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
Abstract
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…
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