ILLUSTRATE, RADIANCE, and ERASE: What Do the Imaging Trials With Torcetrapib Tell Us?

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

Introduction

Until December 2006, the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, appeared to represent the best hope for an effective drug to raise endogenous high-density lipoprotein (HDL) cholesterol levels. On December 2, 2006, however, the company developing the drug, Pfizer (New York, NY), announced that all clinical trials of the drug had ceased after the early termination of the international phase 3, 15,000-patient clinical trial, Investigation of Lipid Level management to Understand its impact IN ATherosclerotic Events (ILLUMINATE).[1] The trial had already recorded 82 deaths in the patients taking torcetrapib-atorvastatin vs 51 in patients taking atorvastatin alone. In addition to the increase in mortality, the rates of myocardial infarction (MI), revascularization, angina, and heart failure were higher in the torcetrapib-atorvastatin arm.

The failure of torcetrapib was greeted with dismay by many academic researchers as well as those in the pharmaceutical industry, and according to Daniel J Rader, MD (University of Pennsylvania, Philadelphia), speaking later at the American College of Cardiology (ACC) 56th Annual Scientific Session, it "sent shudders through the HDL world about what would be the impact on the HDL hypothesis.[2]"

Because the early-phase trial results with torcetrapib had appeared to be so positive, a decision was taken to initiate 2 imaging studies -- assessing 2 "surrogate" endpoints, coronary atherosclerotic plaque burden, using intravascular ultrasound (IVUS), and carotid artery intimal media thickness (CIMT) -- to run concurrently with a longer-term, clinical endpoints morbidity/mortality trial. The imaging studies were planned to conclude first, with results hopefully presented early in 2007. When the clinical endpoints trial, ILLUMINATE, was terminated early, the 2 imaging studies took on added interest, and the results of these trials, presented at the 2007 ACC meeting, are summarized with commentary below.

Finally, a third imaging study was also presented at this year's ACC conference, assessing whether another approach, reconstituted HDL, would have a positive effect on atheroma volume, and the results of this IVUS study are discussed in conclusion.

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