ADA 2017 Abstract Embargo is lifted now. Here is the full abstract to be presented on June 11th from 12 PM to 1 PM at ADA 2017 in San Diego.

Apabetalone (RVX-208) Lowers Major Adverse Cardiovascular Events (MACE) in CVD Patients with Diabetes Mellitus by Affecting Complement Pathway and Microbiome Activity

In phase 2b trials lasting 6 months, patients (n=499) given 200 mg/d of apabetalone had a 55% relative risk reduction in MACE that was lowered further in diabetes mellitus (DM). These findings underpin our interest to explore potential mechanism(s) behind MACE reductions arising from RVX-208, a selective BET inhibitor (BETi) that acts via displacing acetylated-lysine moieties in histones from the 2nd ligand domain in bromodomain extra-terminal (BET) proteins. Previous studies showed RVX-208 may lower CVD risks by affecting inflammation, metabolism, coagulation and complement. Studies here examine how RVX-208 may block actions of a suspected culprit in atherosclerosis, trimethyl amine oxide (TMAO) derived from microbiome activity. Huh-7 hepatoma cells or primary hepatocytes (PH) were examined using RT-PCR and western-blots. In high glucose (25.6 mM) Huh-7 cells exposed to 1-100 uM TMAO acted within 6-48 hrs to induce mRNA encoding MBL2 and complement C3 members of the complement pathway by 40 and 20%, respectively in a time and dose dependent manner. RVX-208 blocked TMAO induction of MBL2 and C3 in these cells. However, TMAO had no effect on complement C5. In contrast, all 3 genes in euglycemia (5.6 mM) was not induced by TMAO but RVX-208 still lowered their expression. The microbiome transforms dietary phospholipids to TMA the substrate for hepatic flavin mono-oxygenase-3 (FMO3) converting it to TMAO. In PH, RVX-208 acted within 24 hrs to repress FMO3 mRNA and protein levels by 40 and 30%, respectively.

In summary, hepatoma cells and hepatocytes cultured in high or euglycemic media reflect diabetic state or not, respectively. TMAO induces complement MBL2 and C3 in cells exposed to hyperglycemia while RVX-208 blocks this induction. Additionally, BETi lowers FMO3 mRNA and protein. Thus RVX-208 blocks both detrimental effects of TMAO and its production as potential mechanisms for how apabetalone lowers MACE in DM.