title: RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease.
abstract: High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.
authors: Resverlogix Corp., Calgary, Canada.
authors: Dean
authors: D
authors: Gilham
authors: Resverlogix Corp., Calgary, Canada.
authors: Sylwia
authors: S
authors: Wasiak
authors: Resverlogix Corp., Calgary, Canada.
authors: Laura M
authors: LM
authors: Tsujikawa
authors: Resverlogix Corp., Calgary, Canada.
authors: Christopher
authors: C
authors: Halliday
authors: Resverlogix Corp., Calgary, Canada.
authors: Karen
authors: K
authors: Norek
authors: Resverlogix Corp., Calgary, Canada.
authors: Reena G
authors: RG
authors: Patel
authors: Resverlogix Corp., Calgary, Canada.
authors: Ewelina
authors: E
authors: Kulikowski
authors: Resverlogix Corp., San Francisco, USA.
authors: Jan
authors: J
authors: Johansson
authors: Resverlogix Corp., San Francisco, USA.
authors: Michael
authors: M
authors: Sweeney
authors: Resverlogix Corp., Calgary, Canada. Electronic address: norm@resverlogix.com.
authors: Norman C W
authors: NC
authors: Wong
authors: Allan
authors: A
authors: Gordon
authors: Kevin
authors: K
authors: McLure
authors: Peter
authors: P
authors: Young
mesh_terms: D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D011799:Quinazolines; D052999:Quinazolinones; C000628794:apabetalone
keywords: ApolipoproteinA-I; Atherosclerosis; BET bromomodomain; HDL; RVX-208