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

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. 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. 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). 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. ClinicalTrials.gov identifier-NCT01067820.