New therapeutic agents for raising HDL cholesterol: first clinical data

Early clinical data were presented on two new therapeutic possibilities - RVX-208 and autologous delipidated HDL - for raising high density lipoprotein (HDL) cholesterol at the American Heart Association Annual Scientific Sessions, New Orleans 2008.

 

In the first report, results were presented for the novel compound RVX-208, a small molecule that has been shown to upregulate gene expression of apolipoprotein (apo)A-I and raise HDL cholesterol in non-human primates. In animal studies using African green monkeys, treatment with RVX-208 (7.5, 15 and 30 mg/kg twice daily or 60 mg/kg once daily) for up to 63 days increased average serum levels of apoA-I by 57% and HDL cholesterol by 92%. There was also a significant increase in preb1-LpA-I and larger a1‑LpA-I species.

 

Additionally, in a cell culture model, treatment with RVX-208 promoted cholesterol efflux via ABCA1, ABCG1 or SR-BI dependent pathways.

 

Following on from these studies, a trial in 80 healthy human subjects was conducted. Oral administration of RVX-208 (2, 3 and 8 mg/kg per day for 7 days) increased apoA-I by 11% (p=0.03 vs. placebo), and preb1-LpA-I by 30% (p=0.02). ABCA1-dependent cholesterol efflux was also 10% higher in subjects treated with RVX‑208.

 

The authors concluded that consistent trends in apoA-I production and HDL functionality in both animal and human studies supported further clinical investigation of the therapeutic potential of RVX-208.

 

Krimbou L, Jahagirdar R, Bailey D et al. Compound RVX-208 modulates HDL-C levels and function in non-human primates and in early (phase I) human trials. Circulation 2008;118:S_371. [Abstract 1696].

 

Another report presented findings from a first-in-man study investigating the feasibility of autologous delipidated HDL plasma infusions for treating patients with acute coronary syndrome (ACS). Plasma delipidation converts aHDL to preb HDL, which has been reported to be the most effective form of HDL for removal of lipid from arterial plaque in reverse cholesterol transport.

 

In this study, 28 patients with ACS who were due to undergo cardiac catheterisation for non-obstructive atheroma in at least one native coronary artery, were randomised to HDL delipidation or control and subjected to apheresis/reinfusion (7 sessions at weekly intervals). Intravascular ultrasound evaluation of the target vessel was performed at baseline during diagnostic catheterisation and up to 14 days after the last procedure.

 

Serial infusion of HDL delipidated plasma led to an increase in prebHDL and was associated with a 5-fold increase in cholesterol efflux vs. control. Intravascular ultrasound evaluation suggested that there was a trend towards regression of atheroma volume (mean change in total atheroma volume -12.18 ± 36.75 mm3 in the delipidated group vs. +2.80 ± 21.25 mm3 in the control group). Treatment was well tolerated.

 

The authors concluded that this therapy may offer a potential novel adjunctive treatment for patients with ACS.

 

Waksman R, Kent K, Pichard A et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high density lipoprotein plasma infusions in patients with acute coronary syndrome. Circulation 2008;118:S_371. [Abstract 1697].

 

 


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