Efficacy and safety of ZX-7101A, an inhibitor of influenza cap-dependent endonuclease, in adults with uncomplicated influenza: a randomised, double-blind, placebo-controlled phase 2/3 Trial.

Objectives: To evaluate the efficacy and safety of ZX-7101A: an inhibitor of influenza viral cap-dependent endonuclease, in adults with uncomplicated influenza and explore treatment-emergent resistance.

Methods: We conducted a randomized, double-blind, placebo-controlled, adaptive-design phase 2 and phase 3 studies (ZX-7101A-202) in adults with uncomplicated influenza. Eligible patients were randomised 1:1:1 to receive a single dose of 40 or 80mg ZX-7101A or placebo, stratified by body weight and baseline composite symptom score. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in intention-to-treat infected (ITTI) population.

Results: The phase 2 trial suggested a significantly shorter in TTAS for ZX-7101A compared to placebo: the median TTAS of 40 or 80mg ZX-7101A was 34.7 hours (95% confidence interval [CI], 22.8-43.4; p=0.005) and 45.8 hours (95%CI, 32.0-66.3; p=0.020), compared with 63.6 hours (95%CI, 43.9-93.4) in the placebo group. In the phase 3 trial, the TTAS of both ZX-7101A dose groups was significantly shortened relative to the placebo: the median TTAS was shortened to 48.4 hours (95%CI, 40.5-55.6) for 40mg and 39.4 hours (95%CI, 35.8-49.3) for 80mg, compared with 62.9 hours (95%CI, 56.4-69.3) for placebo (p=0.003 and p<0.001, respectively). In the safety population, ZX-7101A treatment was associated with fewer adverse events (AEs), with 41.8% (100/239) in the 40mg group, 44.2% (106/240) in the 80mg group, and 53.8% (129/240) in the placebo group. The majority of AEs were mild or moderate. Emergence of resistance to ZX-7101A through I38T amino acid substitution was detected in 5/122 (4.1%) patients.

Conclusions: ZX-7101A was an effective treatment for influenza with a single dose of either 40mg or 80mg, with more rapid alleviation of influenza symptoms versus placebo. No safety concerns were identified with single-dose treatment of ZX-7101A.