1090-P: MSDC-0602k, a New Oral Insulin Sensitizer in Insulin Resistant NASH Patients with and without Type 2 Diabetes (T2D)

Use of the first-generation insulin sensitizer pioglitazone is limited by PPARγ-driven side effects. MSDC-0602K was designed to maintain pioglitazone’s effects on the mitochondrial pyruvate carrier (MPC), but with minimal direct PPARγ binding. A 12-month Phase 2b dose-ranging study in NASH (Harrison et al, 2019) demonstrated insulin sensitizing pharmacology without dose-limiting issues. Here we describe ongoing analysis of these data. Steady state exposures of drug and active metabolite at the highest doses averaged 4 to 7 micromolar, 1/10thof the affinity to PPARγ, but within the range for modulation of the MPC in intact cells. The effects on fasting plasma insulin (FPI), fasting plasma glucose, and hemoglobin A1c (HbA1c) plateaued at the mid-dose (125 mg), while adiponectin continued to increase 1.7, 2.5, and 4.1x vs. placebo across the 62.5, 125, and 250 mg doses. Glycemic reductions and the reduction of FPI levels were similar in subjects with or without T2D. The treatment-induced decrease in HbA1c was proportional to the baseline HBA1c and was more than 1% in subjects with a baseline above 7%, including those not well-controlled on GLP-1 agonists. In patients with or without diabetes, baseline mean FPI levels exceeded 20 μU/ml (139 pmol/L), levels in the upper quartile of historical T2D studies, and continued to increase in placebo-treated subjects but decreased on treatment with MSDC-0602K. Treatment with MSDC-0602K decreased FPI more than C-peptide. The ratio of C-peptide/FPI increased vs. placebo at end of study (8.54 ± 0.49, 9.69 ± 0.44, 10.45 ± 0.43, and 10.9 ± 0.53 for placebo and the three dose groups, respectively) suggesting both decreased need for secreted insulin and increased clearance of insulin. These data suggest that the new generation insulin sensitizer MSDC-0602K, focused toward MPC and away from PPAR, may be useful to treat patients suffering from combined fatty liver disease and T2D and highlight the importance of FPI. Disclosure J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. B. Lee: Employee; Self; Cirius Therapeutics. J.S. Iwashita: Employee; Self; Cirius Therapeutics. H.C. Dittrich: Employee; Self; Cirius Therapeutics. S.A. Harrison: Consultant; Self; Akero, Altimmune, Axcella, Cirius, Cirius Therapeutics, Genentech, Inc., Hightide Bio, HistoIndex, Intercept Pharmaceuticals, Inc., Madrigal.