Pharmacokinetics, Safety, and Exploratory Efficacy of Onradivir in Children with Acute Uncomplicated Influenza: A Multicenter, Dose-Ranging, Phase 2 Study

Seasonal influenza brings high morbidity and mortality in children, with current antivirals limited by low efficacy and rising resistance. Onradivir (ZSP1273), a polymerase basic protein 2 (PB2) cap-binding inhibitor effective in adults, remains unstudied in pediatric influenza A. This phase 2 study evaluated its safety, pharmacokinetics, and preliminary efficacy in affected children. This multicenter randomized open-label phase 2 trial enrolled children under 18 years with confirmed influenza A at 31 Chinese sites. Participants were 1:1 randomized to 5-day high-dose or low-dose onradivir granules stratified by age and weight. Primary endpoints covered safety and steady-state pharmacokinetics; exploratory outcomes included symptom relief, fever resolution, viral kinetics, and exposure–response correlation. Seventy-two participants were enrolled and randomized; 70 entered the intention-to-treat infected population. The high-dose regimen achieved systemic exposures matching efficacious adult targets. Onradivir was well tolerated: most adverse events were mild or moderate, with no serious adverse events or adverse events leading to treatment discontinuations; gastrointestinal events were mild and infrequent. Median symptom alleviation was 28.6 h (95% confidence interval 17.9–59.1) high dose vs. 33.7 h (19.4–42.7) low dose. Influenza A viral ribonucleic acid declined rapidly, falling 1.5 log10 copies/ml at 24 h and 2.4 log10 copies/ml by day 5. No resistance-associated PB2 substitutions were detected. Analyses showed a flat exposure–response relationship across clinical and virological endpoints. Onradivir was well tolerated, achieved adult-equivalent exposure, and was associated with rapid symptom resolution and viral suppression. These findings support the selected pediatric dosing strategy and warrant confirmatory comparative trials. NCT06656026.