“The results provide important information regarding the safety of this novel molecule,” said principal investigator Professor Thomas F. Lüscher from the University Hospital, Zurich, Switzerland. He added that dal-VESSEL was the largest multicentre trial ever performed with brachial flow-mediated dilatation measured as a marker of endothelial function and cardiovascular risk.
Dal-VESSEL was an exploratory phase IIb randomised, double-blind, placebo-controlled trial in patients with coronary heart disease (CHD), or CHD risk equivalents, in which 476 patients with HDL-C levels <50 mg/dL were recruited. They received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. The primary efficacy endpoint was change from baseline in brachial flow mediated dilation after 12 weeks. The primary safety endpoint was 24-hour ambulatory blood pressure monitoring assessed at week four. Patients were treated for a total period of 36 weeks.
Results showed that dalcetrapib reduced CETP activity by almost 50% and increased high-density lipoprotein cholesterol (HDL-C) levels by 31% without changing nitric-oxide-dependent endothelial function or markers of inflammation and oxidative stress. No safety signals were observed during the whole study, and 23 pre-specified positively adjucated events occurred with an even distribution in both treatement arms (11 with dalcetrapib and 12 with placebo).
Dalcetrapib raises functional HDL-C by modulating CETP activity through a mechanism which differs from other CETP inhibitors, and, in earlier experimental studies, promoted efflux of cholesterol from cells. The hypothesis that it will similarly remove cholesterol from atherosclerotic plaques in humans, potentially reducing the occurrence of cardiovascular events, is currently being tested in phase III studies.
Results of a second phase 2b study of dalcetrapib, dal-PLAQUE, showed similarly "encouraging" results in atherosclerotic disease progression - no evidence of pro-inflammatory effects as measured by positron emission tomography/computed tomography (PET/CT) at six months, nor on plaque progression measured by magnetic resonance imaging after 12 months.
"High density lipoprotein removes cholesterol from atherosclerotic plaques," said Lüscher, "so drugs which improve this functionality may slow the progression of atherosclerosis and prevent cardiovascular events. Results so far suggest that dalcetrapib does not have pro-inflammatory or pro-atherogenic effects, does not affect blood pressure and is generally well tolerated by patients treated for up to two years."