RVX 208: A novel BET protein inhibitor, role as an inducer of apo A‐I/HDL and beyond

Abstract

Low-density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high-density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of proinflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis. RVX 208 is a novel, orally active, BET protein inhibitor and the only BET inhibitor currently available in the field of atherosclerosis. RVX 208 acts primarily by increasing apo A-I (apolipoprotein A-I) and HDL levels. RVX 208 has a novel action of increasing larger, more cardio-protective HDL particles. Post hoc analysis of Phase II trials also showed that RVX 208 reduced major adverse cardiovascular events (MACE) in treated patients, over and above that of apo A-I/HDL increasing action. This MACE reducing actions of RVX 208 were largely due to its novel anti-inflammatory actions. Currently, a phase III trial, BETonMACE, is recruiting patients to look for the effects of RVX 208 in patients with increased risk of atherosclerotic cardiovascular disease. So BET inhibitors act in multiple ways to inhibit and modulate atherosclerosis and would be an emerging and potential option in the management of multifactorial disease like coronary artery disease by inhibiting a single substrate. But we need long-term phase III trial data's to look for effects on real-world patients.

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

“…In CRISPR-edited stem cell-derived human ECs, the deletion of rs9349379 increased the gene expression of endothelin 1 (EDN1), which is located 600 kb upstream of PHACTR1. Interestingly, 4C-seq revealed a very low contact probability between rs9349379 and the EDN1 promoter, but a relatively high contact probability between rs9349379 and the EDN1 downstream SEs marked with high levels of H3K27ac, suggesting a potential role of rs9349379 in SE function (Gupta et al, 2017). In addition, cardiovascular disease-related SNPs are highly enriched in vascular endothelial growth factor (VEGF)-regulated compartments.…”

High-Density Lipoprotein: From Biological Functions to Clinical Perspectives

“…Recently, phase II trials showed that RVX-208 reduces MACE in treated patients, over and above that of apoA-I/HDL increasing action. This MACE reducing actions of RVX-208 is largely due to its novel anti-inflammatory actions [193,194]. Currently, a phase III trial, BETonMACE, is ongoing to look for the effects of RVX-208 in CVD patients.…”

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

“…These findings offered a possible mechanism of inhibitor action. With these encouraging effects, BET inhibitors offer new therapeutic possibilities, mainly for blood cancers and inflammation (Belkina & Denis, 2012;Ceribelli et al, 2014;Berthon et al, 2016;Ghosh et al, 2017). With these encouraging effects, BET inhibitors offer new therapeutic possibilities, mainly for blood cancers and inflammation (Belkina & Denis, 2012;Ceribelli et al, 2014;Berthon et al, 2016;Ghosh et al, 2017).…”

“…These drugs also inhibit inflammation and ameliorate related diseases, including LPSinduced sepsis, EAE-based neuroinflammation, diabetes, and cardiovascular diseases (Nicodeme et al, 2010;Bandukwala et al, 2012;Anand et al, 2013;Belkina et al, 2013;Mele et al, 2013;Brown Jonathan et al, 2014;Fu et al, 2014;Duan et al, 2017). With these encouraging effects, BET inhibitors offer new therapeutic possibilities, mainly for blood cancers and inflammation (Belkina & Denis, 2012;Ceribelli et al, 2014;Berthon et al, 2016;Ghosh et al, 2017).…”