768-P: MSDC-0602 Is a Direct Mitochondrial Pyruvate Carrier Inhibitor That Modulates Central Carbon Metabolism in Mice and Humans

Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-0602, a PPARγ-sparing, TZD-like molecule that inhibits the MPC, was recently tested in a phase 2B trial for treating NASH, which reported beneficial effects on glucose and insulin homeostasis. Yet, the broad, in vivo metabolomic effects of MSDC-0602 treatment have remained undefined. Here, we tested MSDC-062 metabolic mechanisms of action in vitro and in vivo, spanning from mitochondrial pyruvate uptake assays in isolated mouse mitochondria, through cultured mouse liver cells, in vivo in mice, and in humans participating in the EMMINENCE trial. First, we examined MSDC-0602’s effect in isolated mouse liver mitochondria: Pyruvate-oxidation was decreased by MSDC-0602, and 2.5 µM MSDC-0602 was sufficient to decrease mitochondrial pyruvate uptake by >50%. We extended these findings to AML12 mouse liver cells and mouse liver in vivo. In AML12 cells, MSDC-0602 treatment increased pyruvate and lactate and decreased alanine. These results were comparable but not identical to results from parallel testing of the specific MPC inhibitor UK5099. 14-day treatment of NCD and HFD fed mice with MSDC-0602 decreased liver alanine and branched chain amino acids. As we previously observed with MPC liver-specific knockout mice, the HFD-induced liver TCA intermediate pool size expansion was mitigated by MSDC-0602. Accordingly, MSDC-0602-dependent metabolomic changes were more pronounced in HFD- versus NCD-fed mice. Human EMMINENCE trial participants receiving MSDC-0602 showed decreased circulating alanine, ketone bodies, and glucose. Similarly, circulating and liver glucose were decreased in HFD mice treated with MSDC-0602. Together, these data are consistent with MSDC-0602 modulating in vivo metabolism in a partially MPC-dependent manner and by additional mechanisms that remain to be understood. Disclosure A. J. Rauckhorst: None. D. J. Pape: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. E. B. Taylor: None. Funding American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institute of Diabetes and Digestive and Kidney Diseases (DK104998); Cirius Therapeutics