Oral nonpeptide GLP-1 receptor agonist VCT220 for obesity treatment: a randomized, double-blind, phase II trial.

VCT220 is a novel nonpeptide, orally available glucagon-like peptide-1 receptor agonist (GLP-1RA) designed to reduce the complex administration of injectable GLP-1RAs and the limited bioavailability of on-marketing oral agents for obesity care. We conducted a multicenter, randomized, double-blind, placebo-controlled, phase II trial (Registration no. CTR20233978 and NCT06569355) across 13 sites in China. Adults aged 18-75 years with overweight (BMI 24-28 kg/m² plus ≥ 1 comorbidity) or obesity (BMI ≥ 28 kg/m²) were randomly assigned (3:1) to receive once-daily VCT220 (80 mg, 120 mg, or 160 mg with slow or fast titration) or placebo for 16 weeks, alongside lifestyle counselling. The primary endpoint was the percentage change in body weight from baseline to week 16. Two-hundred and fifty participants were randomized (61 to placebo, 189 to VCT220). At week 16, mean body weight decreased by -5.75% (80 mg) to -9.73% (160 mg-FT) versus -1.61% with placebo (all p < 0.001). The proportion achieving ≥5% weight loss ranged from 55.4% (80 mg) to 90.3% (160 mg-ST) with VCT220 versus 13.1% with placebo. VCT220 also improved HbA1c, fasting insulin, and blood pressure. Adverse events were mainly mild-to-moderate gastrointestinal events, most common during titration, and rarely led to discontinuation. VCT220, a once-daily oral nonpeptide GLP-1RA, produced rapid and clinically meaningful weight loss with metabolic benefits over 16 weeks, showing a tolerability profile consistent with the class. These findings support further global phase III evaluation to further verify the efficacy and safety of VCT220 as well as potential cardiometabolic benefits.