RVX abstract from the IDF 2015 Word Diabetes Congress in Vancouver Nov 30 to Dec 4

Epigenetic actions of RVX-208 lower major adverse cardiovascular events, MACE in patients with diabetes mellitus and CVD

Co-authors: N.C. Wong1, E. Kulikowski2, L. Tsujikawa2, D. Gilham2, S. Wasiak2, C. Halliday2, K. Lebioda2, J. Johansson3, M. Sweeney3.

1University of Calgary, Medicine, Calgary, Canada.

2Resverlogix Corporation, Clinical Development, Calgary- AB, Canada.

3Resverlogix Corporation, Clinical Development, San Francisco- CA, USA.

p128 Poster Display

Basic and clinical science - Genetics and epigenetics

01-Dec-2015 00:00 00:00

Title: 0165-PD

Background: RVX-208 binds selectively to and inhibits the 2nd ligand domain of Bromodomain Extra-Terminal (BET) proteins. Each BET protein has 2 bromodomains that bind acetylated lysines in histones to affect epigenetic processes which modify gene activity. Post-hoc analysis of pooled data from phase 2b trials; SUSTAIN and ASSURE revealed a 55% relative risk reduction (RRR) of MACE in RVX-208 treated patients (n=331) vs. placebo (n=168) with a more pronounced 77% RRR of MACE in those with diabetes mellitus (DM). RVX-208 increases ApoA-I to yield more functional high-density lipoprotein (HDL) particles and thereby lower MACE, but the magnitude exceeded expectations.

Aim: To identify RVX-208 actions beyond ApoA-I/HDL.

Method: Plasma biomarker analyses of 2b trials. RVX-208 treated primary human hepatocytes (PHH) or human whole blood (HWB) microarrays.

Results: Biomarker increases (p<0.05, unless specified) between RVX-208 vs. placebo included; HDL-c (3mg/dL), ApoA-I (7.5mg/dL), large HDL (0.7umol/L), HDL size (0.1nm), and total HDL particles (1.8umol/L, p<0.07). Glucose in all patients (n=499) or in those with DM (n=192) given RVX-208 or placebo was unchanged but in 119 patients with DM & low HDL (<40mg/dL), RVX-208 reduced glucose by -0.3 mmol/L but in placebos it increased +0.9 mmol/L. These modest changes do not predict the reductions in MACE, thus leading us to search for added actions of RVX-208 in PHH and HWB using microarrays. In PHH, RVX-208 lowered expression of genes in pathways for cholesterol & fatty acid synthesis, glucose processing and acute phase response. Most profound were effects on complement and coagulation cascades, where RVX-208 lowered activity of 19/26 and 20/33 genes, respectively. These data were confirmed by RT-PCR of key mRNAs in the cascades and measure of specific proteins in trial samples showing decreases of 7-12% vs. baseline. In HWB exposed ex-vivo to RVX-208, it targeted pathways connected to atherogenesis such as; pro-inflammatory signaling, cell-cell interactions and extracellular matrix organization with significant downregulation of 43/56 pro-atherogenic genes but upregulation of 9/17 anti-atherogenic genes, involved in monocyte migration, macrophage function, and plaque stability.

Discussion: RVX-208 lowers MACE in CVD patients and especially in ones with DM. RVX-208 inhibits BET proteins to affect many biological processes underlying CVD such as; reverse cholesterol transport, vascular inflammation, innate immunity, atherosclerosis and thrombosis in lowering MACE.