Pfizer illustrates torcetrapib failure

The first of two articles published online on the New England Journal of Medicine website provided evidence that Pfizer's drug, torcetrapib, actually increased disease progression during a clinical trial.

The second article, discussing a different trial, showed that torcetrapib did not stall the progression of atherosclerosis in coronary arteries.

Both trials also reported a significant increase in systolic blood pressure.

Other pharma companies working on similar drugs to torcetrapib will be keen to find out as much as possible about the drug's failure, before deciding whether to pursue their own development programmes.

"The results will be pretty interesting.

They won't do much for torcetrapib but they will help people understand where to go next in heart disease," said Pfizer research and development chief John LaMattina at a recent conference.

"There will still be a lot of questions that need answering," he said.

"Is it a class effect?

Is HDL overrated?"

The failure of torcetrapib was also a major blow for Pfizer - the drug was touted as a key foundation for Pfizer's cholesterol business.

It would have been prescribed in combination with Lipitor (atorvastatin) - the world's best selling drug by far.

Lipitor reduces low density lipoprotein (LDL) - or bad cholesterol - and the two together would allow Pfizer to defend its franchise in the build up to patent expiry in 2010.

High levels of LDL and low levels of high density lipoprotein (HDL), or good cholesterol, have been linked to increased heart disease and strokes.

HDL is thought to remove cholesterol from plaques in arteries and transport it to the liver, where it is excreted or reused.

This process is mediated by cholesteryl ester transfer protein (CETP), the target torcetrapib was designed to block.

In this way, the drug was designed to increase levels of good cholesterol.

Pfizer wasn't the only ones looking at this target.

Roche and Japan Tobacco are collaborating on R1658, a small molecule CETP inhibitor designed to treat dyslipidaemia.

Merck & Co has also been rumoured by industry analysts to be developing a CETP inhibitor.

The ILLUSTRATE trial studied over a thousand patients treated for two years with torcetrapib and Lipitor, compared to Lipitor alone.

Most importantly, although the size of plaques decreased by 50 per cent compared to Lipitor alone, the percentage of the blood vessel occupied by the plaques only decreased by 37 per cent.

This could suggest the blood vessel also shrank during the trial.

The results were obtained using ultrasound probes.

The second trial (RADIANCE 1) looked at the effect of torcetrapib in patients who have abnormally high levels of cholesterol.

These patients were chosen as it was thought any positive effects of the drug would be particularly noticeable, according to the clinicians.

However, there was no change in the maximum thickness of the artery wall, indicating torcetrapib did not reduce atherosclerosis.

Startlingly, torcetrapib was also associated with disease progression, as assessed by the average change in artery thickness over a year.

In both trials, the poor results run counter intuitively to significant reductions in LDL levels and up to a 60 per cent increase in HDL levels.

Both trials also showed torcetrapib significantly increased blood pressure.

One possible explanation for the poor results, in light of some positive data, is that torcetrapib also interacts with other proteins and reactions as well as CETP.

Such off-target effects are often the cause of side-effects in drug therapy.

For example, the drug may activate the renin-angiotensin system or damage blood vessels in other ways, according to Dr Alan Tall, from Columbia University in New York.

In an editorial in the journal, which discusses the ILLUSTRATE trial, he wrote that there is still a "glimmer of hope for this class of drugs" .

Although not the actual ILLUMINATE trial which led to Pfizer's torcetrapib being scrapped, the results from both trials are due in print in the journal on 29 March and 19 April.

"A deeper understanding of the different function of HDL and their associated biomarkers is badly needed," Dr Tall concluded.

So it seems that other pharma companies developing CETP inhibitors don't need to pull the plug just yet.