Study: torcetrapib ills not class effect

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A Pfizer analysis released this week brought new hope to a class of drugs designed to clear arteries by boosting the protective form of cholesterol. The findings could help firms like Roche and Merck determine whether to continue developing similar agents.

"We're begining to get  a clear picture, but additional studies need to be done," Merck spokesman Ron Rogers told MM&M regarding the firm's own lipid program, which has been somewhat in limbo. "The new Pfizer data need to be evaluated. The company will do that and some additional, ongoing expeirments, and the company will make a decision."

The study, called Illuminate, had been canceled by Pfizer last year after independent reviewers noticed a surprisingly high number of deaths in the cohort of patients taking the experimental agent along with Lipitor. It contains a record of what really happened with torcetrapib, a so-called CETP inhibitor that cost Pfizer $1 billion to develop.

Since Illuminate was canceled, a veil of secrecy has surrounded torcetrapib and the reasons behind its failure. A study of 910 patients released last March, called Illustrate, added to the mystery as it seemed to show the drug had no benefit.

The study released Monday at the American Heart Association meeting involved 15,000 patients. It showed that torcetrapib's mechanism of action actually reduces atherosclerosis. That finding was significant, as some thought leaders and physicians had speculated that inhibition of CETP may lead to a kind of dysfunctional HDL.

Another finding was equally encouraging: torcetrapib raised levels of adrenal hormones known to boost fatty plaque formation and blood pressure, an “off-target” effect which may have been responsible for the increase in deaths. Forty patients taking torceptrapib died of causes other than heart disease.

Some had feared that the same glitch that felled torcetrapib would doom the entire CETP field, but the newly released data appeared to assuage that fear. The Cleveland Clinic's Steven Nissen, MD, who led the Illustrate trial, told Bloomberg News that torcetrapib “has a bizarre, off-target toxicity that caused it to produce harm and concealed the benefit” of raising good cholesterol. “Now there's a race on. We can get back on the horse and try again.”

Those looking to get back in the saddle could include Roche, whose R1658 was shelved in Phase II. Merck's HDL drug anacetrapib (formerly MK-0859) was suspended after a Phase IIb study showed it reduced LDL and raised HDL. Anacetrapib appears to raise HDL levels by 140% without the unsavory effect on the adrenal gland, according to data from that trial which Merck shared with USA Today.

To move ahead, companies will need to determine the reasons behind the adrenal toxicity. The off-target effect doesn't explain the rapid increase in blood pressure seen with torcetrapib. In other data read at the cardiology meeting, Merck and Pfizer presented preclinical studies showing torcetrapib increased blood pressure and had a three-fold increase in aldosterone. Anacetrapib showed none of those effects.

Before its development was stopped, analysts had forecast $15 billion in worldwide annual sales for torcetrapib.

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