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

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.

• Authors: Sergey Filippov, Stephen L Pinkosky, Roger S Newton
• Journal: Current opinion in lipidology (Curr Opin Lipidol) Vol. 25 Issue 4 Pg. 309-15 (Aug 2014) ISSN: 1473-6535 [Electronic] England
• PMID: 24978142 (Publication Type: Journal Article, Review)

Chemical References

• Anticholesteremic Agents
• Cholesterol, LDL
• ATP Citrate (pro-S)-Lyase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• ATP Citrate (pro-S)-Lyase (antagonists & inhibitors, metabolism)
• Anticholesteremic Agents (pharmacology, therapeutic use)
• Cholesterol, LDL (metabolism)
• Humans
• Hypercholesterolemia (drug therapy, enzymology, metabolism)
• Molecular Targeted Therapy (methods)