763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study

Background: Accumulating evidences suggest that dual GLP-1/GIP receptor agonist can achieve prominent glycemic control and body weight loss. Here we report the results of a phase 1 SAD and MAD study of HRS9531 in healthy subjects (NCT05152277). Methods: In the SAD, healthy subjects were randomized (4:1) to receive subcutaneous injection of HRS9531 (0.1, 0.3, 0.9, 2.7, 5.4, and 8.1 mg) or placebo. In the MAD, healthy subjects were randomized (4:1) to receive HRS9531 (0.9, 2.7, and 5.4 mg [2.7/2.7/4.0/5.4 mg titration]) or placebo once a week for 4 wks. The primary endpoints for both parts were safety and tolerability. Results: Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD; all considered mild to moderate in severity (mostly mild). No severe hypoglycemia or serious events occurred. Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively. Fasting plasma glucose (FPG) levels decreased dose-dependently after single and multiple dosing. The 0 to 2 h glucose AUC during oral glucose tolerance test (OGTT) on D23 decreased dose-dependently relative to placebo in MAD. In SAD, body weight loss was dose-dependent and the maximal mean loss on D8 was 3.8 kg (4.9%) in 8.1 mg group. In MAD, the mean weight loss on D29 (after 4 wks treatment) ranged 4.3-7.7 kg (6.7%-9.3%) across 0.9-5.4 mg groups, and maximal loss (8.0 kg, 10.0%) occurred on D36 in 5.4 mg group. Conclusions: HRS9531 was well tolerated, had favorable PK, and led to evident glucose decrease and body weight loss. These data support further clinical development of HRS9531 for metabolism-related disorders such as T2DM and obesity. Disclosure K.He: None. F.Wei: None. H.Chen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y.Zhang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z.Sheng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q.Wen: None. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.