Dr. Philip Barter of the Heart Research Institute of Sydney, Australia, presented an update of the disappointing ILLUMINATE clinical drug trial for the once-promising drug, torcetrapib, at the 2007 American Heart Association meetings in Orlando, Florida.
The crash and burn of drug manufacturer Pfizer's torcetrapib in December 2006 made headlines and prompted enormous disappointment for many patients and doctors who had hoped for a new drug choice to raise HDL cholesterol. Pfizer executives and investors were also disappointed, anticipating release of a drug that might have become the number one biggest selling drug in the world-ever, surpassing even Lipitor®.
Torcetrapib is the first among a new class of drugs given the tongue-twisting name of "cholesteryl-ester transfer protein inhibitors," or CETP-inhibitors, drugs that block the release of cholesterol from HDL particles and prevent formation of the unwanted small LDL particles. Preliminary efforts had suggested that, not only did the drug do the job, but the effects were positively enormous.
However, in the first large trial of efficacy and safety, a Data Safety Monitoring Board, charged with monitoring ongoing trial safety, terminated the 15,000-participant trial after 550 days into the effort when an excess of deaths were identified among the group taking the experimental drug (59 deaths in control group; 93 deaths in the torcetrapib group). In addition, cardiovascular events were 24% greater in the control group numbered 373 compared to 464 in the torcetrapib group, including a substantially greater number of heart attacks and hospitalizations. Another surprise came in the way of cause of death among some of the torcetrapib patients, with an excess of deaths due to cancers (twice as many in the torcetrapib group), strokes, and infections.
Hopes at first were high for the success of the drug, since interim analysis of the data showed a 72% rise in HDL, ordinarily a notoriously difficult value to increase, along with a further 25% decrease in LDL cholesterol when added to atorvastatin (Lipitor®). Despite these favorable changes, the dangers of the drug were undeniable.
Why the discrepancy: enormous improvements in cholesterol values, yet a serious increase in an array of adverse effects including more heart attack? Some detective work by the principal investigators of the trial uncovered unexpected distortions of electrolytes like sodium and potassium. They then re-analyzed blood samples from participants on both sides of the trial and discovered that participants taking torcetrapib experience a significant rise in the blood pressure hormone, aldosterone. This, they surmised, also likely accounted for the 4 mmHg average rise in blood pressure among those taking the experimental drug. (This is the same pathway that is blocked by blood pressure drugs like ACE inhibitors lisinopril and enalapril.)
Anacetrapib to the rescue?
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