Oral HRS-7535 achieves dose-dependent weight loss up to 9.36% in obese Chinese adults

The global burden of obesity necessitates effective and accessible treatment options. While injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionized weight management, their parenteral administration can pose adherence challenges and limit broader accessibility. There is a significant clinical gap for convenient, orally active alternatives that can offer comparable efficacy. Developing small-molecule, non-peptide GLP-1R agonists is crucial to overcome these limitations, potentially expanding treatment reach and improving patient compliance for chronic weight management.

This multicenter, randomized, double-blind, placebo-controlled phase 2 trial enrolled 235 Chinese adults with obesity (BMI 28.0-40.0 kg/m²) without diabetes. Participants were randomized 1:1:1:1:1 to once-daily oral HRS-7535 at target doses of 30 mg (n=48), 60 mg (n=47), 120 mg (n=46), or 180 mg (n=48), or placebo (n=46) for 26 weeks. The primary endpoint was the percentage change in body weight from baseline to Week 26, with all randomized participants included in the analyses.

At Week 26, oral HRS-7535 demonstrated dose-dependent and clinically meaningful weight loss. The least-squares (LS) mean percentage changes in body weight were -2.99% with 30 mg, -7.09% with 60 mg, -6.17% with 120 mg, and -9.36% with 180 mg, compared to -2.50% with placebo. The corresponding placebo-adjusted LS mean differences were -0.49% (P=0.7104), -4.60% (P=0.0006), -3.67% (P=0.0062), and -6.87% (P<0.0001) for the 30 mg, 60 mg, 120 mg, and 180 mg groups, respectively. The 180 mg dose achieved the most significant weight reduction. Gastrointestinal adverse events were the most common, predominantly mild to moderate, and occurred more frequently during dose escalation, consistent with the known profile of GLP-1R agonists. No new safety signals were identified. Overall, doses of 60 mg or higher produced clinically meaningful weight loss. > The 180 mg dose of oral HRS-7535 led to a 9.36% mean body weight reduction, representing a 6.87% placebo-adjusted difference (P<0.0001).