Efficacy and safety of a biased GLP-1 receptor agonist ecnoglutide in adults with overweight or obesity: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ecnoglutide is a novel cyclic adenosine monophosphate (cAMP)-biased GLP-1 receptor agonist currently in development for weight management. We aimed to assess the efficacy and safety of once weekly ecnoglutide versus placebo for the treatment of overweight or obesity in Chinese adults. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 medical centres across China. Eligible adults were aged 18-75 years with overweight or obesity (defined as BMI ≥28 kg/m or ≥24 kg/m with at least one weight-related comorbidity [prediabetes, hypertension, hyperlipidaemia, metabolic dysfunction-associated steatotic liver disease, obstructive sleep apnoea syndrome, or weight-bearing joint pain]), without diabetes (type 1 or 2). Participants were randomly assigned (3:3:3:1:1:1) via computer-generated random sequencing to receive subcutaneous ecnoglutide (1·2, 1·8, or 2·4 mg) or volume-matched placebo (1·2, 1·8, or 2·4 mg), once weekly, stratified by BMI at screening (≥28 kg/m and <28 kg/m). The coprimary endpoints were percentage change in bodyweight and proportion of participants with a reduction in bodyweight of 5% or more at week 40 (using the treatment policy estimand in the full analysis set). The full analysis set included all randomly assigned participants who were exposed to at least one dose of study drug or placebo according to their assigned treatment group. Safety was assessed in all participants who received at least one dose and had a safety assessment after medication. This study was registered with ClinicalTrials.gov, NCT05813795, and is complete. FINDINGS: Between April 5, 2023, and June 20, 2024, 882 participants were screened and 664 were randomly assigned to receive ecnoglutide 1·2 mg (n=166), ecnoglutide 1·8 mg (n=166), ecnoglutide 2·4 mg (n=167), or placebo (n=165). At week 40, the least-squares mean percentage change in bodyweight was -9·1% (SE 0·8) in the ecnoglutide 1·2 mg group, -10·9% (0·9) in the ecnoglutide 1·8 mg group, and -13·2% (0·8) in the ecnoglutide 2·4 mg group versus 0·1% (0·8) in the placebo group, and the respective estimated treatment differences compared with placebo were -9·2% (97% CI -11·0 to -7·5), -11·1% (-13·1 to -9·1), and -13·3% (-15·3 to -11·3), respectively (all p<0·0001). The proportion of participants who achieved at least a 5% reduction in bodyweight at week 40 was 77% in the ecnoglutide 1·2 mg group, 84% in the ecnoglutide 1·8 mg group, and 87% in the ecnoglutide 2·4 mg group versus 16% of participants in the placebo group, and the respective estimated treatment differences versus placebo were 60% (98% CI 50 to 71), 68% (58 to 78), and 70% (61 to 80; all p<0·0001). Treatment-emergent adverse events were observed in 155 (93%) of 166 participants in the ecnoglutide 1·2 mg group, 154 (93%) of 166 participants in the ecnoglutide 1·8 mg group, 156 (93%) of 167 participants in the ecnoglutide 2·4 mg group, and 139 (84%) of 165 participants in the placebo group. The most common adverse events were mild-to-moderate gastrointestinal related events. Ten participants treated with ecnoglutide discontinued treatment due to adverse events. INTERPRETATION: In adults with obesity or overweight without diabetes (type 1 or 2), individuals administered ecnoglutide had superior and sustained reduction in bodyweight versus placebo with a favourable safety profile, supporting its potential use for weight management. FUNDING: Hangzhou Sciwind Biosciences.