849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats

Abstract

Background: TLC-3595 is a potent (IC50=14nM), selective, small molecule, allosteric inhibitor of acetyl-CoA carboxylase 2 (ACC2). TLC-3595 provides a novel therapeutic approach for type 2 diabetes (T2D), via reduction in intramyocellular lipid (IMCL) content, that is complementary to approved therapies. Reduced IMCL strongly correlates with insulin sensitivity (IS). Here, we demonstrate antidiabetic effects of TLC-3595 in Zucker Diabetic Fatty (ZDF) rats. Methods: IMCL was measured by 1H-MRS. T2D progression and IS by hyperinsulinemic-euglycemic clamp were assessed in 30% diet-restricted ZDF rats treated with TLC-3595 (1.67, 5, or 15mg/kg) or pioglitazone (Pio, 0.75mg/kg) daily for 5-12 weeks. Results: TLC-3595 or an analog caused rapid and sustained IMCL reduction (~50%) in lean and dysmetabolic rodents. TLC-3595 enhanced systemic fatty acid oxidation (increased plasma beta-hydroxybutyrate) and reduced cardiac lipid in ZDF rats. TLC-3595 dose-dependently delayed β-cell failure in ZDF rats and was non-inferior to Pio for reductions in hyperglycemia (15-25% lower glucose AUC) and HbA1c (0.6-1.6% vs. vehicle) (Fig A, B). TLC-3595 improved IS and increased clamp glucose infusion rate by 29%, (Fig C). Conclusion: TLC-3595 reduced IMCL, improved IS, and delayed T2D progression comparable to Pio in ZDF rats. These data provide strong rationale for evaluation of TLC-3595 to treat insulin resistance and T2D. Disclosure A. Vijayakumar: Employee; OrsoBio Inc, Gilead Sciences, Inc. E. Murakami: Employee; OrsoBio. R.S. Huss: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. N. Sroda: None. A. Shimazaki: Employee; Shionogi & Co. Ltd. Y. Kashiwagi: Employee; Shionogi & Co. Ltd. R.P. Myers: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. M. Subramanian: Other Relationship; OrsoBio Inc. G.I. Shulman: Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC. Consultant; Novo Nordisk. Other Relationship; iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc. Consultant; DiCerna Pharmaceuticals, Inc. Other Relationship; Equator Therapeutics, Inc., Generian Pharmaceuticals. Stock/Shareholder; Levels Health, Inc. Other Relationship; Fortress Biotech, Inc. Consultant; Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc. Other Relationship; OrsoBio, Aro Biotherapeutics Company.