First-in-human study of HDM1002, a GLP-1 receptor agonist: Safety, tolerability, pharmacokinetics and pharmacodynamics of escalating single oral doses in healthy volunteers.

Aims: To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single oral doses of HDM1002 in healthy adult participants.

Materials and methods: This was a first-in-human, randomized, double-blind, placebo-controlled, 2-part study. Healthy participants aged 18 to 55 years with a body mass index (BMI) of 19.0 ~ 32.0 kg/m² were eligible. In the single ascending dose (SAD) part, eligible participants were randomized (8:2) to receive a single oral escalating dose of HDM1002 (10-600 mg) or placebo. In the food effect (FE) part, participants were randomized (7:7) to receive HDM1002 (200 mg) in the fasted and fed states with a two-period, crossover design.

Results: A total of 79 participants enrolled and completed the study. The most common adverse events (AEs) were nausea, diarrhoea, vomiting and decreased appetite, which increased in a dose-dependent manner. No serious AEs were reported. C_max and AUC appeared to be dose-proportional from 10 to 600 mg by a power model. The geometric mean t_1/2z ranged from 4.99 to 7.10 h. C_max and AUC of HDM1002 were similar under fed and fasted conditions. HDM1002 significantly lowered postprandial glucose in a dose-dependent manner and maintained the glucose-lowering effect at both 6 and 12 h at 100-600 mg doses.

Conclusions: HDM1002 was safe and well tolerated at 10-600 mg. HDM1002 showed linear pharmacokinetics, and a standardized high-fat meal did not impact systemic exposure. These results provide preliminary evidence supporting further clinical development of HDM1002 in individuals with type 2 diabetes.