Vascular Discovery Abstracts now out. Posters should be up later this week on the respective presentation days.

Wednesday May 15: 407 - Apabetalone (RVX-208) Inhibits Key Pro-Atherogenic Mediators and Pathways in Diabetes and Inflammatory Conditions; in vitro and in Patients. Abstract available here.

"Apabetalone (RVX-208) is a small molecule bromodomain & extraterminal (BET) protein inhibitor that targets the second bromodomain (BD2) within BET proteins. In phase 2 trials, apabetalone treatment reduced relative risk of MACE events by 57% in patients with cardiovascular disease (CVD) and type II diabetes (T2DM). In both CVD and T2DM, elevated circulating glucose, inflammatory mediators, and cell surface adhesion molecules drive vascular inflammation (VI), resulting in the recruitment, adhesion, and infiltration of leukocytes to the atherosclerotic plaque. Continuous inflammation promotes cytokine production, immune cell infiltration, and plaque rupture, which accounts for 67% of fatal myocardial infarctions (MIs) and sudden cardiac deaths. Here we show in vitro that TNFα and high glucose treatment induced significant adhesion of THP-1 monocytes to endothelial cells, an outcome inhibited by apabetalone treatment. Apabetalone suppressed the transcription of critical drivers of pro-inflammatory signaling (RELA), immune cell activation and recruitment (MCP-1), and plaque rupture (IL-8) in endothelial cells. Ingenuity® Pathway Analysis (IPA®), GSEA, and GO analysis of human umbilical vein endothelial cell (HUVEC) gene expression data predicted that apabetalone would inhibit pro-atherogenic pathways, gene sets, and upstream regulators. These include cytokine and chemokine signalling, immune and inflammatory response, Toll-Like Receptor (TLR) signalling, and TNFα signalling. In addition, IPA® disease and biological function analysis predicted inhibition of immune cell recruitment and activation by apabetalone. These in vitro effects are consistent with plasma proteomic results (SOMAscan®) from apabetalone-treated CVD T2DM patients, which demonstrated inhibitory effects on TNFα signalling, acute phase response, intrinsic prothrombin activation, leukocyte extravasation signalling and coagulation. Amelioration of diabetes and inflammation driven atherogenesis by apabetalone treatment likely contributes to the reduction in MACE observed in phase 2. The ongoing phase 3 post-ACS clinical trial in T2DM patients, BETonMACE, is investigating the effect of apabetalone on MACE reduction and will report in 2019."

Thursday May 16: 671 - Hepatic Expression of C-Reactive Protein is Epigenetically Regulated by BET Proteins and Inhibited by Apabetalone (RVX-208) in vitro and in CVD Patients. Abstract available here.

"Chronic inflammation contributes to cardiovascular disease (CVD) and is characterized by elevated plasma levels of interleukin (IL)-6, IL-1β and C-reactive protein (CRP). CRP serves as a CVD stratification marker as it correlates with major adverse cardiac events (MACE). Here we show that hepatic induction of CRP in response to chronic cytokine signaling is regulated by epigenetic mechanisms in vitro and in patients. Apabetalone is a small molecule inhibitor of epigenetic readers called bromodomain and extraterminal (BET) proteins that bind to acetylated DNA-associated proteins to regulate inflammatory gene transcription. In vitro, apabetalone attenuated CRP gene and protein expression under basal conditions in cultured primary human hepatocytes (PHH). Moreover, IL-6 and IL-1β mediated induction of CRP expression was also suppressed by apabetalone in both PHH and the HepaRG hepatic cell line (>50%). In HepaRG, PROTAC MZ-1 targeted degradation of BET proteins also reduced cytokine mediated CRP expression (93%), demonstrating that inflammatory expression of CRP is BET-dependent. Short-term cytokine treatment increased occupancy of the BET family member BRD4 on the CRP promoter, which was countered by either apabetalone or a structurally unrelated BET inhibitor JQ1. These data directly link BRD4 to CRP transcription. In a pooled analysis of phase 2 trials ASSERT, SUSTAIN and ASSURE, treatment with apabetalone resulted in a 62% relative risk reduction in MACE in CVD patients with elevated CRP (>2mg/L). In both ASSERT (12 weeks; n=55) and ASSURE (26 weeks; n=94), a comparison of baseline and end-of-study plasma proteome (SOMAscan 1.3K platform) detected a downregulation of inflammatory mediators, including CRP, in apabetalone treated patients versus placebo. Consequently, Ingenuity®-powered bioinformatics analysis of the proteomics data predicted an apabetalone-driven downregulation of inflammatory pathways. Based on this data, we predict that apabetalone reduces CVD associated chronic inflammation, contributing to the reduction in MACE in patients with high residual CVD risk. This is currently being explored in the phase 3 cardiovascular outcomes trial BETonMACE enrolling patients with CVD, type 2 diabetes mellitus and low HDL-c."