Understanding Key Pathways

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 calcium, or Lipitor.

The Esperion team is building on its prior work of discovering and exploring biologic pathways. This will enable us to develop novel, small molecule therapies that target inhibition of another key enzyme on the cholesterol biosynthesis pathway, ATP citrate lyase (ACL). It will also allow us to activate a complementary enzyme, 5′-adenosine monophosphate-activated protein kinase (AMPK).


ETC-1002, our novel, 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 and activates AMPK. 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, as well as glucose production in the liver.

ETC-1002’s activation of AMPK complements the effects of hepatic ACL inhibition and contributes to the beneficial effects on other cardiometabolic risk factors including hsCRP, insulin sensitization, blood pressure and weight. While the relative contributions of ACL inhibition and AMPK activation are not yet known, improvements in these other cardiometabolic risk factors are consistent with these mechanisms. This dual mechanism of action has the potential to regulate metabolic imbalances in both the lipid and carbohydrate metabolic pathways, which do not function normally in patient populations with specific cardiometabolic risk factors.


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

ETC-1002 Mechanism of Action