The second poster that Resverlogix presented for the abstract below at AHA 2018 is now posted to the Resverlogix website.

November 12, from 1:00 PM – 2:15 PM CST: "Apabetalone (RVX-208) Suppresses Expression of Key Vascular Inflammation Markers in Monocytes, Endothelial Cells and LPS-Challenged Mouse Liver and Monocyte Adhesiveness to Activated Endothelial Cells."

Abstract

Apabetalone (RVX-208), a small molecule bromodomain & extraterminal (BET) protein inhibitor that selectively targets the second bromodomain (BD2), ameliorates vascular perturbation including vascular inflammation (VI). A phase 3 trial (BETonMACE) is being conducted to evaluate apabetalone’s ability to prevent major adverse cardiac events in post-acute coronary syndrome patients with type 2 diabetes mellitus (DM) and low-HDL-C. Cardiovascular disease (CVD) patients enrolled in phase 2b trials demonstrated a 44% relative risk reduction in CVD events with apabetalone treatment (Nicholls 2017). In CVD and DM, elevated cytokines drive VI. TNFα activation of NF-κB is linked to the induction of inflammatory and adhesion marker expression (Pierce 1988, Baltimore 2011). Apabetalone treatment did not prevent TNFα-induced translocation of NF-κB subunit p65 to the nucleus in endothelial cells (HUVECs) but did inhibit the transcription of genes regulated by p65. These include cell adhesion molecules (CD44, E-selectin, VCAM-1 and MCP-1) and inflammatory cytokines (IL-6, IL-8, IL-1β, and CSF2). At the protein level VCAM1, CCL2, and E-selectin expression was also suppressed. In TNFα-stimulated monocytes (THP-1 cells), apabetalone also reduced the upregulation of inflammatory and adhesion molecule expression (CCR1, CCR2, IL-1β, MCP-1, MYD88, TLR4, TNFα, and VLA-4). In vivo, leukocytes adhere to an inflamed endothelium where they extravasate into arterial walls and initiate atherosclerotic plaque formation. In our in vitro assays, apabetalone suppressed monocytic THP-1 cell adhesion to inflamed endothelial cells under both static (HUVEC) and flow (HAEC) conditions. Acute endotoxemia is associated with activation of liver macrophages and endothelial cells and infiltration of immune cells. In mice exposed to 50 ug of LPS for 24h, apabetalone reduced liver mRNA marker expression for infiltrating monocytes, activated macrophages, and cellular adhesion (CCR2, ICAM and P-selectin). Our data indicate that apabetalone attenuates VI through the regulation of transcription. Downregulation of VI by apabetalone may contribute to the reduction in CVD events observed in phase 2 studies. This hypothesis is being tested in the ongoing BETonMACE phase 3 trial.