title: Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial.
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 mm(3) in the placebo group (P = 0.01 compared with baseline) and 4.2 mm(3) 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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier-NCT01067820.
authors.affiliation: South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia. stephen.nicholls@sahmri.com.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Puri
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Wolski
authors.affiliation: Section of Cardiovascular Research, Baylor College of Medicine and the Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: University of New South Wales, Sydney, NSW, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: Medstar Research Institute, Hyattsville, MD, USA.
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Medicine, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Uno
authors.affiliation: South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kataoka
authors.affiliation: Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Jean-Paul R
authors.initials: JP
authors.lastname: Herrman
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Bela
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Borgman
authors.affiliation: Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
mesh_terms: D000368:Aged; D016632:Apolipoprotein A-I / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000188:drug therapy*; D011446:Prospective Studies; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011799:Quinazolines; D052999:Quinazolinones; C000628794:apabetalone