Physicians' Academy for Cardiovascular Education

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 Disease

Nicholls SJ, Ray KK, Johansson JO et al. - Am J Cardiovasc Drugs. 2017 Oct 12. doi: 10.1007/s40256-017-0250-3

Background

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 [1], and elevated inflammatory markers have also been linked to residual CV risk in statin-treated patients [2]. Moreover, a prothrombotic state also affects incident and recurrent ischemic CV events [3].

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 [4]. BRD and extra-terminal (BET) proteins have been linked to regulation of inflammatory and thrombotic pathways involved in the pathogenesis of ischemic CV events [4].

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 [10]. 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 [9], SUSTAIN [8] and ASSURE [10]) of patients with established CAD disease. Data of 798 patients could be analyzed, and study durations ranged from 12-26 weeks.

Main results

Conclusion

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

References

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Find this article online at Am J Cardiovasc Drugs