MPC-Directed Insulin Sensitizer MSDC-0602K Combines with Tirzepatide to Maintain Muscle Mass/Function and Restructure Adipose Tissue

Introduction and Objective: GLP1s promote weight loss, but do not address underlying metabolic dysfunction and cause loss of skeletal muscle mass/function. Azemiglitazone potassium (MSDC-0602K), a late-stage clinical candidate insulin sensitizer targeting the mitochondrial pyruvate carrier (MPC) may solve the shortcomings. Methods: MSDC-0602K was evaluated in combination with tirzepatide (10-30nmol/kg) in two separate studies of diet-induced obese mice over 4 weeks or 6 weeks and in a pilot study in obese T2D subjects. Results: Concomitant 30 mg/kg 0602K did not impede the 29% body weight loss and increased lean mass by 3 grams as measured by MRI (confirmed by tissue weight). There was 50% increase in wire hang time (34 s tirzepatide to 51 s combination) and increased ratio of mitochondrial/nuclear DNA. With or without tirzepatide, 0602K both decreased visceral:subcutaneous adipose ratio and increased brown adipose tissue. The combination treatment resulted in profound remodeling of adipose tissue (Figure 1 H&E 40X). Three-month treatment of obese T2D subjects with 0602K resulted in a 50% increase in insulin-mediated glucose disposal as measured during euglycemic insulin clamp and a 50% reduction in intramyocellular lipid by MRS. Conclusion: Metabolic reprogramming with 0602K may extend the benefits of weight loss with GLP1 receptor agonists through effects in multiple tissues including muscle and adipose. Disclosure: M. Abu-Farha: None. J. Abubaker: None. F. Almulla: None. M. Abdul-Ghani: None. L. Norton: None. R.A. DeFronzo: Advisory Panel; AstraZeneca. Research Support; AstraZeneca. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Corcept Therapeutics, Novo Nordisk. Speaker's Bureau; Corcept Therapeutics. Research Support; 89bio, Inc, Amgen Inc. J.R. Colca: Stock/Shareholder; Cirius Therapeutics, Inc. K.S. McCommis: Research Support; Cirius Therapeutics, Inc.