BET inhibition may lower CV events in high risk CVD patients, suggests hypothesis-generating analysis
Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery DiseaseNicholls SJ, Ray KK, Johansson JO et al. - Am J Cardiovasc Drugs. 2017 Oct 12. doi: 10.1007/s40256-017-0250-3
The residual CV risk that remains in patients with a history of CVD despite treatment with lipid-lowering drugs, antiplatelet therapy and blood-pressure lowering drugs, highlights the need for new therapeutic strategies. Vascular inflammation is involved in atherogenesis , and elevated inflammatory markers have also been linked to residual CV risk in statin-treated patients . Moreover, a prothrombotic state also affects incident and recurrent ischemic CV events .
Bromodomains (BRDs) are a family of amino acid sequences in proteins that recognize acetylated lysine residues on chromatin. By binding to the acetylated lysine residues, BRDs modulate chromatin organization, which affects gene transcription . BRD and extra-terminal (BET) proteins have been linked to regulation of inflammatory and thrombotic pathways involved in the pathogenesis of ischemic CV events .
Apabetalone is a selective BET inhibitor that specifically targets BET protein 4 (BRD4) [5-7]. In perturbed states the level of BET proteins is higher, permitting apabetalone to normalize gene transcription [5-7]. Although developed as a lipid-modifying agent based on preclinical observations that apabetalone increased levels of ApoA-I and HDL-c, early studies evaluating administration of apabetalone for 3-6 months in statin-treated patients with CAD showed only modest elevation of apoA-I and HDL-c [8,9]. Coronary atherosclerosis volume did not regress with short-term treatment with apabetalone . More recent insights suggest that apabetalone may also suppress genes that may be involved in the pathogenesis of atherothrombotic events, including IL-6, monocyte chemoattractant protein-1, complement component 9 and thrombin [5-7, 11].
Since the effect of apabetalone on clinical events is unknown, this study aimed to study the impact of this BET inhibitor on CV event rates in a pooled analysis of phase II clinical studies (ASSERT , SUSTAIN  and ASSURE ) of patients with established CAD disease. Data of 798 patients could be analyzed, and study durations ranged from 12-26 weeks.
- Apabetalone treatment yielded dose-dependent increases in apoA-I (up to median change from baseline: 6.7% vs. 2.69% with placebo, P<0.001) and HDL-c (median: 6.52% vs. 0.00% with placebo, P<0.001), and a median increase in the concentration of large HDL particles of 23.3% was seen (vs. 1.74% with placebo, P<0.001), as well as an increase in HDL particle size of 1.15% (vs 0.0% with placebo, P<0.001).
- A dose-dependent decrease in hsCRP of -21.1% (median change from baseline, vs. -13.33 with placebo, P=0.04).
- Change in LDL-c from baseline did not differ significantly between treatments (-4.98% vs. -3.57% from baseline, P=0.33).
- Patients treated with apabetalone experienced fewer major adverse CV events (MACE: death, myocardial infarction, coronary revascularization, and hospitalization for cardiovascular causes, 5.9% (24/556) vs 10.4% (19/242) with placebo, P=0.02).
- In exploratory subgroup analyses, less MACE was associated with apabetalone treatment in in patients with diabetes (5.4% vs. 12.7%, P=0.02), but not in those without diabetes (6.2% vs. 9.0%, P=0.30).
- Similarly, in those with HDL-c <39 mg/dL, apabetalone was associated with fewer MACE (5.5% vs. 12.8%, P-0.01) or with baseline hsCRP >2 mg/L (5.4% vs. 9.0%, P=0.02), but in those with HDL-c ≥39 mg/dL or with normal hsCRP levels, treatment did not affect the rate of MACE.
- After adjustment for baseline risk factors and study duration, apabetalone treatment remained associated with fewer CV events in the pooled cohort (HR: 0.51, 95%CI: 0.27-0.93, P=0.03), in those with diabetes (HR: 0.38, 95%CI: 0.15-0.99, P=0.04) and in those with elevated hsCRP levels at baseline (HR: 0.39, 95%CI: 0.19-0.83, P=0.01).
- Overall, apabetalone was well tolerated. Treatment was associated with a higher incidence of liver transaminase elevation (>3 ULN occurred in 8%, none with placebo), without concomitant elevation in total bilirubin or cases of Hy’s law.
This study provides hypothesis-generating data for a reduction in CV events with apabetalone treatment. This BET-inhibitor may provide CV benefit in high-risk patients. Note that the individual studies were not powered to detect an effect on CV outcomes. Since previously, no effect of apabetalone on coronary plaque volume could be detected, the current findings may suggest a potential influence on atherosclerotic plaque stability. These findings strengthen the rationale for the ongoing BET-on-MACE outcome trial evaluating apabetalone in patients with T2DM and recent ACS