Safety, tolerability, pharmacokinetics and pharmacodynamics of GZR4, a novel once‐weekly basal insulin, in healthy participants: A randomized trial

Abstract Aims Insulin GZR4 (GZR4), a novel once‐weekly basal insulin, has demonstrated a favourable safety and low toxicity profile, as well as notable in vivo glycaemic control effects, in preclinical studies. The study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GZR4 in healthy Chinese participants. Methods In this randomized, single‐blind, dose‐escalation Phase 1a study, healthy male adults aged 18–45 years, with a BMI of 19–24 kg/m 2 were enrolled in five cohorts. Participants in Cohorts 1–4 were randomized 4:1 to receive subcutaneous injections of GZR4 at doses of 1, 3, 6, and 12 nmol/kg or placebo. Participants in Cohort 5 received 0.4 U/kg (2.4 nmol/kg) of insulin degludec (IDeg). Euglycaemic glucose clamps were conducted 24–48 h (Day 2) and 144–168 h (Day 7) after GZR4 administration, and 0–24 h (Day 1) after IDeg administration. The primary endpoints were the safety and tolerability of GZR4. Results A total of 43 participants were enrolled, and 42 of them completed the study. No deaths, serious adverse events (SAEs), or discontinuations related to the investigational product were reported. The most common treatment‐emergent adverse events (TEAEs) were hypoglycaemia, which occurred exclusively in the 12 nmol/kg GZR4 group. All TEAEs were mild to moderate in severity. The PK parameters of GZR4 increased linearly with the dose from 1 to 12 nmol/kg, and the glucose‐lowering effect was sustained for approximately 1 week. The AUC GIR,24‐48h and AUC GIR,144‐168h for the 6 nmol/kg GZR4 dose (54.91 and 37.84 h × mg/kg/min) were comparable with that of IDeg (AUC GIR,0‐24h , 40.59 h × mg/kg/min), suggesting that GZR4's potency may be approximately 3.2‐times greater than IDeg weekly. Conclusion Once‐weekly GZR4 demonstrated good safety and tolerability in healthy participants. It exhibited a dose‐dependent and sustained glucose‐lowering effect over a full week and demonstrated stronger daily glucose‐lowering efficacy than once‐daily IDeg under similar molar concentrations. These results support further investigation of once‐weekly GZR4 for glycaemic control in patients with diabetes.