1199-OR: Inhibition of ALDH1A3 Restores Beta-Cell Function in Type 2 Diabetes and Offers First-in-Class Potential as an Oral, Safe, and Disease-Modifying Therapeutic

by sugaradmin



Introduction and Objective: The increasing prevalence of type 2 diabetes (T2D) requires a novel, disease-modifying treatment to target the root cause of diabetic progression: the loss of pancreatic β cell function. Recent clinical data has shown that patients diagnosed with T2D have a >80% loss in functional pancreatic β cell mass, which is not reversed by the current best-in-class therapies, such as GLP-1 receptor agonists. We and others have shown that these β cells do not die but rather dedifferentiate into a progenitor-like state through the activity of aldehyde dehydrogenase 1a3 (ALDH1a3). Here we developed and tested KAYO-1732, a 1st-in-class, oral ALDH1a3 inhibitor, as a candidate therapy to reverse β cell decline in T2D preclinical models.Methods: KAYO-1732 was tested in rodent models to assess whether ALDH1a3 inhibition can either prevent T2D onset in prediabetic models or restore functional β cell mass in severe T2D models. Key markers of β cell function, glycemic control, metabolism, and organ damage were assessed. Toxicology, pharmacokinetic and safety-pharmacology studies were conducted to identify dose levels for IND-enabling studies.Results: In severe models of T2D, ALDH1a3 inhibition dose-dependently improved insulin secretory capacity and glycemic control by promoting pancreatic β cell regeneration. ALDH1a3 inhibition was also able to prevent T2D onset in prediabetic models and resulted in a unique metabolic signature that was distinct from the glycemic control induced by GLP-1R agonists. Safety studies identified a wide therapeutic margin and enabled the initiation of IND-enabling studies for KAYO-1732.Conclusion: KAYO-1732, a 1st-in-class ALDH1a3 inhibitor, demonstrates β cell restoring capacity in preclinical models of T2D and cardiometabolic disease. These findings support a clinical approach designed to assess the restoration of functional β cell mass as a disease-modifying strategy for T2D.

Disclosure

M. Esposito: Board Member; Current; Kayothera Inc. F. Briand: Employee; Current; PHYSIOGENEX. Stock/Shareholder; Current; PHYSIOGENEX.



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