And just so people can compare the ESC 2015 abstract with the upcoming EASD 2015 abstract for their oral presentation on Friday September 18th at ~ 12PM (Sweden), I've pasted the EASD abstract below. A lot of similarities, but the EASD is focused on the diabetes patients and also looks at many more plasma biomarkers than discussed in the ESC abstract.

"RVX-208 acts via an epigenetic mechanism to lower Major Adverse Cardiovascular Events (MACE) in patients with atherosclerosis and especially in those with diabetes mellitus.

N.C.W. Wong1, E. Kulikowski1, L. Tsujikawa1, D. Gilham1, S. Wasiak1, C. Halliday1, K. Lebioda1, J.O. Johansson2, M. Sweeney2; 1Clinical Development, Resverlogix Corporation, Calgary, Canada, 2Clinical Development, Resverlogix Corporation, San Francisco, USA.

Background and aims: RVX-208 binds selectively to the second ligand domain of Bromodomain and Extra-Terminal (BET) proteins and inhibits their activity. Each BET protein has two bromodomains that bind acetylated lysines in histones. When a BET protein binds ligand, it recruits transcriptional machinery to DNA and thereby modifies gene activity. Analysis of pooled data from two 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). But in those with diabetes mellitus (DM) RVX-208 treatment lead to a 77% RRR of MACE vs. placebo. RVX-208 increased production of ApoA-I yielding more high-density lipoprotein (HDL) particles. While these effects should lower MACE, the magnitude was more than expected, prompting studies to identify properties of RVX-208 beyond its effects on ApoA-I/HDL.

Materials and methods: Plasma biomarkers from SUSTAIN and ASSURE trials were analyzed. Microarray data from RVX-208 treated primary human hepatocytes (PHH) or human whole blood (HWB) were used to identify differentially expressed genes, and guide measurements of specific proteins in clinical samples to confirm key findings.

Results: Biomarkers from the trials showed significant increases (p<0.05, unless specified) between RVX-208 vs. placebo in: 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 vs baseline. In patients with DM (n=119) and low HDL (<40mg/dL), RVX-208 reduced glucose by -0.3 mmol/L but in placebo it increased +0.9 mmol/L. These modest changes do not predict the MACE reductions. Thus microarrays were used to survey PHH and HWB exposed to RVX-208. In PHH, RVX-208 decreased expression of genes in pathways for cholesterol & fatty acid synthesis, innate immunity and glucose processing. Most profound were effects on complement and coagulation pathways, where RVX-208 downregulated expression of 19/26 and 20/33 genes respectively. These data were confirmed by RT-PCR of key mRNAs. Furthermore, specific complement and coagulation proteins were found to be decreased in plasma from the trials (range 7-12% vs. baseline). Microarrays from HWB exposed ex-vivo to RVX-208 identified pathways with known roles in atherogenesis including: pro-inflammatory signaling, cell-cell interactions and extracellular matrix organization. RVX-208 significantly downregulated several pro-atherogenic genes (43/56) but upregulated anti-atherogenic genes (9/17), that control monocyte recruitment, migration and activation, macrophage function, inflammatory signaling and plaque stability to suggest an overall antiatherosclerotic benefit.

Conclusion: RVX-208 treatment is associated with marked MACE reductions in SUSTAIN and ASSURE patients and especially in those with DM. RVX-208 modifies cellular epigenetics to impact multiple biological processes that underlie CVD. Combined effects of RVX-208 on reverse cholesterol transport, vascular inflammation, innate immunity, atherosclerosis and thrombosis may explain its efficacy in reducing MACE.

Clinical Trial Registration Number: NCT01423188, NCT01067820