Dalcetrapibの血管機能に対する効果

dal-VESSEL：Phase IIbトライアルにおいて、研究段階の分子がコレステロールエステル転送蛋白活性を低下させHDLを増加させた

dal-VESSEL: An investigational molecule reduced cholesteryl ester transfer protein activity and increased HDL in Phase IIb trial
2011年European Society of Cardiology学会で発表されたphase IIb dal-VESSELスタディの結果、コレステロールエステル転送蛋白（CETP）として作用する研究段階の分子であるdalcetrapibは血管内皮機能（血流依存性血管拡張反応で示された）を障害したり血圧を上昇させたりしないことが示された。Dal-VESSELは、冠動脈疾患（CHD）または CHD相当のリスクを有し、HDL-Cレベルが50mg/dL未満の患者476人を対象とした試験的phase IIb無作為化二重盲検プラセボコントロールトライアルである。患者は既に行われている治療に加え600mg/dayのdalcetrapibまたはプラセボを投与された。一次有効性エンドポイントは12週後の橈骨動脈の血流依存性血管拡張反応のベースラインからの変化であった。一次安全性エンドポイントは第4週目に施行された24時間血圧測定の結果であった。患者は計36週間の薬物投与を受けた。その結果dalcetrapibは、一酸化窒素依存性血管内皮機能および炎症や酸化ストレスのマーカーを変化させることなくCETP活性をほぼ50%低下させ、高密度リポ蛋白コレステロール（HDL-C）レベルを31%上昇させた。スタディ全期間中において安全信号は認められず、予め明記されていた陽性と判断されたイベントは両群において均等な分布で発現した（dalcetrapib群で11件およびプラセボ群で12件）。
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Results of the phase IIb dal-VESSEL study show that dalcetrapib, an investigational molecule which acts on cholesteryl ester transfer protein (CETP), did not impair endothelial function (as indicated by flow-mediated dilatation) or increase blood pressure, and was generally well tolerated in patients with or at risk of coronary heart disease. The study was presented at the European Society of Cardiology 2011 conference.

"The results provide important information regarding the safety of this novel molecule," said principal investigator Professor Thomas F. Luscher from the University Hospital, Zurich, Switzerland. He added that dal-VESSEL was the largest multicenter 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 treatment 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 Luscher, "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."