The safety, tolerability, pharmacokinetics and pharmacodynamics of GZR18 in healthy American and Chinese adult subjects

Aims: GZR18, a novel long-acting GLP-1 receptor agonist, has demonstrated substantial metabolic improvements in diabetic and obese animal models. The present studies aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the ascending dose of GZR18 in healthy American and Chinese subjects. Materials and Methods: In these phases 1, randomized, double-blind, placebo-controlled, sequential, dose-escalation US and Chinese studies, healthy American and Chinese adults with similar age were enrolled to once-weekly subcutaneous injection of GZR18 or placebo. The studies included three cohorts of male American subjects (cohorts US-1-3) and six cohorts of Chinese subjects (cohorts CN-1-6, male and female), each with a specified target dose of GZR18 ranging from 1 to 50 mu g/kg (1-10 mu g/kg for US study and 5-50 mu g/kg for Chinese study). The primary endpoints were the safety and tolerability of GZR18. Blood samples were collected for PK and PD analysis of GZR18 before and after dosing. A population PK analysis of GZR18 was conducted to ascertain whether there are ethnic PK differences between American and Chinese adults. Results: The exposure of GZR18 was comparable between healthy American and Chinese subjects, with the geometric mean ratio between the two populations for AUC(0-t) and C-max close to 1. A dose-dependent increase in AUC(0-t) and C-max occurred in both populations. The median time to maximum plasma concentrations (T-max) in American subjects ranged from 72 to 96 h, and the mean T-max ranged from 60 to 72 h in Chinese subjects. The half-life of GZR18 was approximately 7 days in both American and Chinese subjects. Evident body weight reduction was observed in GZR18 treatment groups in Chinese subjects (cohorts CN-3-6 on Day 15, -1.25 to -1.86 kg; -1.88% to -3.11%). No deaths, serious adverse events or hypoglycaemia were reported. Decreased appetite and nausea were the most frequently reported treatment-emergent adverse events, observed in Chinese study and mild in severity. The safety profile of GZR18 was generally consistent with the same class of drugs. Conclusions: GZR18 demonstrates good tolerability in healthy American and Chinese subjects. No ethnic differences were observed between healthy American and Chinese subjects. The safety, PK and PD profiles of GZR18 support its further clinical evaluation for glycaemic and body weight control.