Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease

Stephen J. Nicholls, Kausik K. Ray, Jan O. Johansson, Alan Gordon, Michael Sweeney, Chris Halliday, Ewelina Kulikowski, Norman Wong, Susan W. Kim, Gregory G. Schwartz

Inhibition of bromodomain and extra-terminal (BET) proteins can modulate lipoprotein and inflammatory factors that mediate atherosclerosis. The impact of the BET inhibitor, apabetalone, on cardiovascular events is unknown. Our objective was to investigate the impact of apabetalone on cardiovascular event rates in a pooled analysis of clinical studies in patients with established coronary artery disease. We conducted a pooled analysis of patients (n = 798) with coronary artery disease who participated in clinical trials (ASSERT, ASSURE, SUSTAIN) that evaluated the impact of 3-6 months of treatment with apabetalone on lipid parameters and coronary atherosclerosis. The incidence of major adverse cardiovascular events (death, myocardial infarction, coronary revascularization, hospitalization for cardiovascular causes) in the treatment groups was evaluated. At baseline, patients treated with apabetalone were more likely to be Caucasian, have a history of dyslipidemia, and be undertreated with ß-blocker and anti-platelet agents. Treatment with apabetalone produced the following dose-dependent changes compared with placebo: increases in apolipoprotein A-I (apoA-I) of up to 6.7% (P < 0.001), increases in high-density lipoprotein cholesterol (HDL-C) of up to 6.5% (P < 0.001), increases in large HDL particles of up to 23.3% (P < 0.001), and decreases in high-sensitivity C-reactive protein (hsCRP) of - 21.1% (P = 0.04). Apabetalone treatment did not affect atherogenic lipoproteins compared with placebo. Patients treated with apabetalone experienced fewer major adverse cardiovascular events than those treated with placebo (5.9 vs. 10.4%; P = 0.02), a finding that was more prominent in patients with diabetes (5.4 vs. 12.7%; P = 0.02), with baseline HDL-C < 39 mg/dl (5.5 vs. 12.8%; P = 0.01), or with elevated hsCRP levels (5.4 vs. 14.2%; P = 0.02). Pooled analysis of short-term studies demonstrated fewer cardiovascular events among patients treated with the BET protein inhibitor, apabetalone, than among those treated with placebo. BET protein inhibition warrants further investigation as a novel approach to cardiovascular risk reduction.