Author + information
- Received August 19, 2009
- Revision received January 8, 2010
- Accepted February 1, 2010
- Published online June 8, 2010.
- Dana Bailey, MSc*,
- Ravi Jahagirdar, DVM, MS†,
- Allan Gordon, MD, PhD†,
- Anouar Hafiane, MSc*,
- Steven Campbell, BSc*,
- Safia Chatur, BSc*,
- Gregory S. Wagner, PhD†,
- Henrik C. Hansen, PhD†,
- Fabrizio S. Chiacchia, MBT†,
- Jan Johansson, MD, PhD†,
- Larbi Krimbou, DES*,
- Norman C.W. Wong, MD†,* ( and )
- Jacques Genest, MD*
- ↵*Reprint requests and correspondence:
Dr. Norman C. W. Wong, Resverlogix Corporation, Suite 202-279 Midpark Way Southeast, Calgary, Alberta T2X-1M2, Canada
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 μmol/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-β-migrating and α-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-β1-LpA-I and α1-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-β-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-β1-LpA-I and α-LpA-I levels and enhances cholesterol efflux. Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis.
This research was supported by Resverlogix Corp., CIHR Grants MOP-15042(to Drs. Krimbou and Genest), and HSF of Québec. Ms. Bailey, Dr. Wagner, Dr. Johansson, and Dr. Wong are employees of and have stock options with Resverlogix. Dr. Gordon is an employee of and gets a salary from Resverlogix. Dr. Hansen and Mr. Chiacchia are employees of Resverlogix. Ms. Bailey, Dr. Jahagirdar, and Dr. Gordon contributed equally to this work.
- Received August 19, 2009.
- Revision received January 8, 2010.
- Accepted February 1, 2010.
- American College of Cardiology Foundation