.

Prespecified safety outcomes did not differ between groups in the abstract. Mortality was 6.1% with ensitrelvir and 4.4% with placebo, while hemorrhagic events occurred in 3.4% and 0.3%, respectively. These were numerical imbalances rather than a confirmed safety difference. The authors concluded that ensitrelvir did not improve clinical recovery when added to standard of care for hospitalized adults with COVID-19. They also suggested that lower illness severity in the Omicron era and frequent remdesivir and corticosteroid use may have contributed to the absence of clinical benefit.