Understanding Cholesterol Lowering

At Esperion, we are leveraging our experience and understanding of key biological pathways to develop and commercialize first-in-class, oral, low-density lipoprotein cholesterol (LDL-C) lowering therapies for the treatment of hypercholesterolemia and other cardiometabolic risk markers including hsCRP, a key measure of inflammation.

In the past, cholesterol drug discovery and development efforts were aimed primarily at therapies designed to inhibit a key enzyme on the cholesterol synthesis pathway, HMG coA Reductase. Esperion’s founder, Dr. Roger Newton, co-discovered and helped lead the development of the most successful drug to inhibit HMG coA Reductase atorvastatin, or Lipitor® (atorvastatin calcium).

The Esperion team leverages its understanding of, and experience with, key biological pathways to discover and develop innovation therapies for the treatment of patients with hypercholesterolemia who have uncontrolled cholesterol levels despite the use of currently available therapies. This enables us to develop an innovative novel, oral small molecule therapy that inhibits another key enzyme on the cholesterol biosynthesis pathway, ATP citrate lyase (ACL).

ETC-1002 INHIBITS ATP Citrate Lyase

ETC-1002, our innovative, first-in-class, orally available, once-daily, small molecule for lowering LDL-C is absorbed rapidly in the small intestine. It enters the liver through cell surface receptors different from those transporters that selectively take up statins.

Once in the liver, ETC-1002 inhibits ACL. Pre-clinical studies show that in the liver, ETC-1002 is converted to a derivative coenzyme, or ETC-1002-CoA, which directly inhibits ACL, a key enzyme that supplies substrate for cholesterol and fatty acid synthesis in the liver.

ETC-1002 Has Reduced Potential for Muscle-Related Adverse Events

In a small portion of the population that has genetically impaired organic anion transporters, statins are unable to enter the liver and, as a result, accumulate in the blood, ultimately concentrating in the muscles. These deposits lead to muscle pain and weakness. In addition, some patients without impaired organic anion transporters still experience muscle pain and weakness due to increased levels of statin in the blood on higher doses of statins. Importantly, impaired organic anion transporters do not lead to increased levels of ETC-1002 circulating in the blood or the muscle pain or weakness associated with statins.

 

 

ETC-1002 Mechanism of Action

ESPR MOA 061715