RVX-208: A Small Molecule That Increases Apolipoprotein A-I and High-Density Lipoprotein Cholesterol In Vitro and In Vivo

• Published in: Journal of the American College of Cardiology Vol. 55; no. 23; pp. 2580 - 2589
• Main Authors: BAILEY, Dana, JAHAGIRDAR, Ravi, KRIMBOU, Larbi, WONG, Norman C. W, GENEST, Jacques, GORDON, Allan, HAFIANE, Anouar, CAMPBELL, Steven, CHATUR, Safia, WAGNER, Gregory S, HANSEN, Henrik C, CHIACCHIA, Fabrizio S, JOHANSSON, Jan
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 08.06.2010; Elsevier Limited
• Subjects: Animals; Apolipoprotein A-I - biosynthesis; Apolipoprotein A-I - blood; Apolipoprotein A-I - drug effects; Apolipoprotein A-I - metabolism; Apolipoproteins; Atherosclerosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular disease; Cells, Cultured; Cercopithecus aethiops; Cholesterol; Cholesterol, HDL - blood; Cholesterol, HDL - drug effects; Cholesterol, HDL - metabolism; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hep G2 Cells - drug effects; Hep G2 Cells - metabolism; Humans; In Vitro Techniques; Laboratory animals; Lipoproteins; Macaca fascicularis; Male; Medical sciences; Molecular Weight; Probability; Quinazolines - chemistry; Quinazolines - pharmacology; Random Allocation; Risk Assessment; Studies; Apolipoprotein A; In vivo; Molecules; Increase; Circulatory system; Cardiology; Lipoprotein HDL; In vitro; Cholesterol
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2010.02.035

The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels in vitro and in vivo. Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease. HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production. For in vivo studies, African green monkeys (AGMs) received 15 to 60 mg/kg/day RVX-208, and the serum was analyzed for lipoprotein levels, HDL-subparticle distribution, cholesterol efflux, and activity of lipid-modifying enzymes. A phase I clinical trial was conducted in healthy volunteers (given 1 to 20 mg/kg/day of RVX-208) to assess safety, tolerability, and pharmacokinetics. The RVX-208 induced apoA-I messenger ribonucleic acid and protein synthesis in HepG2 cells, leading to increased levels of pre-beta-migrating and alpha-lipoprotein particles containing apoA-I (LpA-I) in spent media. Similarly, in AGMs, RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels (60% and 97%, respectively). In addition, the levels of pre-beta(1)-LpA-I and alpha1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette AI, adenosine triphosphate binding cassette G1, and scavenger receptor class B type I-dependent cholesterol efflux. These changes were not mediated by cholesteryl-ester-transfer protein. Treatment of humans for 1 week with oral RVX-208 increased apoA-I, pre-beta-HDL, and HDL functionality. RVX-208 increases apoA-I and HDL-C in vitro and in vivo. In AGMs, RVX-208 raises serum pre-beta(1)-LpA-I and alpha-LpA-I levels and enhances cholesterol efflux. Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis.