Questions Linger on Pfizer Drug

A new study doesn't explain why torcetrapib failed a trial.
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A new study of a cholesterol drug recently abandoned by

Pfizer

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doesn't answer the question of why the compound failed or whether similar experimental drugs will be successful.

"The lack of efficacy may be related to the mechanism of this drug class or to molecule-specific adverse events," says the Pfizer-sponsored research that was unveiled at the annual meeting of the American College of Cardiology.

The drug is torcetrapib, which Pfizer had hoped would be the successor to Lipitor, the world's best-selling drug and a contributor of $12.9 billion, or 27%, of last year's corporate revenue.

But Pfizer

canceled work on the drug in early December after the company said a clinical trial showed that patients receiving torcetrapib plus Lipitor had a higher-than-expected death rate than patients receiving Lipitor alone.

Pfizer executives were hard-pressed to explain what happened in the 15,000-patient test, whose full results won't be available until later this year. Monday's results of another clinical trial of nearly 1,200 patients only offered possible scenarios.

The latest research found that torcetrapib plus Lipitor failed to significantly reduce the buildup of artery-clogging plaque when compared with Lipitor alone. Patients were tested for 24 months.

As in the larger clinical trial, researchers found that torcetrapib raised patients' blood pressure, lowered so-called bad cholesterol and raised good cholesterol. The research was posted online by

The New England Journal of Medicine

, in advance of publication in its March 29 issue.

The study's authors also told companies working on similar drugs, known as CETP inhibitors, that the Pfizer experience doesn't automatically translate into bad news for their research efforts.

"Given the potential importance" of finding new drugs to raise good cholesterol levels, "it would seem imprudent to abandon studies of CETP inhibition," especially because similar drugs don't appear to raise blood pressure.

Merck

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and Switzerland's

Roche

are developing CETP inhibitors, and they are in the process of deciding whether to move from midstage clinical testing to the third round of human tests.

Phase III testing is the most extensive and expensive clinical trial, and it represents the last clinical research before a drug is submitted to regulators.

CETP stands for cholesteryl ester transfer protein, an enzyme that affects the balance of good cholesterol and bad cholesterol. By inhibiting this enzyme, researchers believe they can tilt the balance in favor of good cholesterol.

Researchers have been looking at ways to raise good cholesterol as to augment the bad cholesterol-lowering ability of statin drugs such as Lipitor.

"Twenty years after the introduction of statins, we are still waiting for the next breakthrough," says the

New England Journal of Medicine

article. The lead author is cardiologist Dr. Steven Nissen of the Cleveland Clinic.

Nissen and fellow authors say "careful consideration" should be given to the theory that good cholesterol produced by the Pfizer drug was "dysfunctional," causing some of the side effects. It's also possible, they say, that the Pfizer drug molecule had "unique" toxic effects.

"It is difficult to determine the extent to which the failure of torcetrapib was the result of dysfunctional

good cholesterol, properties that increased blood pressure, or other toxic effects specific to this agent," the authors say.

CETP inhibitors work differently than several other good-cholesterol-raising drugs on the market, including Niaspan, an extended release form of niacin, and TriCor. Both are sold by

Abbott

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.

The

New England Journal

says TriCor and similar drugs can raise good cholesterol "modestly," usually by 7% to 15% vs. the 61% gain for torcetrapib. The journal says large doses of niacin can raise good cholesterol by 25% or more, but this compound can cause flushing of the skin, occasional liver toxicity and an increase in blood-sugar levels.