Abstracts for the American Diabetes Association meeting were release Friday afternoon. Here is the abstract for the poster presentation from Resverlogix to be given on June 11 in New Orleans.

1208-P / 1208 - RVX-208 Affects Epigenetics to Lower Major Adverse Cardiovascular Events (MACE) in Atherosclerotic Patients and Especially in Ones with Diabetes Mellitus

Authors: EWELINA KULIKOWSKI, SYLWIA WASIAK, DEAN GILHAM, CYRUS CALOSING, LAURA TSUJIKAWA, CHRISTOPHER HALLIDAY, JAN JOHANSSON, MIKE SWEENEY, NORMAN C. WONG.

Apabetalone (RVX-208) inhibits Bromodomain & Extra-Terminal (BET) proteins by displacing their natural ligand, acetylated lysine that populate histone tails. Ligand bound BET proteins recruit transcriptional machinery to DNA & thereby modify gene activity. Patients with cardiovascular disease (CVD, n=499), in phase IIb trials SUSTAIN and ASSURE, given RVX-208 had a 55% relative risk reduction (RRR) in MACE vs. placebo. In diabetes mellitus (DM) patients, RVX-208 lead to a 77% RRR in MACE. RVX-208 raises ApoA-I & high density lipoprotein (HDL) by 7.5 & 3 mg/dL (p<0.05), respectively, but these modest changes do not explain the marked MACE reduction thus leading us to study RVX-208 effects beyond lipids. Plasma glucose in DM patients (n=192) was unchanged given RVX-208 or placebo, except in those (n=119) with low HDL <40 mg/dL, RVX-208 lowered glucose by -0.3 vs. +0.9 mmol/L in placebo. Microarray surveys of primary human hepatocytes (PHH) exposed to RVX-208 had decreased gene expression in several pathways linked to CVD risk with marked downregulation in 19/26 complement & 20/33 coagulation genes. These microarray data were confirmed in hepatocytes by measuring mRNA levels & secreted protein. Next, selected key proteins in affected pathways were assayed in plasma of trial patients & noted to be reduced 4-14% by RVX-208 vs. baseline. Additionally, in PHH RVX-208 suppressed by 25% the mRNA encoding flavin monooxygenase-3 (FMO3), a key hepatic enzyme in the pathogenesis of DM & CVD. Human whole blood (WB) exposed ex-vivo to RVX-208 affected many genes with defined roles in atherogenesis, i.e. suppression of 37/46 pro-atherogenic but induction of 8/18 anti-atherogenic genes. Additionally, RVX-208 suppressed expression of 30 cytokines in WB. In summary, RVX-208 reduces MACE in CVD patients & especially in those with DM. RVX-208 acts by modulating cellular epigenetics which in turn affect multiple biological processes that underlie CVD & DM.