Abstract 17127: RVX-208 a Selective Bromodomain and Extra-terminal BET Protein Inhibitor Acts on Several Pathways to Benefit Cardiovascular Risks

The epigenetic modifying compound RVX-208 selectively inhibits the second ligand binding domain in BET proteins to increase ApoA-I/HDL production. In recent trials of CVD patients given standard of care and RVX-208 (200mg/d) there was a 55% relative risk reduction of MACE vs. placebo. This reduction is greater than expected from modest increases in ApoA-I/HDL, thus suggesting benefits of RVX-208 beyond lipid effects. Whether added benefits exist was explored by microarray survey of differential gene expression in primary human hepatocytes (PHH) and whole blood (WB). In PHH, RVX-208 downregulated genes within the complement, fibrin clotting, cholesterol biosynthesis, fatty acid biosynthesis, diabetes and acute phase response (APR) pathways. These data guided more focused analyses on the known HDL proteome encoded by 89 genes of which 30 were affected by RVX-208 and many of these were members of the APR or complement pathways. In support of the microarray data, we used RT-PCR and found RVX-208 lowered mRNA encoding complement 3, 4a/4b and 5 by >50% in Huh-7 and HepG2 cells exposed to RVX-208. Consistent with the mRNA data, secretion of these complement proteins were less from the treated cells. Next the cells were exposed to cytokines in order to mimic an inflammatory state thus inducing complement expression. Treatment with RVX-208 blocked this effect by >50%. Furthermore, in Huh-7 cells, RVX-208 repressed both fibrin clotting factors II (prothrombin) and XI (thromboplastin antecedent) consistent with the PHH microarray data thus suggesting an anti-thrombotic effect for RVX-208. To further extend findings in vitro from hepatoma cells, plasma from patients in our clinical trials who received RVX-208 were assayed and found to have decreased levels of both APR and complement proteins. Lastly, microarray studies of WB from healthy donors treated ex-vivo with RVX-208 uncovered differential regulation of anti- and pro-atherogenic gene sets that were activated and suppressed, respectively by RVX-208. In summary, RVX-208, a selective BET inhibitor, affects several pathways involved in CVD including; reverse cholesterol transport, atherogenesis, complement, thrombosis and vascular inflammation that cumulatively may reduce MACE in high risk CVD patients.