1794-P: New Insulin Sensitizer CIS-0602K Potential to Expand Treatment Options to Manage Diabetes

Introduction and Objective: Insulin resistance is an underlying pathophysiology of type 2 diabetes inadequately addressed by current treatment options. The new mitochondrially directed insulin sensitizer CIS-0602K was designed to maintain the pharmacology of the first-generation pioglitazone without direct PPARg side effects but which still works independent of weight loss and even when there is a small amount of weight gain. Ongoing studies are evaluating the potential of combining this pharmacology with weight loss therapies. Methods: Clinical studies evaluated the effects of a single daily dose of 250 mg/day 0602K in women with T2D treated with metformin (HbA1c 8.3%) and preclinical studies evaluated the combination of 0602K and tirzepatide (TZP) in DIO Mice. Results: In subjects with T2D, 0602K exerts similar improvements in HbA1c and insulin-stimulated glucose uptake during a euglycemic insulin clamp. These glycemic improvements have also been replicated in a 12-month clinical trial at the 250 mg dose and also at a 125 mg dose, at half the systemic exposure of drug and active metabolite. Preclinical studies in combination with TZP demonstrate that the combined treatment exerts similar weight loss during combined treatment and limits weight regain on termination of TZP. The combined treatment results in synergistic remodeling of skeletal muscle and both subcutaneous and visceral adipose tissue involving major modification of the immune system. Conclusion: CIR-0602K is a logical treatment in combination with weight loss incretin treatment to favor healthy weight loss and to correct the underlying insulin resistance. There should also be a focus on the unique effects of the combination of these mechanisms of action on the immune system, which could have an important impact on health outcomes related to obesity and complicated T2D Disclosure M. Abu-Farha: None. I. Al Khairi: None. J.A. Abubaker: None. R.A. DeFronzo: Advisory Panel; Ended; AstraZeneca. Research Support; Current; AstraZeneca. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Corcept Therapeutics. Speaker's Bureau; Current; Corcept Therapeutics. Consultant; Current; Alnylam Pharmaceuticals, Inc. Advisory Panel; Current; Regeneron Pharmaceuticals Inc., Aardvark. M. Abdul-Ghani: None. L. Norton: None. J.R. Colca: None. F. Al-Mulla: None. K.S. McCommis: Research Support; Current; Cirius Therapeutics, Inc.