Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP‐531, a first‐in‐class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes

_Aim:_ To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP-531, designed to improve glycaemic control and reduce weight. _Methods:_ Assessments, including glucose measurements, were performed in a three-part randomized study. In Part A, healthy subjects [n = 44, age 18–50 years, body mass index (BMI) 20–28 kg/m2] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP-531 or placebo. In Part B, overweight/obese subjects (n = 32, age 18–65 years, BMI 28–38 kg/m2) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18–65 years, BMI 20–40 kg/m2, glycated haemoglobin (HbA1c) 7–10%] received AZP-531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively). _Results:_ AZP-531 was well tolerated. Single- and multiple-dose pharmokinetic variables were similar. Maximum AZP-531 concentrations were typically reached at 1 h post-dose. Observed maximum concentration (Cmax) and area under the curve were dose-proportional. The mean terminal half-life (t1/2) was 2–3 h. In Part B, AZP-531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin-sensitizing effect. AZP-531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In Part C, glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP-531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo). _Conclusions:_ AZP-531 was well tolerated in this first-in-human study. Its pharmacokinetic profile, suitable for once-daily dosing, and metabolic effects support further clinical development for T2D.