Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial

Stephen J. Nicholls, Rishi Puri, Kathy Wolski, Christie M. Ballantyne, Philip J. Barter, H. Bryan Brewer, John J P Kastelein, Bo Hu, Kiyoko Uno, Yu Kataoka, Jean Paul R Herrman, Bela Merkely, Marilyn Borgman, Steven E. Nissen

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Abstract

Background: Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown. Methods: ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed. Results: During treatment, apolipoprotein (apo)A-I increased by 10.6 % with placebo (P < 0.001 compared with baseline) and 12.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1 % with placebo (P < 0.001 compared with baseline) and 11.1 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9 % with placebo (P < 0.001 compared with baseline) and 15.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30 % in placebo-treated patients (P = 0.23 compared with baseline) and 0.40 % in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm3 in the placebo group (P = 0.01 compared with baseline) and 4.2 mm3 in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0 %, P = 0.009). Conclusion: Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo. Trial Registration: ClinicalTrials.gov identifier—NCT01067820.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalAmerican Journal of Cardiovascular Drugs
Volume16
Issue number1
DOIs
Publication statusPublished or Issued - 1 Feb 2016

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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