RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease

Abstract

High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.

Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease

“…This single target approach has the potential to impact multiple dysregulated genes and biological pathways that are known to drive vascular disease. Recent findings have demonstrated apabetalone treatment can reduce expression of calcification and vascular inflammation biomarkers, as well as factors both in the fibrin clotting cascade and the complement system [9, 10]. These pathways play a potential role in the biology underlying the pathogenesis of diabetes and CKD as well as cardiovascular disease.…”

“…A recent pharmacokinetic study of apabetalone treatment in patients with late stage CKD revealed that a single dose of apabetalone rapidly downregulated multiple CKD and CVD protein markers, and associated molecular pathways [11]. Moreover, in the phase II clinical studies with apabetalone, patients treated with apabetalone were less likely to experience a major adverse cardiovascular event (MACE) and experienced reductions in CKD risk factors such as ALP [9]. ALP catalyzes the breakdown of inorganic pyrophosphate, which functions as an important inhibitor of calcification and mineralization [12].…”

“…Pan-BET inhibitors target the BET proteins by binding to bromodomains 1 (BD1) and 2 (BD2) with equal affinity, apabetalone, however binds preferentially to BD2 [8]. Apabetalone is the first BET inhibitor to be evaluated in human clinical trials for treatment of chronic disease, and has been shown to target multiple processes that underlie CVD, including reverse cholesterol transport, atherogenesis, thrombosis and vascular inflammation [9, 10]. A recent pharmacokinetic study of apabetalone treatment in patients with late stage CKD revealed that a single dose of apabetalone rapidly downregulated multiple CKD and CVD protein markers, and associated molecular pathways [11].…”

Bromodomain inhibitors and cancer therapy: From structures to applications

“…It increases apolipoprotein AI (ApoA-I) gene transcription and leads to production of high density lipoprotein (HDL) cholesterol levels in vitro and in vivo , 157 resulting in the stimulation of reverse cholesterol transport. It also represses inflammatory and atherosclerotic pathways that contribute directly to cardiovascular risk 158 . RVX-208 is also being tested in patients with pre-diabetes, demonstrating effects in HDL lipidome and glucose metabolism that may protect against the development of type 2 diabetes 159 …”

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

“…Gene expression was measured by TaqMan-based real-time PCR using the RNA UltraSense One-Step qRT-PCR System, as described previously (McLure et al, 2013;Gilham et al, 2016). mRNA levels were measured relative to an endogenous control on 7500 or ViiA-7 Real Time PCR Instruments (Applied Biosystems, Foster City, CA).…”