Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

Abstract

To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.