776-P: Potent Weight Loss and Favorable Glycemic Control Effects of a Novel Long-Acting GLP-1/GIP/GCG Triple Agonist, HM15275, in Animal Models

Introduction & Objective: The prevalence of obesity is increasing worldwide, urging development of obesity drugs with better efficacies and weight loss qualities. HM15275 is a GLP-1/GIP/Glucagon triple agonist designed to have well-harmonized activities and long-acting property for maximized body weight reduction. To elaborate the effects, a series of studies were conducted to evaluate (1) proper target engagement, (2) pharmacokinetics, and (3) body weight loss effects in DIO mice.

Method: Target receptor engagement of HM15275 was tested by cAMP assay with or without antagonist for each receptor. Plasma concentrations of HM15275 in rat and mouse were measured after a single subcutaneous dosing of HM15275. In DIO mice, body weight loss by HM15275 was compared with semaglutide and tirzepatide after 3 weeks treatment.

Results: Maximal in vitro activities of HM15275 significantly reduced in the presence of selective GLP-1, GIP, or Glucagon antagonist (hGLP-1R: 94.56% to 0.81%, hGIPR: 97.85% to 14.07%, hGlucagonR: 95.16% to 4.14%), indicating proper target engagement. In addition, protracted pharmacokinetic profiles were observed in rodent models, (half-life in mouse: 12 ~ 16 hr and rat: 17 ~ 19 hr). In DIO mice, HM15275 remarkably decreased body weight compared to semaglutide or tirzepatide at week 3 (-39.9%, -15.0%, and -25.3% vs. baseline). Furthermore, pair-fed study showed both food intake inhibition dependent and independent weight loss by HM15275. Energy balance evaluation revealed enhanced energy expenditure by HM15275. ipGTT results indicated favorable glycemic control of HM15275.

Conclusion: As a novel long-acting triple agonist, the molecular characteristics of HM15275 had been elucidated, demonstrating superior weight loss compared to currently available anti-obesity drugs. Therefore, HM15275 could be a valuable therapeutic option for weight control and human study is ongoing to assess clinical relevance of such findings.