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Cholesterol Remains a Sticky Foe

Recent experimental-drug trials have failed to inspire hope.

It was a bad week for good cholesterol.

Test results on several experimental products were released at a recent cardiology conference, and a number of the drugs were ineffective or disappointing.

That means companies such as


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Eli Lilly

(LLY) - Get Eli Lilly and Company (LLY) Report



(AZN) - Get Astrazeneca PLC Sponsored ADR Report

have to decide if they want to spend hundreds of millions of more dollars on new tests.

The stakes are high, but so are the potential rewards. Companies are looking for additional ways to prevent heart disease caused by plaque-clogged arteries. A standard of care is the class of drugs known as statins -- Pfizer's Lipitor and AstraZeneca's Crestor among them -- that reduce low-density lipoprotein, or LDL, the so-called bad cholesterol.

The logical new-drug target is good cholesterol, or high-density lipoprotein. However, raising HDL isn't easy, and the handful of marketed HDL drugs offer modest gains or present unpleasant side effects that hamper their sales.

As doctors, drugmakers and investors learned from the American College of Cardiology meeting March 24 through 27, new effective and safe HDL medications are elusive targets.

For Pfizer, the answer regarding torcetrapib was clear. The

disappointing results of a new study, released March 26, simply provided a footnote to the company's December decision to cancel the drug.

Torcetrapib did a great job of raising HDL, but the latest test findings show that the compound plus Lipitor didn't do any better than Lipitor alone in reducing arterial plaque.


halted work on the product late last year when another study revealed that patients taking torcetrapib and Lipitor had a higher death rate than those taking just Lipitor. Pfizer spent more than $800 million in developing torcetrapib.

A spokeswoman said Thursday that Pfizer hasn't decided if it will continue working on two other compounds in the same class of drugs known as CETP inhibitors. Both are in the early stages of clinical testing.

In that regard it isn't alone. Other companies working on CETP inhibitors include


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. What has to be determined is whether Pfizer's failure highlights a weakness for the whole class or if torcetrapib was a special case.

Authors of the latest torcetrapib study say raising HDL is too important for companies to abandon work on other CETP inhibitors. An editorial in the

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New England Journal of Medicine

, where the Pfizer-sponsored research was published, referred to a "glimmer of hope" for future work on CETP inhibitors.

It's uncertain if there's a glimmer of hope for a Lilly drug that seeks to raise good cholesterol through a different approach than torcetrapib. Two clinical-trial results, reported at the cardiology conference, revealed that Lilly's drug didn't do a better job than


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veteran TriCor in raising HDL, even though Lilly's drug is 10,000 times stronger.

TriCor reduces blood fats known as triglycerides and raises HDL.

In one test, the Lilly medication raised levels of bad cholesterol. Also, both drugs were found to increase levels of serum creatinine, an early warning for potential kidney problems. The Lilly-sponsored research was published in the

Journal of the American Medical Association.

The Lilly drug, licensed from

Ligand Pharmaceuticals


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, was in the second of three phases of clinical trials. Lilly suspended research in September "to assess unexpected findings noted during animal safety studies" and review clinical data already gathered, according to a filing with the

Securities and Exchange Commission


A Lilly spokeswoman said this week that the company will consider "future development options" after analyzing the data. Lilly's compound belongs to a group of drugs known as PPAR-alpha agonists, which includes TriCor and the generic gemfibrozil.

Another type of heart-disease drug has AstraZeneca debating if it wants to take a chance -- and spend a lot more money -- on its collaboration with




The AtheroGenics drug AGI-1067 is designed to reduce arterial plaque, but it isn't an HDL-raising compound. However, recently-released test results show that the drug actually lowered good cholesterol and raised bad cholesterol.

The drug failed to meet its primary goal of significantly reducing the risk of death, heart attack, nonfatal stroke and other heart-disease indicators when compared with a placebo.

AtheroGenics says there's

enough positive information to continue testing, but investors aren't encouraged. The stock is off 66% since the company announced the test results on March 19, just before the cardiology conference.

AstraZeneca has said only that, under terms of the marketing agreement, it can make a decision within 45 days after reviewing the data. Although AstraZeneca has made a $50 million upfront payment based on a marketing deal signed in late 2005, the big payments to AtheroGenics depend on AGI-1067 meeting research and sales goals.

One of those, worth $300 million, is linked to the latest clinical trial. AstraZeneca would pay another $650 million depending on sales goals achieved by the heart drug, as well as sales-based royalties.

AstraZeneca faces a tough call because it has been burned by several expensive failures in recent years involving experimental drugs for treating diabetes, preventing blood clots and reducing the risk of stroke.

Some analysts believe AstraZeneca will cancel its arrangement with AtheroGenics even though the drug giant's near-term R&D pipeline is weak. If AstraZeneca walks away, its next heart hope will focus on a deal with Abbott to combine an updated version of TriCor with Crestor.