Abstract 292: ETC-1002 Reduces Body Weight Gain and Hepatic Triglyceride Content and Improves Glycemic Control in a Mouse Model of Diet-Induced Obesity

Abstract

ETC-1002 is an investigational drug currently in Phase 2 clinical development to treat dyslipidemia and other cardiometabolic risk factors. Previously, ETC-1002 prevented hyperlipidemia and atherosclerosis in rodent models; and improved hepatic triglycerides (TG) as well as fasting blood glucose and insulin in the KKA y insulin resistant mouse model via putative mechanisms including activation of AMP-activated protein kinase. In the present study we investigated the effect of ETC-1002 on body weight, hepatic TG and insulin sensitivity in a diet-induced obese (DIO) mouse model. C57BL/6 mice were fed a 60% high-fat diet beginning at 11 weeks of age. At 12 weeks of age mice were assigned to treatment groups and administered vehicle or ETC-1002 at 3, 10, or 30 mg/kg/day for 9 weeks. A separate cohort of mice was maintained on standard rodent chow diet throughout the study as a comparator. Food consumption, body weight, hepatic TG content, fasting blood glucose, fasting plasma insulin, insulin tolerance tests, and glucose tolerance tests were measured. Mice developed obesity, hyperinsulinemia, mild hyperglycemia and elevated hepatic triglycerides in response to the high-fat diet. ETC-1002 results were dose-dependent and statistically significant at doses of 10 and 30 mg/kg/day. ETC-1002 attenuated body weight gain 8% and 15% with no effect on food consumption. Body weight changes were associated with 12% and 32% decreases in epididymal fat pad mass. Hepatic TG content was also reduced with ETC-1002 by 34% and 46%; respectively. ETC-1002 treatment reduced fasting blood glucose 11% and 16%; plasma insulin 80% and 95%; and resulted in significant improvements in insulin tolerance tests (19% and 22% reduction in AUC) with modestly improved glucose tolerance (not significant). In an intervention study with a 12 week lead-in on high-fat diet, comparable effects on body weight, hepatic TG, and insulin sensitivity were observed. In summary, ETC-1002 reduced obesity and hepatic TG and improved glycemic parameters in a high-fat fed diet-induced mouse model of disease. The present data in the DIO mouse, combined with previously reported efficacy in rodent models supports ETC-1002 as a regulator of imbalances in lipid and carbohydrate metabolism.