ENT-03, a Centrally Acting Endogenous Spermine Bile Acid with PTP1B Inhibitory Activity, Has Potent Effects on Metabolism and Weight in a Mouse Model of Diet-Induced Obesity (DIO)

Background: We have discovered ENT-03, a spermine-bile acid of unprecedented structure in the brain of neonatal mice. ENT-03 appears postnatally at a time when the maternal supply of milk is inadequate to support maximal growth and development. ENT-03 has PTP1B inhibitory activity and acts centrally to normalize glycemia and reverse obesity. Methods: ENT-03 (25mg/kg), semaglutide (0.04mg/kg) or vehicle were administered subcutaneously twice weekly for 10 weeks to DIO mice (n=5/group). Results: In ENT-03 treated mice on a high fat diet, non-fasting glucose rapidly fell to within normal range prior to any significant weight loss (p=2×10-5), remaining normal thereafter. In contrast, in semaglutide treated mice, glucose fell in proportion to weight loss, remaining elevated throughout (p=0.2). ENT-03 treated mice were restored to lean body weight. Body weight and glucose improved partially in semaglutide treated mice. Body fat decreased by 49% in ENT-03 (p=10-5) and by 19% in semaglutide treated mice (p=0.1). Basal glucose uptake in muscle was increased 3-fold in ENT-03 treated mice compared to controls. Conclusion: ENT-03 is a novel endogenous, centrally acting mammalian steroid which rapidly normalizes glucose, independent of body weight and causes gradual but marked weight loss in DIO mice. Phase 1 studies will begin in Q2 2023. Disclosure D.Barbut: None. J.A.Baur: Consultant; Cytokinetics Inc., Pfizer Inc., Other Relationship; Elysium Health, Research Support; Pfizer Inc., Metro Biotech. P.M.Titchenell: Consultant; Alnylam, Guidepoint, AstraZeneca. J.G.Davis: None. M.B.Zemel: None. G.Fleming: Board Member; NuSirt, Consultant; Amolyt, Oramed Pharmaceuticals, Adocia, Aerami, TixiMed, Biocon, Hagar, CMC Magnetics, AdioPharm. A.C.Moses: Advisory Panel; Enterin, ViaCyte, Inc., GentiBio, TixiMed, Consultant; Virta Health Corp., ARMI (Advanced Regenerative Manufacturing Institute), Stock/Shareholder; Minutia. M.Zasloff: None.