The trouble with torcetrapib: Imaging studies shed little light on why HDL-raising drug failed

March 26, 2007

New Orleans, LA - Three new imaging studies have shown that torcetrapib, a novel HDL-raising drug that was recently shown to increase the risk of death and cardiovascular events, failed to halt the progression of atherosclerosis as measured by intravascular ultrasound (IVUS) and carotid intima-media thickness (IMT) [1][2].

Dr John Kastelein

Presenting the results of two carotid IMT studies, known as Rating Atherosclerotic Disease Change by Imaging with a New Cholesteryl-Ester-Transfer Protein Inhibitor (RADIANCE) 1 and 2, at the American College of Cardiology 2007 Scientific Sessions, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), told the press that something "strange" is going on with the novel cholesteryl-ester-transfer-protein (CETP) inhibitor. In all three studies, there were dramatic increases in HDL cholesterol and significant reductions in LDL cholesterol, but this improvement in lipid parameters was offset by significant increases in blood pressure.

"When you focus on the primary end point, there is a striking resemblance to all three imaging trials that actually showed no benefit whatsoever with this drug," said Kastelein.

With an increased risk of cardiovascular events terminating the large torcetrapib morbidity and mortality trial, the neutral imaging studies are good news to investigators who still believe the drug class might eventually come to fruition as an agent to raise HDL-cholesterol levels and combat cardiovascular disease.

"We believe the failure doesn't necessarily rule out the possibility that another drug in the class, one that is completely clean, with no blood-pressure effects and no other evidence of toxicity, could possibly work," said Dr Steven Nissen (Cleveland Clinic, OH), lead author of the IVUS study, a trial known as the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE). "We think that the bar to jump over now has gotten a lot higher, and it's going to be very challenging to move forward, [but] I think we should go forward."

ILLUSTRATE and RADIANCE 1 are published online March 26, 2007 in the New England Journal of Medicine, along with an accompanying editorial by Dr Alan Tall (Columbia University, New York) [3].

RADIANCE 1, 2, and ILLUSTRATE

Dr Steven Nissen

In early December, data from a 15 000-patient morbidity and mortality trial ended all hopes for Pfizer's torcetrapib, although there were red flags raised early with the drug, particularly as numerous reports detailed an increase in blood pressure with the agent. In addition, there were concerns that the mechanism of raising HDL cholesterol with torcetrapib might not work. That mechanism is an inhibition of the CETP, which promotes the transfer of cholesteryl esters from antiatherogenic HDL to apolipoprotein B (apoB)-containing lipoproteins, including very low-density lipoproteins (vLDL), vLDL remnants, and LDL. A deficiency in CETP has been shown to be associated with increased HDL-cholesterol and decreased LDL-cholesterol levels, a typically antiatherogenic profile.

 
We think that the bar to jump over now has gotten a lot higher, and it's going to be very challenging to move forward.
 

While the morbidity and mortality trial was ongoing, investigators conducted three imaging studies to clarify the specific effects of torcetrapib. In the ILLUSTRATE study, 1188 patients with coronary disease were treated with atorvastatin to achieve an LDL-cholesterol level of 100 mg/dL and then randomly assigned to a fixed combination of atorvastatin and torcetrapib 60 mg or atorvastatin monotherapy with placebo. Similarly, in the two-year RADIANCE 1 and 2 studies, patients with familial hypercholesterolemia and mixed hyperlipidemia, respectively, were randomized to treatment with the atorvastatin/torcetrapib combination or atorvastatin alone.

In the ILLUSTRATE trial, when compared with atorvastatin monotherapy, treatment with atorvastatin/torcetrapib was associated with a 61% increase in HDL-cholesterol levels and a 20% decrease in LDL-cholesterol levels. There was, however, a 4.6-mm-Hg increase in blood pressure. Regarding the primary end point, percent atheroma volume, there was no significant difference between the two treatment arms. Regarding a secondary end point, the change in normalized atheroma volume, there was a small favorable effect with torcetrapib, but no significant difference in the change of atheroma volume for the most diseased segment.

