Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial

Abstract

Background: Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.

Methods: This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In Part 1, patients (n = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients (n = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.

Results: No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group.

Conclusions: AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.

Clinical trials registration: NCT02654171.

Keywords: AK0529; fusion inhibitor; infants; respiratory syncytial virus (RSV); ziresovir.

Conflict of interest statement

JZW is a co‐inventor of patents (WO2013020993A, 2012; CN105726488B, 2014) covering a compound targeting RSV diseases and a preparation method of the formula. ST and JZW are co‐inventors of a patent (WO2021083290A1; 2020) covering RSV fusion protein inhibitor composition and its use for the treatment and prophylaxis of RSV. FG, ST, GZ, and JZW are or were employees of and are shareholders in Ark Biosciences. JPD served as a compensated scientific consultant for Ark Biosciences and is a shareholder in the company. All other authors declare no competing interests.

© 2023 Shanghai Ark Biopharmaceutical Ltd Co. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Study flow chart. aOne randomized patient in Part 2 received unblinded treatment with AK0529 (2 mg/kg bid) on a compassionate use basis for the best interest of the patient and was excluded from the efficacy analysis unless specified.

FIGURE 2

(A) Median change in viral load from baseline to 96 h post‐dose in Part 2 (full analysis population). (B) Median change in Wang respiratory score by dose level in Part 2 (full analysis population). *p < 0.05 for the difference between the 2 mg/kg and placebo groups on Wang respiratory score reduction at 96 h.

FIGURE 3

(A) Relationships between viral load and Wang respiratory score: viral load vs. RSV S&S score, p = 0.0001; interception: 95% CI: 1.34–2.92; slope: 95% CI: 0.23–0.61. (B) Relationships between changes in viral load and in Wang respiratory score over time: change in viral load vs. change RSV S&S score, p = 0.006; interception: 95% CI: −1.52– −0.22; slope: 95% CI: 0.06–0.51.