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Sep 12, 2011
 |  BioCentury  |  Product Development

Reviving CETP

Roche, Merck data raise hopes for CETP inhibition for cholesterol lowering

Evidence is accumulating that the next generation of CETP inhibitors may be able to avoid the off-target effects that doomed Pfizer Inc.'s torcetrapib.

Roche reported Phase IIb data in late August showing its dalcetrapib increased HDL without raising blood pressure, inflammatory markers or imaging markers correlated with vascular harm. And Merck & Co. Inc. reported similar blood pressure data for its anacetrapib last year (see BioCentury, Nov. 22, 2010).

Elevated blood pressure was an early warning signal that preceded an increase in deaths seen in a Phase III trial that led Pfizer to scrap its CETP inhibitor.

Increasing high density lipoprotein is expected to be atheroprotective because HDL removes cholesterol from plaques on arterial walls and facilitates its transport to the liver, where it is metabolized.

Whether dalcetrapib or anacetrapib will show any clinical benefit won't be known until Phase III outcomes data are available starting in 2013. But new insights into HDL biology and preclinical work on the mechanisms of the two compounds suggest they can limit the harmful effects of CETP (cholesteryl ester transfer protein) without stripping HDL of its atheroprotective function.

Safety first

Roche designed two Phase IIb trials - dal-VESSEL and dal-PLAQUE - to show dalcetrapib has no vascular toxicity by looking at blood pressure, endothelial function, vessel wall modification and inflammation. Data from both studies were presented last month at the European Society of Cardiology (ESC) Congress in Paris.

The double-blind, placebo-controlled dal-VESSEL trial enrolled 476 patients with coronary heart disease (CHD) and low levels of HDL (<50 mg/dL). Patients received 600 mg/day of dalcetrapib or placebo, plus existing treatments, such as statins and angiotensin-converting enzyme (ACE) inhibitors.

Dalcetrapib met the primary efficacy endpoint of change from baseline in brachial flow mediated dilation at week 12 by showing no difference from placebo. This demonstrated dalcetrapib did not impair endothelial function.

The primary safety endpoint was 24-hour ambulatory blood pressure at week 4. Dalcetrapib was no different from placebo for both systolic and diastolic blood pressure. The trial was 90% powered to exclude a 2 mm of mercury difference, which was considered a clinically relevant change in blood pressure.

A 3-4 mm increase...

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