 
Obviously, this molecule is dead.
 

In the RADIANCE 1 and 2 studies, torcetrapib again led to dramatic increases of HDL-C and robust decreases of LDL-C but, despite these improvements, had no benefit on atherosclerosis progression. Again, blood pressure was increased, although less than in the ILLUSTRATE trial. An analysis of the common carotid artery, a secondary end point, suggested progression of disease in torcetrapib-treated patients.

Nissen and Kastelein said their groups would continue to analyze the data.


"The bottom line is that in a clinical trial, you can't find out everything in a single study," said Nissen. "Obviously, this molecule is dead, but my view is that we can't slam the door on the class when the only data we have are for a drug that had this very unusual toxicity."

What went wrong with this drug?

Dr James Stein (University of Wisconsin Medical School, Madison, WI), who chaired the late-breaking clinical trials session where the results were presented, told heart wire that these imaging results leave many questions unanswered.

"The big question that every scientist and everybody on Wall Street wants to know is whether or not it was the drug or the approach to raising HDL cholesterol," said Stein. "Is it CETP inhibition or is it something unique to torcetrapib alone? Most people seem to think it's unique to torcetrapib alone, because people who have mutations in the CETP genes don't get high blood pressure. There are also other CETP inhibitors in the pipeline that don't raise blood pressure."

Nissen said the absence of a beneficial effect on progression was particularly striking for the achieved LDL-cholesterol level of 70 mg/dL. As to why the drug failed, he gave three potential reasons: the first is that the CETP-inhibition mechanism did not generate HDL particles that function normally in reverse cholesterol transport. The second is that increases in blood pressure might have counterbalanced any favorable effects of lipid levels. And finally, the increase in blood pressure might reflect a more generalized toxicity that prevents the beneficial effects on progression as well as increases events.

Lead investigator of the torcetrapib morbidity and mortality trial that was stopped, Dr Philip Barter (Heart Research Institute, Sydney, Australia), echoed the general sentiment that the imaging studies provide very few easy answers.

 
But the big question that every scientist and everybody on Wall Street wants to know is whether or not it was the drug or the approach to raising HDL cholesterol.
 

"There are some things that you can say absolutely," Barter told heart wire . "One is that torcetrapib does not work. But these data today don't give any clue why there was an excess of mortality in the morbidity and mortality trial. My take on the data is that they confirm the fact that torcetrapib is not a good drug, but they don't tell us anything about the mechanism of the excess mortality."

Barter believes there is an off-target effect of torcetrapib, of which blood-pressure elevation is one manifestation, resulting in a generalized vascular toxicity. Had the imaging studies shown progression, that would have almost been the death knell for the drug class, said Barter. Also speaking with heart wire , Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) said the data are good news for imaging proponents, especially as the study results line up with the findings from the morbidity and mortality trial.

"These studies allow us to maintain our enthusiasm for using carotid IMT and intravascular ultrasound for the development of other new classes of drugs coming down the pike," he said. "They seem to go along well with the clinical outcome we saw with torcetrapib."

 
CETP inhibition is still an interesting approach, but I think it's less promising than it was before.
 

Stein, however, had a different interpretation of the data. With one secondary IVUS end point in ILLUSTRATE showing an improvement with torcetrapib, he contends that carotid IMT is a more reliable surrogate marker of coronary risk. He also told heart wire that he would have liked to have the investigators adjust for blood-pressure changes in their analyses to better tease out what is causing the adverse cardiovascular events. Without researchers being able to answer the question of whether it is the drug or the mechanism, other agents remain in limbo as companies struggle with development, he said.

"I think the FDA is going to dramatically raise the hurdle and is going to require specific studies looking at blood pressure alone, specific studies looking at progression, and it's also possible that new drugs won't get approved unless they show cardiac-event reduction," said Stein. "CETP inhibition is still an interesting approach, but I think it's less promising than it was before."

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