Key result
RVX-208 increases HDL-C ~97% in African green monkeys.
Why the study?
Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease, and the effects of the novel small molecule RVX-208 on these parameters were unknown.
Does RVX-208 increase apoA-I and HDL-C levels in vitro, in animal models, and in healthy human volunteers?
Does RVX-208 increase apoA-I and HDL-C levels in vitro, in animal models, and in healthy human volunteers?
Effect estimate: increased by 60% (apoA-I) and 97% (HDL-C) in AGMs
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We're left with an inability to accurately or confidently assess the effect of any intervention to raise HDL levels or to enhance one function or another in terms of its actual impact on atherosclerosis and cardiovascular disease risk. We cannot assume that apoA-1 synthesis induction will necessarily be antiatherogenic.”
“The drug had been developed with the thought that it would be a potent oral compound from the perspective of an HDL therapeutic and would be comparable to infusional approaches that we have seen prevent regression of plaque. That is clearly not the case.”
“Our results show that RVX-208 treatment did not result in any measurable incremental benefit on plaque regression for patients with coronary artery disease and low HDL cholesterol. The findings could reflect either a lack of efficacy of RVX-208, or the general inability to improve on the benefits produced by statins and other cardiovascular therapies.”
The small molecule RVX-208 successfully induces apoA-I and HDL-C production, suggesting potential therapeutic utility for treating atherosclerosis.
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 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.
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Bailey et al. (2010) studied Healthy volunteers (clinical phase); atherosclerosis target. RVX-208 was evaluated on Apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels (increased by 60% (apoA-I) and 97% (HDL-C) in AGMs). In African green monkeys, RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels by 60% and 97%, respectively.
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