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

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

Effect of Reconstituted HDL on Atherosclerosis and Efficacy (ERASE)

Another imaging study of an HDL-targeted therapy involved short-term infusions of a reconstituted form of HDL (CSL-111) currently being investigated by CSL (Parkville, Australia) for prevention of secondary events in patients who have had an acute coronary syndrome (ACS) event and for treatment of acute ischemic stroke.

CSL developed proprietary technology to manufacture reconstituted HDL (rHDL) through its subsidiary CSL Behring in Switzerland. CSL-111 is a synthetic lipoprotein particle manufactured from apoA-I isolated from human plasma and phosphatidylcholine derived from soybean lipids in a molecular ratio of 1:150. Previous studies indicated that administration of CSL-111 increased cholesterol mobilization and reverse cholesterol transport in healthy volunteers and restored function of endothelial cells in patients with high cholesterol levels. With the same administration schedule as used in a trial of recombinant apoA-I Milano (ETC-216),[13] it was suggested that CSL-111 might be antiatherogenic.

The Effect of Reconstituted HDL on Atherosclerosis and Efficacy (ERASE) trial evaluated the effects of short-term rHDL infusions on coronary atherosclerosis regression as assessed by IVUS and quantitative coronary angiography (QCA) in patients following a recent ACS event. A secondary objective was evaluation of patient safety. The results of the study were presented by Jean-Claude Tardif, MD (Montreal Heart Institute, Montreal, Quebec, Canada),[14] and published simultaneously in JAMA.[15] The results of ERASE demonstrated that CSL-111 did not significantly reduce atheroma volume compared with placebo, although it did significantly improve the plaque characterization index and coronary score on QCA.

The randomized, controlled, blinded ERASE trial was coordinated by the Montreal Heart Institute with 17 sites throughout Canada. Between July 2005 and October 2006, 183 patients (mean age, 57 years; > 90% on statins) with a clinical need for diagnostic coronary angiography were randomized to receive either placebo (normal saline) or rHDL infusions within 2 weeks of having an ACS event (unstable angina, or non-ST segment- or ST-segment elevation MI). Qualifying patients received up to 4 volume-matched, weekly infusions of either placebo, 40 mg/kg rHDL, or 80 mg/kg rHDL.

IVUS examinations of the designated target coronary artery and QCA were scheduled to be performed at baseline and at 2-3 weeks after the fourth study infusion. A total of 145 patients completed the study and had repeat IVUS at a mean of 43 days after the first examination. All IVUS examinations and angiograms were analyzed by a core laboratory at the Montreal Heart Institute.

The higher dosage of CSL-111 was discontinued after a planned interim review revealed a high incidence of liver function test abnormalities. The primary efficacy endpoint, the change from baseline in atheroma volume on IVUS, did not differ significantly between the CSL-111 and placebo groups, although the change with CSL-111 from baseline was statistically significant (P < .0001) ( Table 9 ). The absolute change in plaque volume with CSL-111 was also significantly different from baseline (P < .0001). The change in plaque volume was also significant in the placebo group, an effect that Dr. Tardif and colleagues attributed to either the small number of patients in the study or to the intensive statin therapy that ACS patients usually receive.

Secondary IVUS endpoints of plaque characterization indexes (arc index and inner perimeter index) differed significantly between the CSL-111 and placebo groups ( Table 10 ).

The baseline QCA coronary score, a marker of atherosclerosis progression, showed a significant interaction with study treatment (P = .03).

Serious AEs reported in the study were, overall, mild or moderate, and did not differ in frequency between the 2 study groups. The only AE with a higher frequency in the CSL-111 group was hypotension (13.8% vs 7.1% with placebo). The liver function test abnormalities that led to discontinuation of the higher dose of CSL-111 also occurred with the lower dose and with placebo. However, all increases were self-limiting and returned to normal without clinical consequence or intervention, Dr. Tardif reported. He speculated that these effects could be due to transient dysfunction of hepatocytes reacting to the sudden return of a huge amount of cholesterol.

Dr. Tardif and his colleagues believe that their results "contribute to the rationale for larger, longer, and more definitive clinical studies of CSL-111 with morbidity and mortality endpoints," but they do not yet provide the rationale for clinical application. A larger trial in patients with CAD would have been premature in the early assessment of CSL-111, given the efficacy and safety evaluations involved in this study, the investigators believe. However, elevation of HDL remains a valid target in atherosclerosis, and further evaluation of the effects of CSL-111 on clinical outcomes is warranted," they believe. Lipid data from ERASE were not yet available at the time of the meeting, but Dr. Tardif explained that CSL-111 infusion has been shown in earlier studies to produce a transient (< 1 week) increase of 50% to 75% in HDL cholesterol.

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