The upcoming American Diabetes Association 2018 conference in Orlando is on June 22-26, 2018. In the ADA 2018 conference app, I was able to find that Norman Wong is presenting a poster on Sunday June 24th. The abstract is embargoed right now, but is very likely similar if not identical to abstract #669 (can found here) from the Vascular Discovery 2018 meeting and the ISA 2018 meeting abstract referenced below. Both had the same title and were presented recently.

1136-P - Apabetalone (RVX-208) Lowers Major Adverse Cardiac Events (MACE) in Diabetes Mellitus Patients with CVD by Attentuating Monocyte Adhesion to Endothelial Cells. 

Apabetalone (RVX-208) Lowers Risk of Major Adverse Cardiovascular Events (MACE) in T2D Patients with CVD By Attenuating Monocyte Adhesion to Endothelial Cells Laura Tsujikawa(1), Ewelina Kulikowski(1), Cyrus Calosing(1), Sylwia Wasiak(1), Dean Gilham(1), Christopher Halliday(1), Jan Johansson(2), Mike Sweeney(2), Norm Wong(1). 1. Resverlogix Corp., Calgary, AB, Canada, 2. Resverlogix Inc., San Francisco, CA, USA

Objective: Apabetalone (RVX-208, 200 mg/d) taken orally by patients with diabetes mellitus (DM) and CVD leads to a 57% relative risk reduction in major adverse cardiovascular events (MACE). Potential actions of RVX-208, an inhibitor (BETi) of bromodomain extra-terminal (BET) proteins that are epigenetic readers of histone acetylated lysines, in lowering MACE is explored for its effect on genes mediating monocyte adhesion to endothelial cells in response to high glucose (HG, 25.6 mM) and dietary metabolite trimethyl-amine oxide (TMAO).

Methods: Cultured THP-1 monocytes, HUVEC endothelial cells and primary human hepatocytes (PHH) exposed to varying concentrations of glucose and TMAO.

Results: We showed that HG induced Very Late Antigen-4 (VLA-4) mRNA, a gene mediating THP-1 adhesion by 1.3-fold and RVX-208 suppressed it >50%. Similarly, BETi blocked TMAO induction of VLA-4 mRNA by >50% in THP-1. In HUVECs RVX-208 abrogated HG induction of E-selectin and MYD88 mRNA by 2- and 1.3-fold, respectively and lowered TMAO induction of these mRNAs by >50%. Microbiome processing of dietary phospholipids followed by hepatic flavin mono-oxygenase-3 (FMO3) metabolism yields TMAO. In PHH exposed for 24 hrs to RVX-208, FMO3 mRNA was lower by 40% but it also suppressed a transcriptional regulator of FMO3, farnesoid X receptor (FXR). BETi suppressed both FXR mRNA and protein within 6 hrs by >80% suggesting a direct effect of BETi on gene encoding FXR. Furthermore, ChiP data showed that BRD4, a BET protein, dissociated immediately from FXR gene upon exposure to RVX-208. Since BRD4 guides a complex containing RNA pol II along actively transcribed genes containing histones that are highly acetylated, dissociation of BRD4 from FXR DNA would halt transcription of this gene.

Conclusions: Apabetalone inhibits HG and TMAO enhanced adhesion of THP-1 to HUVECs this process mimics a step in the pathogenesis of CVD. RVX-208 suppresses genes underlying cellular adhesion; VLA-4 in THP-1 and both E-selectin plus MYD88 in HUVECs. BETi blocks not only activity of TMAO but also its production by inhibiting FXR expression, a regulator of FMO3 gene transcription. The rapid actions of BETi in dissociating BRD4 from FXR DNA suggests a direct effect of RVX-208 on transcription of this gene.