865-P: Efficacy and Safety of a Novel Oral Small Molecule GLP-1RA in Chinese Obese Adults without Diabetes

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Introduction and Objective: HRS-7535, a novel small molecule GLP-1RA, demonstrated promising weight loss (WL) in a phase 1 trial. This phase 2 study evaluated its efficacy and safety in obese adults without diabetes. Methods: In this randomized, double-blind, placebo (PBO)-controlled, multicenter study, 235 participants (pts) (BMI 28-40 kg/m²) were randomized (1:1:1:1:1) to receive oral HRS-7535 at target doses of 30, 60, 120, or 180 mg QD or PBO for 36 wks (a 26-wk core treatment period followed by a 10-wk extension). Primary endpoint was percentage change in body weight (BW) from baseline (BL) at wk 26. Results: At BL, mean BMI is 32.5 kg/m², and mean BW is 91.6 kg; 48.5% of pts were female. At wk 26, the least-squares (LS) mean percentage changes in BW from BL were -2.99% with HRS-7535 30 mg, -7.17% with 60 mg, -6.17% with 120 mg, and -9.36% with 180 mg, vs. -2.50% with PBO. The PBO-adjusted LS mean changes were -0.49% for 30 mg, -4.67% for 60 mg, -3.67% for 120 mg, and -6.87% for 180 mg (P = 0.7091, 0.0005, 0.0061, <0.0001). BW reduction in the 180 mg group was sustained over the 10-week extension; at wk 36, LS mean percentage change in BW from BL was -9.5% with HRS-7535 180 mg vs. -1.4% with PBO; 35.4% of pts on HRS7535 180 mg achieved ≥10% WL vs. 6.5% with PBO. In the PBO-controlled period, TEAEs occurred in 87.2-95.8% of pts on HRS-7535 and 87.0% on placebo. Most common TEAEs with HRS-7535 were gastrointestinal events (nausea:16.7-54.2%, diarrhea: 16.7-21.7%, vomiting: 15.7-37.5%), which were mostly mild to moderate in severity, and occurred more frequently during titration. No trends in elevated liver enzymes were observed. Of 31 pts (13.2%) who discontinued study treatment early, 5 (2.1%), all in HRS-7535 groups, discontinued due to TEAEs. Conclusion: In obese adults without diabetes, HRS-7535 at doses of 60, 120, or 180 mg QD resulted in clinically meaningful and statistically significant reductions in BW at wk 26 compared with PBO. HRS-7535 exhibited a safety profile consistent with other GLP-1 RAs. Disclosure W. Gu: None. L. Zhang: None. L. Li: None. D. Wei: None. L. Qifu: None. Y. Zong: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. C. Shu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. W. Dai: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Mu: None. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd

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