Abstracts for the American College of Cardiology 2017 conference are now out. You can search for abstracts here. The abstract that Resverlogix is presenting is copied below and linked here. Also, on a side note a nice abstract entitled "Genetic Target Validation for ATP-Citrate Lyase Inhibition" related to Esperion's ETC-1002 LDL-lowering drug mechanism of action is also being presented there and is linked here.

1139M-11 - Apabetalone (RVX-208) Lowers Cardiovascular Disease (CVD) in Diabetes Mellitus by a Mechanism Involving Microbiome Mediated Activity on the Complement Pathway

Authors: Norman C. Wong, Ewelina Kulikowski, Cyrus Calosing, Laura Tsujikawa, Sylwia Wasiak, Dean Gilham, Christopher Halliday, Jan Johansson, Michael Sweeney, Resverlogix Corp, Calgary, Canada

Background: In our phase 2b trials, patients (n=499) given 200 mg/d apabetalone (RVX-208) for 6 months were observed to have a 55% relative risk reduction of major adverse cardiovascular events (MACE) that was further reduced in diabetes mellitus (DM) patients. These findings underpin our interest to explore potential mechanism(s) by which RVX-208, a selective BET inhibitor (BETi) that displaces binding of acetylated-lysine marks on histone tails to the 2nd ligand domain in bromodomain extraterminal (BET) proteins. Micro-array data point to RVX-208 effects on known CVD risks; inflammation, metabolism, coagulation and complement. Studies here examine how RVX-208 may block actions of a suspected culprit in atherosclerosis, namely trimethyl amine oxide (TMAO) derived from microbiome activity on dietary meats.

Methods: Primary hepatocytes (PH) or Hep G2 exposed to RVX-208 followed by RT-PCR and western analysis of proteins of interest.

Results: Hep G2 cells grown in high glucose (25.6 mM) exposed to 1-100 uM TMAO acted within 6-48 hrs leading to a time and dose dependent induction of mRNA encoding Mannose Binding Lectin-2 (MBL2) and Complement-3 (C3) members of the complement pathway by 20 and 40%, respectively. But TMAO had no effect on another complement C5. Addition of RVX-208 to the same cells blocked TMAO induction of MBL2 and C3. In contrast, all 3 genes in euglycemic (5.6 mM) media were not induced by TMAO but RVX-208 still lowered expression of these genes. The microbiome transforms dietary phospholipids to TMA that is acted upon by hepatic flavin mono-oxygenase-3 (FMO3) converting it to TMAO. In PH, RVX-208 acts rapidly within 24 hrs to repress FMO3 mRNA and protein levels by 40 and 30%, respectively.

Conclusions: Studies here examine the epigenetic actions of RVX-208 in PH or Hep G2 cells exposed to high or euglycemic media reflecting CVD states with or without DM, respectively. TMAO induces MBL2 and C3 but not C5 in hyperglycemic cells and adding RVX-208 blocked the induction of these complement members. Additionally, BETi lowers FMO3 mRNA and levels of this enzyme. The additive effects of RVX-208 in blocking not only actions of TMAO but also its production may underlie the ability of RVX-208 to reduce MACE.