RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo.
OBJECTIVE
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 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.


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 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.


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.
Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec, Canada.
Dana
D
Bailey
Ravi
R
Jahagirdar
Allan
A
Gordon
Anouar
A
Hafiane
Steven
S
Campbell
Safia
S
Chatur
Gregory S
GS
Wagner
Henrik C
HC
Hansen
Fabrizio S
FS
Chiacchia
Jan
J
Johansson
Larbi
L
Krimbou
Norman C W
NC
Wong
Jacques
J
Genest
D000818:Animals; D006224:Cricetinae; D005260:Female; D006801:Humans; D008297:Male; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008970:Molecular Weight; D011336:Probability; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones; D011897:Random Allocation; D018570:Risk Assessment
C000628794:apabetalone; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D011799:Quinazolines; D052999:Quinazolinones