78-OR: KAYO-1732, a First-in-class Oral ALDH1A3 Inhibitor, Blocks Retinoid Nuclear Receptor Signaling to Regenerate Pancreatic Islets and Reverse Type 2 Diabetes

Introduction and Objective: The increasing prevalence of type 2 diabetes (T2D), particularly in non-European ethnicities that exhibit high rates of β cell failure, necessitates the development of novel disease-modifying treatments to reverse diabetic progression. We have shown that aldehyde dehydrogenase 1a3 (ALDH1a3) is a key driver of β cell failure through its role in activating the retinoid nuclear receptor (RAR) pathway. The RAR pathway is clinically validated to drive T2D pathogenesis and cardiovascular mortality, yet has long been considered undruggable. Here we developed and tested a 1st-in-class, oral, small molecule ALDH1a3 inhibitor as a candidate therapy for T2D patients. Methods: We evaluated this ALDH1a3 inhibitor in rodent models of T2D and obesity to evaluate the effects on glycemic control, β-cell function, and multi-organ damage. Extensive ADME, pharmacokinetic and safety profiling were performed to advance the inhibitor to development candidate stage. Dose range-finding studies were conducted in rat and minipig to identify doses for IND-enabling studies. Results: Our novel ALDH1a3 inhibitor significantly improved glycemic control by promoting pancreatic β cell regeneration and further protected against diabetic kidney disease, dyslipidemia and liver damage. Moreover, the compound exhibited superior efficacy compared to GLP-1RAs in ameliorating metabolic dysfunction in diet-induced obesity models while promoting insulin sensitization. Conclusion: This 1st-in-class ALDH1a3 inhibitor demonstrates disease-modifying potential in preclinical models of T2D and cardiometabolic disease. These findings support the clinical development of this compound as a novel therapeutic strategy for T2D, particularly for patients with primary β-cell dysfunction. Disclosure M. Esposito: Board Member; Kayothera Inc. F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. Funding NIH: National Institute of Diabetes and Digestive and Kidney Diseases (R43DK13642)