Dihydroceramide Desaturase-1 Inhibitors for Treatment of Diabetes and Other Metabolic Diseases

NIH SBIR Phase 2B Title: Dihydroceramide Desaturase-1 Inhibitors for Treatment of Diabetes and Other Metabolic DiseasesPotrero Hill Therapeutics Project Summary/Abstract:Despite the current FDA-approved glucose-lowering agents, the prevalence of type 2 diabetes (T2D) and its complications continues to reach epidemic proportions. Globally, 387 million people have overt diabetes, and the prevalence of impaired fasting glucose (precursor to T2D referred to as “pre-diabetes”) is 26% of the US population. Consequently, T2D and its frequent complications (high triglycerides, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis [NAFLD/NASH], diabetic kidney disease (DKD), and cardiovascular disease) increasingly account for a large proportion of global end-stage renal and liver failure, limb amputations, blindness, myocardial infarctions, and strokes. To address this highly unmet need, Potrero Hill Therapeutics (“PHT”) is developing highly-potent, drug-like, and orally-active small molecule inhibitors of dihydroceramide desaturase-1 (DES1), a key enzyme which catalyzes the final step in the de novo formation of ceramides, molecules which drive insulin resistance, high triglycerides, NAFLD/NASH, and DKD when produced in excess. This work has been partially funded through SBIR Phase 1 and Phase 2 grants, and in this Phase 2B grant, PHT will take the next critical steps of advancing its lead preclinical development candidate into IND-enabling activities, including GMP process development and GLP toxicology/safety studies. In addition, efficacy in a validated rodent model of DKD will also be explored. Ultimately, completion of these aims will get us to the point of being ready to open an initial IND to execute a first-in-human Phase 1a clinical trial.