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

Stephen J. Nicholls, Allan Gordon, Jan Johansson, Kathy Wolski, Christie M. Ballantyne, John J.P. Kastelein, Allen Taylor, Marilyn Borgman, Steven E. Nissen

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135 Citations (Scopus)

Abstract

Objectives 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)

Original languageEnglish
Pages (from-to)1111-1119
Number of pages9
JournalJournal of the American College of Cardiology
Volume57
Issue number9
DOIs
Publication statusPublished - 1 Mar 2011
Externally publishedYes

Keywords

  • apoA-I
  • coronary artery disease
  • high-density lipoprotein
  • prevention
  • risk factors

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