TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy - TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy Abstract Patients with lipodystrophies exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis (NASH), and have limited effective treatment options. Lipodystrophy is characterized by the ectopic accumulation of lipids in liver and muscle. Increased lipids, specifically sn-1,2- diacylglycerol, within plasma membranes interfere with insulin receptor signaling and are a central mechanism for insulin resistance. Mitochondrial protonophores reduce intracellular lipids by increasing lipid oxidation in the mitochondria. Mechanistically, mitochondrial protonophores shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. The therapeutic efficacy of protonophores is linked to 1) increased oxidation of fatty acids to compensate for inefficient ATP production, 2) a decrease in the production of reactive oxygen species (ROS) from the electron transport chain, and 3) activation of the expression of AMP protein kinase (AMPK), the master regulator of cellular energy homeostasis. Thus, small molecule mitochondrial protonophores represent a novel strategy to reduce ectopic lipid accumulation by increasing cellular energy expenditure. Indeed, multiple groups have validated this mechanism of action by demonstrating large improvements in insulin sensitivity and dyslipidemia, with concomitant reductions in hepatic triglycerides and markers of inflammation in relevant nonclinical models. TLC-1235 is a functionally liver-targeted, controlled-release mitochondrial protonophore (CRMP) that will promote selective mitochondrial uncoupling in the liver while minimizing high systemic exposures (Cmax) that have been associated with adverse effects of systemic uncoupling including hyperthermia, excessive weight loss, and muscle injury. During this Direct-to-Phase-2 project, we will initiate Investigational New Drug (IND)-enabling activities for TLC- 1235, including Good Laboratory Practice (GLP) manufacturing, drug metabolism and pharmacokinetics (DMPK), and toxicology and safety pharmacology studies. Additional work to support the filing of an IND will be funded by the Company.
