Safety, tolerability, pharmacokinetics and pharmacodynamics of HSK31858, a novel oral dipeptidyl peptidase-1 inhibitor, in healthy volunteers: An integrated phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study.

Abstract

Aim: Dipeptidyl peptidase-1 (DPP-1) inhibitors have been studied for the treatment of neutrophil-mediated inflammatory diseases including bronchiectasis, bronchial asthma and cystic fibrosis. This study evaluated the pharmacokinetics, pharmacodynamics, safety and tolerability of DPP-1 inhibitor HSK31858 in healthy Chinese volunteers.

Methods: Volunteers in Part A randomly received single doses of HSK31858 (15, 40, 60 and 80 mg) or placebo in fasted states. The 40-mg cohort also received HSK31858 40 mg or placebo in fed states. In Part B, volunteers randomly received HSK31858 10, 20 and 40 mg or placebo once daily for 28 days in fasted states. The primary endpoints were safety and tolerability of HSK31858.

Results: Among 38 volunteers in Part A and 36 in Part B, HSK31858 was well tolerated; no deaths, serious adverse events, or discontinuations due to adverse events occurred. The median T_max was 0.75 to 1.0 h and the mean terminal t_1/2 was 16.5 to 21.0 h in the fasted state with single doses of HSK31858. Both C_max and AUC_0-t exhibited a dose-dependent rise. Food had no effect on AUC. Multiple doses of HSK31858 demonstrated a similar pharmacokinetics profile, with about 2-fold accumulation in AUC. HSK31858 dose-dependently inhibited neutrophil count-normalized neutrophil elastase (NE_norm) activity. The maximal percentage decrease in NE_norm activity relative to baseline during 28 days of HSK31858 treatments was 13.6% and 76.4% with HSK31858 10 and 40 mg once-daily, respectively.

Conclusion: HSK31858 was safe and well tolerated. The pharmacokinetics and pharmacodynamics profile of HSK31858 supports further clinical development for the treatment of neutrophil-mediated inflammatory diseases.

Trial registration: NCT05663593.