Ensitrelvir represents a potential treatment option for children aged 6 to <12 years.A phase III study from Japan demonstrates the safety and tolerability of ensitrelvir in paediatric patients with mild-to-moderate COVID-19.
“In children aged 6 to <12 years with mild-to-moderate COVID-19 treated with ensitrelvir, we observed a favourable safety profile, adult-matched plasma concentration-time profile, and a greater reduction in viral RNA vs placebo,” the investigators said.
After study drug administration, 41 percent of participants in the ensitrelvir group and 31 percent of those in the placebo group experienced ≥1 treatment-emergent adverse event (TEAE). All TEAEs were mild or moderate, transient, and none were serious or led to treatment discontinuation or death, they noted.
The investigational group had a higher rate of treatment-related AEs (TRAEs; 19 percent vs 3 percent), but all were mild and resolved by day 28. The most frequent TRAEs with ensitrelvir were decreased HDL (14 percent) and vomiting (4 percent).
Plasma concentration-time profile
In the ensitrelvir group, there were no notable differences in plasma concentration-time profile between bodyweight categories. [J Pediatric Infect Dis Soc 2026;15:piag071]
In children weighing ≥20 kg, plasma concentrations of ensitrelvir were generally ≤90 percent of the predicted range for the approved adult dose (8.4–46.8 μg/mL for 125 mg) and did not exceed those reported for adults/adolescents receiving the 250-mg dose. [Clin Pharmacokinet 2024;63:1723-1734]
In participants weighing 30 to <40 kg, who required higher doses per body weight, ensitrelvir exposure was slightly higher, but it also did not exceed those reported in adults receiving the 250-mg dose. [JAMA Netw Open 2024;7:e2354991]
“Body weight can influence the pharmacokinetics of ensitrelvir. These findings suggest that the safety and effectiveness of ensitrelvir in adult patients can also be expected in their paediatric counterparts, and that the dosage regimen used in this study was appropriate for paediatric patients and achieved antiviral efficacy without exceeding safety thresholds,” the researchers explained.
Other outcomes
The reduction in SARS-CoV-2 viral RNA was greater with ensitrelvir vs placebo between baseline and day 4 (least-squares mean [LSM] difference, −0.96 log10 copies/mL), as was the reduction in SARS-CoV-2 viral titre between baseline and day 2 (LSM difference, −0.39 log10 50% tissue culture infectious dose/mL).
Compared with the placebo group, the ensitrelvir group had shorter time-to-resolution of two COVID-19 symptoms (stuffy/runny nose and cough) plus fever (median, 140.5 hrs vs 146.2 hrs).
Oral 3C-like protease inhibitor
“Children aged <12 years with COVID-19 have limited treatment options. Currently approved oral antivirals are restricted by age or bodyweight,” the researchers said.
Ensitrelvir, a novel, once-daily, oral 3C-like protease inhibitor that prevents viral replication, has received fast-track designation from the US FDA. [Commun Biol 2023;6:694; https://www.shionogi.com/us/en/news/2025/09/fda-accepts-shionogis-ensitrelvir-nda-as-the-first-oral-therapy-for-the-prevention-of-covid-19-following-exposure.html, accessed October 24, 2026]
The study included 117 participants (median age 10 years, 54 percent female) presenting ≤72 hrs after COVID-19 onset. They were randomized 2:1 to receive ensitrelvir (bodyweight-based dosing) or placebo QD for 5 days.
“The findings provide important evidence supporting the safety and plasma concentration-time profiles, antiviral efficacy, and clinical benefit of oral ensitrelvir for the treatment of mild-to-moderate COVID-19 in children aged 6 to <12 years,” the researchers noted. “[Hence,] ensitrelvir represents a potential treatment option for this underserved paediatric population.”
However, the study’s small sample size and geographic restriction to Japan may have limited the findings. The investigators called for larger trials to validate the results. “Furthermore, studies of ensitrelvir effectiveness according to vaccination history and against emerging SARS-CoV-2 variants may provide broader insights.”