European Atherosclerosis Society Congress is May 29, 2016 to June 1, 2016 in Innsbruck, Austria. Normal Wong will give an oral presentation On Monday May 30th.

YIS03 Young Investigator Session, Clinical Epidemiology and Pharmacology

Oral Presentation

Abstract: APABETALONE (RVX-208) DECREASES ATHEROGENIC, THROMBOTIC AND INFLAMMATORY MEDIATORS IN VITRO AND IN PLASMA OF PATIENTS WITH CARDIOVASCULAR DISEASE (CVD).

N. Wong 1, E. Kulikowski 1, S. Wasiak 1, D. Gilham 1, C. Calosing 1, T. Laura 1, C. Halliday 1, J. Johansson 2, M. Sweeney 2. 1Resverlogix Corporation, Pharmacology, Calgary, Canada; 2Resverlogix Corporation, Clinical Development, San Francisco, USA

Aim: RVX-208 inhibits bromodomain and extra-terminal (BET) proteins from binding to acetyl-lysine marks on histone tails, thereby modulating gene activity. In SUSTAIN and ASSURE phase IIb trials of patients (n=499) with CVD, RVX-208 lead to a 55% relative risk reduction in major adverse cardiovascular events (MACE) vs. placebo. This marked reduction is unlikely from RVX-208’s modest induction of ApoA-I/HDL, thus prompting studies of RVX-208 for benefits beyond lipids.

Methods: Microarrays of human whole blood (WB) or primary hepatocytes (PH) exposed to RVX-208. Cytokines assayed in LPS and RVX-208 treated U937 macrophage and peripheral blood mononuclear cells (PBMC). Patient’s plasma proteins assayed by SOMAScan.

Results: In WB, microarray data showed RVX-208 affected atherogenesis by suppressing 37/46 pro-atherogenic while inducing 8/18 anti-atherogenic genes. In addition, RVX-208 had potential anti-thrombotic properties by affecting 18 genes related to platelet function (e.g. downregulation of CD64 and thrombospondin 1). RVX-208 had anti-inflammatory effects on expression of >25 cytokines, including downregulation of MCP-1, osteopontin and PARC genes in WB, U937 and/or PBMCs. Furthermore, plasma protein levels of MCP-1, osteopontin and PARC were lower in treated patients. Why RVX-208 affected genes connected to CVD was explored by exposing PH to RVX-208. This lead to a 25% reduction in mRNA encoding flavin mono-oxygenase-3 (FMO3), an enzyme that produces trimethylamine oxide (TMAO) a metabolite which predicts CVD risk.

Conclusion: Epigenetic actions of RVX-208 leading to beneficial effects on many genes with known roles in atherogenesis, thrombosis and inflammation may underlie the ability of RVX-208 to reduce MACE in clinical trials.