474-P: Apabetalone (RVX-208) Attenuates an Inflammatory Milieu that Enhances Adhesion of Monocytes to Endothelial Cells in Type 2 Diabetes Mellitus with Cardiovascular Disease Patients

Abstract

To explore mechanisms underlying a 57% relative risk reduction of major adverse cardiovascular events (MACE) in type 2 diabetes mellitus (T2DM) patients (pts) with CVD given 200 mg apabetalone (APL) by mouth. APL is a small molecule that inhibits bromodomain and extra-terminal (BET) proteins, which are epigenetic readers of acetylated lysine in histones contained within actively transcribing chromatin. Inhibiting BET proteins attenuates transcribed genes that are upregulated in disease states. Studies here used SOMAscan proteomics of patient plasma given placebo (n=30) or APL (n=25) and cultured monocyte (THP-1) or endothelial (HUVEC) cells. Results showed differences in the proteome spanning 4 CVD pathways: acute phase response, intrinsic prothrombin activation, leukocyte extravasation signaling, and coagulation. This data showed TNFα target genes were preferentially upregulated in T2DM+CVD (p<0.001; z-score = 2.270) vs. euglycemic pts, suggesting an inflammatory state that was attenuated by APL (p<0.001; z-score = -2.308). To mimic inflammation in vitro, TNFα (10 ng/ml) added to co-culture of THP-1 and HUVEC induced adhesion 12-fold in euglycemia; APL inhibited it by 44%. HUVECs exposed to TNFα induced IL-1β, E-selectin, VCAM1 and IL-6 mRNA by 1685, 1164, 196 and 9-fold respectively while APL inhibited (50-99%). In THP-1, TNFα induced IL-1β, MYD88 and CD-44 mRNA by 3.5, 2.6, and 1.8-fold respectively; inhibited by APL (39-84%). To mimic T2DM, high glucose (HG, 25.6 mM) induced adhesion of THP-1 to HUVEC by 2.4-fold was blocked by APL. In HG, Very Late Antigen-4 (VLA-4) mRNA, a THP-1 adhesion gene, rose 1.3-fold; APL blocked it >50%. HG induced adhesion genes in HUVECs, E-selectin and MYD88, by 2- and 1.3-fold was lowered by APL. In summary, APL lowers MACE in T2DM+CVD pts by attenuating expression of genes that mediate adhesion of monocytes to endothelial cells. This hypothesis is being tested in a phase 3 trial BETonMACE. Disclosure L. Tsujikawa: None. E. Kulikowski: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. C. Calosing: None. S. Wasiak: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. D. Gilham: Employee; Self; Resverlogix Corp. C. Halliday: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp. J.O. Johansson: Employee; Self; Resverlogix Corp. M. Sweeney: Employee; Self; Resverlogix Corp. N.C. Wong: Employee; Self; Resverlogix Corp. Stock/Shareholder; Self; Resverlogix Corp.