Novel small molecule increases HDL cholesterol and apoA-1 levels
MedWire News: A novel small molecule, RVX-208, increases levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-1 in vivo and in vitro, researchers report.
The team examined the impact of RVX-208 in liver cells, African green monkeys, and in a short, phase I clinical trial.
ApoA-1 messenger RNA and protein levels rose in HepG2 cells treated in vitro with between 0 and 60 µmol/l RVX-208 in a dose-responsive manner.
Increased apoA-1 production was associated with an abundance of larger, α-lipoprotein particles containing apoA-1 (LpA-1) and lipid-poor pre-β-migrating particles.
Monkeys treated with 60 mg/kg RVX-208 once daily had a mean 60% increase in serum apoA-1 from baseline at day 63 of treatment, from 133 to 213 mg/dl.
There was also a corresponding 97% increase in HDL cholesterol levels, from 57 to 112 mg/dl (1.47 to 2.90 mmol/l). There was no significant increase in either measure when animals received vehicle treatment.
Daily treatment with 60 mg/kg also more than doubled triglyceride levels, from 28 to 64 mg/dl (0.32 to 0.73 mmol/l), but the researchers say a dose of 30 mg/kg twice daily had no such effect.
Elevations in serum apoA-1 and HDL-C induced by RVX-208 were accompanied by changes in the HDL size distribution, mirroring that observed in the liver cells.
The RVX-208 treatment also enhanced adenosine triphosphate binding cassette (ABC)G1 and scavenger receptor class B type I (SR-BI)–mediated cholesterol efflux.
Treating 18 healthy volunteers with between 2 and 8 mg/kg of RVX-208 per day for 1 week resulted in a significant 10% higher plasma apoA-1 than in placebo-treated individuals.
Increases in HDL cholesterol and larger α-HDL particles were not statistically significant. Nonetheless, there was a significant increase in pre-β1-HDL levels and ABCA1-mediated cholesterol efflux, of 42% and 11%, respectively.
Reporting in the Journal of the American College of Cardiology, Norman Wong (Resverlogix Corporation, Calgary, Canada) and colleagues conclude: “Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis.”
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By Anita Wilkinson