March 27, 2007 (New Orleans, LA) - Torcetrapib may be dead, but the HDL field is not, with efforts now moving to other methods of increasing this lipoprotein. One such idea, using a new reconstituted HDL product, has shown some promising effects in reducing coronary atherosclerosis, and experts in the field say that further studies of this agent are warranted.

Presenting the results of the ERASE study with CSL-111 at the American College of Cardiology 2007 Scientific Sessions, Dr Jean-Claude Tardif (Montreal Heart Institute, QC) said: "This was just a proof-of-concept study, but the results are quite exciting. Taken together, all the efficacy results suggest a favorable rapid treatment effect. They also suggest that HDL remains a valid target for the treatment of vascular disease."

The results of the ERASE study are also published online March 26, 2007 in the Journal of the American Medical Association [ 1].

Other cholesterol experts were also positive about the study and CSL-111. Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) said: "I think this product has great promise. This is a form of baby HDL--it has not yet acquired a great load of cholesterol ester, so it has the capacity to do this once in the body. The results shown in this study are quite impressive. The primary end point may not have been significant, but the results overall are significant enough to me to justify moving on to the next stage with this agent."

Dr Steven Nissen (Cleveland Clinic, OH) agreed: "By most standards, this was a very small trial. To see a regression of disease that has taken several decades to develop with just four doses is really asking a lot for a drug. This definitely justifies larger trials to see whether more doses give a progressive effect over time. The authors of this study have certainly opened a door; we now need to see if they can jump through it. We must be cautious, as the primary end point was not met, but we have had so many failures that anything that shows a glimmer of hope now makes us excited."

CSL-111, which chemically and biologically resembles native HDL and contains apolipoprotein A-1 (apoA-1) isolated from human plasma, is in development by CSL Australia. The ERASE trial randomized 183 patients who had had a recent ACS event within the previous two weeks to four weekly infusions of placebo or CSL-111 at two different doses--40 mg/kg or 80 mg/kg. The 80-mg/kg dose of CSL-111 was discontinued early, after just 12 patients were treated because of liver-function-test abnormalities. Assessment of coronary arteries was performed using intravenous ultrasound (IVUS) and quantitative coronary angiography at baseline and at two to three weeks after the study infusions.

A total of 145 patients had evaluable, serial IVUS examinations. The primary end point--the difference in reduction in coronary atheroma volume as measured by IVUS after four weekly infusions of CSL-111 vs placebo--was not statistically significant but did show a strong trend in the right direction. But when compared with baseline values, CSL-111 did show a statistically significant effect on reducing atheroma volume.

ERASE: IVUS results

Group Change in atheroma volume (%) p vs placebo p vs baseline
Placebo (n=47) -1.62 -- 0.07
CSL-111 (n=89) -3.41 0.48 <0.001

In addition, secondary end points of plaque characterization indexes on IVUS and coronary score on quantitative coronary angiography were significantly different between the CSL-111 and placebo groups, suggesting a beneficial effect of CSL-111 on atherosclerosis.

Liver abnormalities: Are they important?

Tardif noted that the liver-enzyme changes seen with the 80-mg/kg dose were only transient, returning to normal after the treatment was stopped, and there was no evidence of liver failure or permanent damage. In addition, although minor changes in liver function were also seen with the 40-mg/kg dose, these were mild to moderate, self limiting, and not associated with hepatic-dysfunction indicators. "These enzyme elevations may just be a biochemical reaction of the liver to the sudden huge amounts of cholesterol it has to deal with." But one of the cochairs at the late-breaking clinical-trial session at which the study was presented cautioned that these liver-enzyme changes could have important implications for HDL-based therapy, saying: "We have thought the higher the better for HDL, but this may cause us to think again on this."

Regression similar to apo-A1 Milano

Tardif noted that the 3.4% regression of atheroma seen in this study is similar to that seen with the reconstituted HDL product containing apoA-1 Milano ( ETC-216), which showed a 4.2% regression. "So there is external validity for our results," he commented.

ETC-216, which is owned by Pfizer, has not been moved forward after its initial promising studies, possibly because, as an IV infusion, it would have a somewhat limited market compared with an oral agent such as torcetrapib. But Nissen, who conducted the regression studies with ETC-216, says he would like to see this agent move ahead again now.

He told heart wire that these HDL mimetics do have the downside of having to be given by injection but that subcutaneous formulations may be possible, and there may even be a way to engineer an oral formulation. "Initial formulations would definitely be given by injection and thus would probably be limited to short-term treatments for high-risk patients such as those who have recently had an MI to give them a boost," he suggested.

Another possible issue for the CSL product is that it is derived from human plasma. But Tardif pointed out that after all the steps taken to purify the product, the risk of infection was "less than one in a million."

  1. Tardif JC, Gregoire J, L'Allier PL, et al. Effects of reconstituted high density lipoprotein infusions on coronary atherosclerosis. A randomized controlled trial. JAMA 2007; DOI: 10.1001/jama.297.15.jpc70004. Available at: .

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