TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulinresistance in patients with severe lipodystrophy Patients with lipodystrophies exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes mellitus,and nonalcoholic steatohepatitis (NASH), and have limited effective treatment options. Lipodystrophy ischaracterized 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 mechanismfor insulin resistance. Mitochondrial protonophores reduce intracellular lipids by increasing lipid oxidation in themitochondria. Mechanistically, mitochondrial protonophores shuttle protons across the inner mitochondrialmembrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncouplingnutrient oxidation from ATP production and dissipating the proton gradient as heat. The therapeutic efficacy ofprotonophores 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 lipidaccumulation by increasing cellular energy expenditure. Indeed, multiple groups have validated this mechanismof action by demonstrating large improvements in insulin sensitivity and dyslipidemia, with concomitantreductions in hepatic triglycerides and markers of inflammation in relevant nonclinical models. TLC-1235 is afunctionally liver-targeted, controlled-release mitochondrial protonophore (CRMP) that will promote selectivemitochondrial uncoupling in the liver while minimizing high systemic exposures (Cmax) that have been associatedwith 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 befunded by the Company.
Public Health Relevance Statement: Narrative
Patients with lipodystrophies exhibit hypertriglyceridemia, severe insulin resistance, diabetes, and fatty liver,
and have limited treatment options. We have identified a lead small-molecule drug, TLC-1235, based on
extensive biological characterization in relevant animal models of disease to address this condition with very
high unmet medical need. During this project, we will carry out activities to enable preparation of an Investigation
New Drug (IND) application to the Food and Drug Administration (FDA).
Project Terms: <1,2-diacylglycerol> | |
