Safety, pharmacokinetics, and pharmacodynamics of GS1-144, a neurokinin-3 receptor antagonist: A randomized phase 1 single and multiple ascending dose and food effect study

GS1-144 is a neurokinin-3 receptor (NK3R) antagonist in development for treating menopausal vasomotor symptoms (VMS). This first-in-human, randomized phase 1 study (NCT06385158) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GS1-144 in healthy Chinese participants following single and multiple ascending doses (SAD/MAD), and food effect (FE). In Part 1 (SAD), GS1-144 (5-90 mg) or placebo was administered to healthy participants. In Part 2 (FE), GS1-144 30 mg was given under fasted and fed conditions in a two-period crossover in healthy participants. In Part 3 (MAD), healthy female participants of childbearing potential and postmenopausal women received GS1-144 (15-120 mg) or placebo once- (q24h) or twice-daily (q12h) fasted for 7 consecutive days. Primary endpoints included safety and tolerability. Secondary and exploratory endpoints included PK, QT/QTc interval changes, and PD (luteinizing hormone [LH] suppression). Overall, 38, 24, and 66 participants were enrolled in Parts 1-3, respectively. GS1-144 was well-tolerated with no serious adverse events (AEs), deaths, or treatment discontinuations. Most AEs were mild and not dose-related. GS1-144 was rapidly absorbed (median T_max 0.5-2.0 h) with a linear PK profile after single 5-90 mg and multiple 15-120 mg q24h dosing. Mean half-life at steady state was 5.36-5.96 h, with no dose-dependent changes. Dose-dependent LH reductions were observed across 15-120 mg, with consistent effects between 30 mg q12h and 60 mg q24h (MAD). GS1-144 could be administered with or without meals with no clinically significant impact on PK exposure. These results support further clinical development of GS1-144 for the treatment of VMS.