Lipid Management That’s on Target

The Esperion team leverages its experience and understanding of cholesterol biosynthesis to develop and commercialize convenient, complementary, consistent, once-daily, oral, low-density lipoprotein cholesterol (LDL-C) lowering therapies for patients with elevated LDL-C who are inadequately treated with current lipid-modifying therapies.

In the past, cholesterol drug discovery and development efforts were aimed primarily at therapies designed to inhibit a key enzyme on the cholesterol biosynthesis 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, Lipitor® (atorvastatin calcium).

Our approach to cholesterol regulation has enabled us to develop new complementary, non-statin, once-daily, oral small molecule therapies that target another key enzyme on the cholesterol biosynthesis pathway, ATP-citrate lyase (ACL), upstream of HMG-CoA reductase.

Bempedoic Acid: Mechanism of Action

Bempedoic acid’s mechanism of action is similar to that of statins – the most successful LDL-C lowering drugs on the market. Bempedoic acid inhibits cholesterol synthesis and upregulates LDL receptors on liver cells and lowers LDL-C. However, unlike statins, bempedoic acid does not inhibit the cholesterol biosynthesis pathway in skeletal muscle, nor promote the associated cytotoxicity believed to lead to muscle-related side effects. It is differentiated in one key way: bempedoic acid is inactive until it enters the liver where it is converted to its active form by the enzyme, ACSVL1, an enzyme not found in skeletal muscle cells. For more detail, visit the Publications section to review the definitive paper from Stephen Pinkosky and colleagues from Esperion on the mechanism of action of bempedoic acid.

Bempedoic Acid Targets ATP-Citrate Lyase (ACL)

Bempedoic acid (ETC-1002), our convenient, complementary, consistent, once-daily, oral small molecule for lowering elevated LDL-C works solely in the liver to block cholesterol biosynthesis.

Once in the liver, bempedoic acid is converted to a coenzyme A (CoA) derivative, or ETC-1002-CoA, which directly inhibits ACL, a key enzyme that supplies substrate for cholesterol and fatty acid synthesis in the liver. Inhibition of ACL by ETC-1002-CoA results in reduced cholesterol synthesis and upregulation of LDL receptor activity in the liver. This promotes the removal of LDL-C from the blood.

Bempedoic Acid / Ezetimibe Combination: Mechanism of Action

Through the complementary mechanisms of action of inhibition of cholesterol synthesis (bempedoic acid) and inhibition of cholesterol absorption (ezetimibe), the bempedoic acid / ezetimibe combination pill is our lead, non-statin, once-daily, oral, LDL-C lowering therapy. Inhibition of ATP Citrate Lyase (ACL) by bempedoic acid reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor. Inhibition of Niemann-Pick C1-Like 1 (NPC1L1) by ezetimibe results in reduced absorption of cholesterol from the gastrointestinal tract, thereby reducing delivery of cholesterol to the liver, which in turn upregulates LDL receptors.

Bempedoic Acid May Potentially be Associated With Lower Occurrence of Muscle-Related Side Effects

It has been hypothesized that muscle pain associated with statin use is linked to the ability of statins to inhibit cholesterol synthesis in skeletal muscle cells. Bempedoic acid is specific to the liver and cannot inhibit cholesterol synthesis in skeletal muscle cells, thereby having the potential to reduce muscle-related side effects.