2550-P: Enhanced Weight Loss when HTD1801 Is Combined with GLP-1RAs in DIO Mice

Introduction and Objective: HTD1801 is an anti-inflammatory metabolic modulator that activates AMPK and inhibits NLRP3. Here, we evaluated the weight loss effect of HTD1801 (1801), in combination with glucagon-like peptide-1 receptor agonists (GLP-1RAs), using the diet-induced obese (DIO) mouse model. Methods: DIO mice were treated for 4 wks with 1801, semaglutide (Sema), tirzepatide (Tirze), or combinations of 1801 with Sema or Tirze to evaluate weight loss. In a separate study, DIO mice received Sema for 3 wks followed by 1801 for 3 wks to evaluate weight rebound. Body weights, fat mass and lean mass were monitored. Results: Compared with Sema or Tirze mono, combination with 1801 produced significantly greater weight loss. High dose Sema or Tirze combined with 1801 showed additional weight loss and was well-tolerated. This effect was driven by further reductions in fat mass with minimal impact on lean mass. After Sema discontinuation, 1801 significantly reduced body weight rebound with lower fat mass ratio, higher lean mass ratio, and significantly attenuated glucose rebound. Conclusion: HTD1801 enhances weight loss with improved weight loss quality when combined with a GLP-1RA and mitigates body weight and glycemic rebound after GLP-1RA discontinuation. Disclosure R. Bai: Employee; Current; HighTide Therapeutics Inc. L. Liu: Employee; Current; HighTide Therapeutics Inc. J. Cheng: Employee; Current; HighTide Therapeutics Inc. M. Yu: Employee; Current; HighTide Therapeutics Inc. L. MacConell: Employee; Current; HighTide Therapeutics Inc. F. Surmont: Consultant; Current; HighTide Therapeutics Inc, Medical AI.