SLIMMER: Ecnoglutide Demonstrates Weight Loss Potential in Phase 3 Trial

A phase 3 trial from China indicates use of ecnoglutide, a biased GLP-1 receptor agonist, could provide significant reductions in body weight among patients with overweight or obesity.

Named the SLIMMER trial, results of the study, which were presented at the 85th Scientific Sessions of the American Diabetes Association (ADA 2025), offer evidence of the agent’s safety and effects on body weight at 40 weeks among more than 600 participants.1

Formerly known as XW003, ecnoglutide is a novel cAMP-biased GLP-1 analogue that selectively induces cAMP production over β-arrestin recruitment, which developers suggest could improve efficacy.1

The SLIMMER study enrolled 664 participants who were randomized 3:3:3:1:1:1 to ecnoglutide at doses of 1.2 mg, 1.8 mg, or 2.4 mg, or corresponding volume-matched placebo, for 40 weeks. For inclusion in the trial, patients were required to have a BMI between 24 and 28 kg/m2 with at least 1 weight-related comorbidity.The cohort had a mean age of 34.2 years (SD, 7.6), a mean bodyweight of 91.3 kg (SD, 16.1), a mean BMI of 32.5 (4.1) kg/m2, and a mean waist circumference of 104 (SD, 10.7) cm.1

The coprimary endpoints were the percentage change in bodyweight and the proportion of participants achieving at least 5% weight loss at week 40.1

Primary results showed dose-dependent weight loss across all ecnoglutide arms compared to placebo (P <.0001):

• Ecnoglutide 1.2 mg: –9.1% (SE, 0.8)
• Ecnoglutide 1.8 mg: –10.9% (SE, 0.9)
• Ecnoglutide 2.4 mg: –13.2% (SE, 0.8)
• Placebo: +0.1% (SE, 0.8)

Results demonstrated the proportion of patients achieving weight loss of 5% or more 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. In contrast, this was achieved by 16% of the placebo group (P <.0001 for all). Investigators noted the respective estimated treatment differences relative to placebo were 60% (98% CI, 50 to 71), 68% (98% CI, 58 to 78), and 70% (98% CI, 61 to 80).1

Analysis of safety data indicated adverse events were reported in 93% of ecnoglutide-treated participants and 84% of those on placebo, with mild-to-moderate gastrointestinal issues being most common. Investigators noted a total of 10 participants discontinued due to adverse events. Investigators also pointed out data from the study suggested patients receiving higher doses of ecnoglutide continued to see weight loss up to week 48, which could indicate a greater benefit achieved with continued care.1

In a linked editorial, Tricia Tan, MBChB, PhD, of Imperial College London, commended study investigators of their efforts and applauded the community’s enthusiasm for development of GLP-1 receptor agonists but questioned the viability of these agents in the growing landscape of established therapies.2

“The development of biased GLP-1 receptor agonists has been met with enthusiasm from the pharmaceutical industry, but does this design feature really confer any added clinical advantage? Unfortunately, these results, taken together with those from orfloglipron, do not provide any direct evidence to support this hypothesis,” Tan wrote.2 “To address this question, a study comparing the clinical effects of a biased GLP-1 analogue with those of a pharmacokinetically matched but balanced GLP-1 analogue would be needed: only then will the clinical role of this design feature be clear.”

References:

1. Ji L, Gao L, Xue H, et al. 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. The Lancet Diabetes & Endocrinology. Published online June 21, 2025. doi: 10.1016/s2213-8587(25)00141-x

2. Tan TM-M. Is biased agonism helpful in the treatment of obesity with the GLP-1 receptor analogues? The Lancet Diabetes & Endocrinology. Published online June 21, 2025. doi: 10.1016/s2213-8587(25)00157-3