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Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial.

AbstractOBJECTIVES:
The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis.
BACKGROUND:
No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development.
METHODS:
A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated.
RESULTS:
For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels.
CONCLUSIONS:
Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018).
AuthorsStephen J Nicholls, Allan Gordon, Jan Johansson, Kathy Wolski, Christie M Ballantyne, John J P Kastelein, Allen Taylor, Marilyn Borgman, Steven E Nissen
JournalJournal of the American College of Cardiology (J Am Coll Cardiol) Vol. 57 Issue 9 Pg. 1111-9 (Mar 1 2011) ISSN: 1558-3597 [Electronic] United States
PMID21255957 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Quinazolines
  • RVX 208
Topics
  • Aged
  • Apolipoprotein A-I (biosynthesis, blood, drug effects)
  • Cholesterol, HDL (blood, drug effects)
  • Coronary Artery Disease (blood, drug therapy)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage)
  • Male
  • Prospective Studies
  • Quinazolines (administration & dosage)
  • Treatment Outcome

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