An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels

Author:

Rhainds David1,Arsenault Benoit J1,Brodeur Mathieu R1,Tardif Jean-Claude12

Affiliation:

1. Atherosclerosis Research Group, Montreal Heart Institute, 5000 Belanger St., Montreal, Quebec, H1T 1C8, Canada.

2. Faculty of Medicine, Université de Montréal, 2900, Boulevard Édouard-Montpetit Montréal, Québec H3T 1J4, Canada

Abstract

CETP is the target of CETP inhibitors such as anacetrapib and the modulator dalcetrapib. Both molecules have entered Phase III clinical trials, with the ultimate goal of reducing cardiovascular events by raising HDL cholesterol. At the 600-mg dose selected for the dal-OUTCOMES study, dalcetrapib is expected to inhibit CETP activity by approximately 30% and raise HDL-C by approximately 30% with limited effects on LDL cholesterol. Importantly, dalcetrapib does not raise blood pressure or aldosterone levels, two effects previously associated with the CETP inhibitor torcetrapib. Dalcetrapib has been well tolerated at the 600-mg dose. In the dal-PLAQUE atherosclerosis imaging study, dalcetrapib reduced the enlargement of total vessel area over time. In May 2012, following the results of the second interim analysis of dal-OUTCOMES, the Data and Safety Monitoring Board recommended stopping the study owing to a lack of clinically significant benefit, which was followed by Roche’s (Basel, Switzerland) decision to terminate the study and the dalcetrapib program (dal-HEART). Contrary to anacetrapib, a potent CETP inhibitor that markedly increases HDL cholesterol and significantly reduces LDL cholesterol, dalcetrapib has allowed us to test the hypothesis that an isolated, moderate elevation in HDL cholesterol prevents cardiovascular events.

Publisher

Future Medicine Ltd

Subject

Cardiology and Cardiovascular Medicine,Molecular Medicine

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