Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.

Abstract

OBJECTIVES:

The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia.

BACKGROUND:

ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors.

METHODS:

This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150-<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, and cardiometabolic risk factors; and safety.

RESULTS:

ETC-1002 40, 80, and 120 mg lowered least-squares mean ± SE LDL-C levels by 17.9 ± 2.2%, 25.0 ± 2.1%, and 26.6 ± 2.2%, respectively, versus a reduction of 2.1 ± 2.2% with placebo (all, p < 0.0001); LDL-C lowering was similar between the subgroups with nonelevated and elevated triglycerides. ETC-1002 also lowered non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, and LDL particle number (all, p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments.

CONCLUSIONS:

ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides and was generally safe and well tolerated. ETC-1002 has a novel mechanism of action and may be useful for reducing LDL-C. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638).

• Authors: Christie M Ballantyne, Michael H Davidson, Diane E Macdougall, Harold E Bays, Lorenzo A Dicarlo, Noah L Rosenberg, Janice Margulies, Roger S Newton
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 62 Issue 13 Pg. 1154-62 (Sep 24 2013) ISSN: 1558-3597 [Electronic] United States
• PMID: 23770179 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Dicarboxylic Acids
• Fatty Acids
• Hypolipidemic Agents
• 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
• ATP Citrate (pro-S)-Lyase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (drug effects)
• ATP Citrate (pro-S)-Lyase (antagonists & inhibitors)
• Aged
• Dicarboxylic Acids (administration & dosage, adverse effects)
• Double-Blind Method
• Fatty Acids (administration & dosage, adverse effects)
• Female
• Humans
• Hypercholesterolemia (drug therapy)
• Hypolipidemic Agents (administration & dosage, adverse effects)
• Male
• Middle Aged
• Risk Factors