LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase

Sergey Filippov, Stephen L Pinkosky, Roger S Newton, Sergey Filippov, Stephen L Pinkosky, Roger S Newton

Abstract

Purpose of review: To review the profile of ETC-1002, as shown in preclinical and clinical studies, including LDL-cholesterol (LDL-C)-lowering activity and beneficial effects on other cardiometabolic risk markers as they relate to the inhibition of adenosine triphosphate-citrate lyase and the activation of adenosine monophosphate-activated protein kinase.

Recent findings: ETC-1002 is an adenosine triphosphate-citrate lyase inhibitor/adenosine monophosphate-activated protein kinase activator currently in Phase 2b clinical development. In seven Phase 1 and Phase 2a clinical studies, ETC-1002 dosed once daily for 2-12 weeks has lowered LDL-C and reduced high-sensitivity C-reactive protein by up to 40%, with neutral to positive effects on glucose levels, blood pressure, and body weight. Importantly, use of ETC-1002 in statin-intolerant patients has shown statin-like lowering of LDL-C without the muscle pain and weakness responsible for discontinuation of statin use by many patients. ETC-1002 has also been shown to produce an incremental benefit, lowering LDL-C as an add-on therapy to a low-dose statin. In over 300 individuals in studies of up to 12 weeks, ETC-1002 has been well tolerated with no serious adverse effects.

Summary: Because adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase play central roles in regulating lipid and glucose metabolism, pharmacological modulation of these two enzymes could provide an important therapeutic alternative for statin-intolerant patients with hypercholesterolemia.

Figures

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FIGURE 1
FIGURE 1
ETC-1002 Mechanism of Action. ETC-1002 is an ACL inhibitor/AMPK activator that beneficially modulates lipid, lipoprotein, and carbohydrate metabolism, and inflammation. ETC-1002 reduces LDL-C via inhibition of ACL, an enzyme that is upstream of HMG-CoA reductase in the cholesterol synthesis pathway. Activation of AMPK by ETC-1002 is complementary to ACL inhibition, and mediates beneficial effects on other cardiometabolic risk markers.

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