I'm re-posting this from before. RVX presents tomorrow at the IDF 2015 World Diabetes Congress, which is the last event listed for 2015 on the RVX events page.

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.