Ensitrelvir Demonstrates Rapid Antiviral Efficacy Against COVID-19 in Phase 2b Trial

Ensitrelvir was safe and efficacious against mild to moderate COVID-19, though further studies are needed to assess ensitrelvir among patients with severe disease.

Daily treatment with oral ensitrelvir is efficacious and safe for patients with mild to moderate COVID-19 infection, according to study results published in Clinical Infectious Diseases.

In this placebo-controlled phase 2b trial, researchers randomly assigned patients with confirmed COVID-19 infection in a 1:1:1 fashion to receive either a 125- or 250-mg dose of oral ensitrelvir fumaric acid or placebo, all of which were administered once daily for 5 days. This trial was conducted between January and February of 2022 across 87 sites in Japan and South Korea. The coprimary outcomes were change in SARS-CoV-2 titers between baseline and day 4 and mean change in the total score of 12 predefined COVID-19-related symptoms between baseline and 120 hours. The researchers also assessed treatment-emergent adverse event occurrence to evaluate the safety of ensitrelvir.

There were a total of 341 study patients (mean age range, 35.3-37.3 years) in the final efficacy analyses, including 114 in the 125 mg ensitrelvir cohort, 115 in the 250 mg ensitrelvir cohort, and 111 in the placebo cohort. Among patients who received a 125- or 250-mg dose of ensitrelvir, 53.5% and 56.9% were men, 43.0% and 34.5% were outpatients, and 85.1% and 83.6% had received at least 1 COVID-19 vaccine dose, respectively. Of patients who received placebo, 64.9% were men, 43.2% were outpatients, and 87.4% had received at least 1 COVID-19 vaccine dose. In all 3 cohorts, most patients were infected with the Omicron variant.

For patients in all 3 cohorts, mean concentrations of SARS-CoV-2 viral titers decreased between baseline and day 4, remaining stable and below the limit of detection (1.1 log10 50% tissue-culture infectious dose/mL) through day 21. Analysis of covariance showed changes in viral titers between baseline and day 4 were significantly greater among patients who received 125 mg or 250 mg of ensitrelvir vs those who received placebo. Similar findings were observed after adjustments for COVID-19 vaccination history and time between infection onset and treatment allocation.

As the risk of severe COVID-19 increases with age, the safety and efficacy of ensitrelvir in a wide range of patients with COVID-19 will be further assessed…

There was no significant differences in median time to first symptom improvement observed among the 3 cohorts (range, 28.0-36.6 hours). There also were no significant differences observed between patients in the 125 mg or 250 mg ensitrelvir cohorts vs those in the placebo cohort for time-weighted mean change in total scores of the 12 predefined COVID-19-related symptoms from baseline up to 120 hours.

Among patients in the 125 mg ensitrelvir, 250 mg ensitrelvir, and placebo cohorts, 34.3%, 42.9%, and 31.2% reported treatment-emergent adverse events. Of these events, the majority were of mild severity and a decrease in high-density lipoprotein was the most commonly reported. Pharmacokinetic data indicated a 125-mg dose of ensitrelvir was sufficient against COVID-19 infection while minimizing medication exposure.

Limitations include the small number older adults, and these study findings may not be applicable to individuals infected with other COVID-19 variants.

According to the researchers, “As the risk of severe COVID-19 increases with age, the safety and efficacy of ensitrelvir in a wide range of patients with COVID-19 will be further assessed…”

Disclosure: Some authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of disclosures.


Mukae H, Yotsuyanagi H, Ohmagari N, et al. Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study. Clin Infect Dis. Published online December 7, 2022. doi:10.1093/cid/ciac933