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

Objectives 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. Background Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease. Methods HepG2 cells were treated with 0 to 60 mu mol/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. Results 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 alpha 1-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. Conclusions 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. (J Am Coll Cardiol 2010;55:2580-9) (C) 2010 by the American College of Cardiology Foundation