Tuesday, 26 May 2015

12:30-12:40

http://www.isa-2015.com/

Abstract titleRVX-208 A SELECTIVE BROMODOMAIN EXTRA-TERMINAL PROTEIN INHIBITOR REDUCES MACE IN PATIENTS WITH HIGH RESIDUAL RISKS OF CARDIOVASCULAR DISEASE.

AuthorWong , Norman, University of Calgary, Calgary Alberta, Canada (Presenting author)

Co-author(s)Johansson , Jan

Lebioda , Kenneth

Kulikowski , Ewelina

Halliday , Christopher

TopicDyslipidemia; Lipids, Lipoproteins and Apolipoproteins

KeywordsApolipoproteins, Atherosclerosis, HDL, Inflammation

Abstract text

Aim: To determine potential mechanism(s) underlying the beneficial activity of RVX-208 in SUSTAIN and ASSURE trials, n=499. Pooled data showed RVX-208 lead to a -55% (p=0.02) relative risk reduction (RRR) in MACE that was more pronounced (-77%, p=0.01) in those with diabetes mellitus (DM). RVX-208 an orally active small molecule binds selectively to the second ligand domain of bromodomain extra-terminal proteins (BET), alters epigenetics thereby raising ApoA-I and in turn HDL.

Methods: Examination of >60 biomarkers in human trials and in vitro microarrays.

Results: Changes between RVX-208 vs. placebo (change, p value) were; alkaline phosphatase (-6 U/L, <0.0001), HDL-c (+3 mg/dL, <0.001), ApoA-I (+7.5 mg/dL, <0.01), large HDL (+0.7 umol/L, <0.05), HDL size (+0.1, <0.05), and total HDL particles (+1.8 umol/L, <0.1) with pronounced effects in those with DM or chronic kidney disease (CKD). In DM patients (n=192) given RVX-208 glucose was unchanged, placebo rose +0.7 mmol/L a non-significant difference (p<0.1). In patients (n=119) with DM and HDL <40 mg/dL RVX-208 lowered glucose significantly (p<0.01) by -0.3 vs. +0.9 mmol/L in placebo. In CKD (n=48) subjects with eGFR <60 mL/min/1.73m2 given RVX-208 the eGFR rose +3.4% vs. -5.9% (p<0.05) in placebo. Microarrays of primary human hepatocyte mRNA following 3 or 48 hours of RVX-208 (30 uM) caused marked changes in pathways such as; attenuation in inflammation, coagulation, complement and cholesterol synthesis.

Summary: RVX-208 selectively inhibits BET thereby lowering serum ALP, altering HDL profile and pathways to lower MACE in patients with high residual CVD risk, especially in those with DM.