etc-1002 and Disease-Models--Animal

ETC-1002 is a new investigational low density lipoprotein cholesterol (LDL-C)-lowering agent (Esperion Therapeutics, Inc.). ETC-1002 is a dicarboxylic acid derivative with a novel mechanism of action targeting two hepatic enzymes--adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK), inhibiting sterol and fatty acid synthesis and promoting mitochondrial long-chain fatty acid oxidation. This agent is currently in phase II clinical research. Available data report that ETC-1002 significantly decreased LDL-C levels (up to 32%) in both patients with normal and elevated baseline levels of triglycerides. Such beneficial effect is superior to currently approved non-statin lipid lowering agents. The levels of apolipoprotein B (apoB) and non-high density lipoprotein cholesterol (non-HDL-C) were also reduced with beneficial effect on other cardiometabolic factors such as inflammatory markers, blood pressure and body weight. Although, the safety and tolerability of ETC-1002 needs to be confirmed in ongoing and future, larger studies, this agent has, so far, been generally safe and well tolerated. This novel, oral, once-daily, small molecule may lead to effective LDL-C lowering treatment in hypercholesterolaemic subjects who are statin intolerant or as add-on therapy in those who are unable to reach the LDL-C goals despite being on statin therapy. This agent might not only exert lipid-lowering related benefits, but also favourable cardiometabolic effects.

Topics: AMP-Activated Protein Kinases; Animals; Apolipoproteins B; ATP Citrate (pro-S)-Lyase; Blood Pressure; Body Weight; Cholesterol, LDL; Clinical Trials, Phase II as Topic; Dicarboxylic Acids; Disease Models, Animal; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Liver; Mice; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rats

Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.. Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.

Topics: Animals; Carnitine O-Palmitoyltransferase; Cells, Cultured; Cholesterol; Dicarboxylic Acids; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Hepatocytes; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipogenesis; Lipoprotein Lipase; Male; Mesocricetus; Perilipin-1; Protein Kinases; Rabbits; Rats, Wistar

Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia.. Gene targeting has been used to generate Yucatan miniature pigs heterozygous (. In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both

Topics: Animals; Animals, Genetically Modified; Anticholesteremic Agents; Aortic Diseases; Atherosclerosis; Biomarkers; Cholesterol, LDL; Coronary Artery Disease; Dicarboxylic Acids; Disease Models, Animal; Down-Regulation; Fatty Acids; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Hyperlipoproteinemia Type II; Male; Phenotype; Plaque, Atherosclerotic; Receptors, LDL; Swine; Swine, Miniature