June 20, 2025 – ABSTRACT – ENT-03 Has Additive Weight Loss and Insulin Normalization Effects with Semaglutide in Diet-Induced Obesity (DIO) in Mice
Authors
William A. Kinney, Michael B. Zemel, G. Alexander Fleming, Alan C. Moses, Richard S. Larson,
Abstract
Introduction and Objective: Obesity and T2D remain major health concerns worldwide. We have recently described a centrally acting aminosterol, ENT-03, that induces weight loss in obese and lean rodents. ENT-03 is a synthetic version of the mammalian natural product, which is in Phase 1 clinical trials for treatment of type 2 diabetes and obesity. In this study, we examine metabolic effects of ENT-03 alone and in combination with Semaglutide (SG).
Methods: To compare the effects of ENT-03 or SG on DIO mice, animals were treated for 10 wks with either subcutaneous administration of SG (daily at 0.04 mg/kg), ENT-03 (twice weekly at 25mg/kg) or vehicle control. Mice remained on a high fat diet and followed for an additional 10 wks after treatment discontinuation. Body weight, glucose, insulin, and metabolic cage data were monitored.
Results: ENT-03 produced greater weight (31% vs. 20%, p= 0.003) and fat (53% vs. 35%, P=0.01) loss over 10 weeks of treatment vs. SG, but the combination of ENT-03 and SG produced a somewhat greater effect on weight and an additive effect on body fat (p<0.0001). Although ENT-03 animals lost more fat mass, lean mass loss was similar between the two groups (13%), reflecting greater % lean in ENT-03 (p<0.03). After discontinuation of treatment, weight gain occurred rapidly, with SG exceeding their initial starting weight, while ENT-03 treated mice maintained their weight and fat loss 10 wks after treatment discontinuation. After 10wks discontinuation, insulin levels remained lower in ENT-03, but not SG, treated mice. ENT-03 administration rapidly promoted lipid oxidation without evidence of increased energy expenditure.
Conclusion: ENT-03 produces greater weight and fat loss than SG over 10 weeks of dosing, with relative preservation of lean mass and an additive effect on fat loss when used in combination with SG. Weight loss and lower insulin persist for at least 10 weeks after treatment with ENT-03 but not SG.
W.A. Kinney: None. M.B. Zemel: Consultant; AdipoPharm, Aerami Therapeutics, Diasome Pharmaceuticals, Glyscend Therapeutics, Intercept Pharmaceuticals, Inc, NeuroBo Pharmaceuticals, Inc, Rhythm Pharmaceuticals, Inc, TIXiMED, Zealand Pharma A/S, Enterin. G. Fleming: Advisory Panel; Abvance Therapeutics. Consultant; AdipoPharm, ADOCIA, Aerami Therapeutics, Biocon. Stock/Shareholder; Diasome Pharmaceuticals. Consultant; Biomea Fusion, Glyscend Therapeutics, Intarcia Therapeutics, Inc, Kriya Therapeutics. Other Relationship; Juvenile Diabetes Research Foundation (JDRF). Consultant; Oramed Pharmaceuticals, Regor Therapeutics, Rhythm Pharmaceuticals, Inc, Rivus Pharmaceuticals Inc, TIXiMED, vTv Therapeutics, Zealand Pharma A/S, Zucara Therapeutics. A.C. Moses: Consultant; Vertex Pharmaceuticals Incorporated, Virta Health Corp, Alnylam Pharmaceuticals, Inc. Board Member; diaTribe. Stock/Shareholder; Minutia, Inc. Consultant; Scholar Rock. Advisory Panel; TIXiMED. R.S. Larson: Employee; Metabolics Pharma, Enterin Inc.
