A Second Bullet For Cholesterol

Drugmakers are seeking a way to raise the good, not just lower the bad

There is nothing the pharmaceutical industry likes better than a pill that can reduce the risk of disease for millions of people if taken every day. In other words, drugmakers love statins. These cholesterol-lowering medicines, first introduced a decade ago, can cut the risk of heart attack and stroke by a third when taken regularly. As a result, they have become the best-selling drugs in the world, earning billions upon billions for their makers.

But evidence is mounting that lowering bad cholesterol, otherwise known as low-density lipoprotein (LDL) cholesterol, can improve heart health only so much. A just-released study found that upping statin dosages to bring LDL down to extremely low levels offers symptomatic improvement but does not reduce the overall chances of dying from a heart attack.


Something else is needed, and drugmakers are betting that the next new thing could be a drug that raises high-density lipoprotein (HDL) cholesterol, i.e., the "good" cholesterol. Best of all for the drugmakers: HDL drugs would probably be taken in addition to a statin, so they wouldn't cannibalize the industry's cash cows. Pfizer Inc. (PFE ) is confident enough of this two-pronged approach that it is pouring $800 million into the development of a pill that combines an experimental HDL-raising compound with its top-selling statin, Lipitor.

If raising HDL turns out to be as effective as hoped, medicine cabinets all over the world could end up containing a new class of blockbuster drugs. "What LDL was in the 1990s, HDL will be in the new millennium," predicts Dr. Steven E. Nissen, director of the Cleveland Clinic Foundation.

That doesn't mean heart experts have lost their faith in statins. If anything, they say, far more people should be taking these pills, and lowering LDL levels remains an important goal. But statins alone will not end heart disease's reign as the biggest killer in the industrialized world, and drugmakers continue to look for ways to adjust cholesterol levels.


Cholesterol is nothing more than little fat molecules used by all cells as fuel, and labeling them as good or bad is a bit unfair. It is LDL and HDL -- the transporter proteins that carry cholesterol through the blood vessels -- that wear the white or black hats. When cholesterol is attached to LDL (the bad guy), it sticks to vessel walls, where it can harden and turn into dangerous plaque. HDL plays the hero, scouring the artery walls and transporting excess cholesterol away.

Cardiologists are quick to note that there is already a drug on the market, Niaspan, that raises HDL. Kos Pharmaceuticals Inc. (KOSP ) in Cranbury, N.J., has been selling this extended-release form of niacin since 1997, and the company says it currently accounts for about 8% of all prescriptions written by cardiologists. Evidence of Niaspan's effectiveness continues to mount: In a study released in November, Niaspan cleared the buildup of plaque in the arteries of heart-disease patients who had been taking the drug for a year. "That's a very powerful result," says study leader Dr. Allen J. Taylor, director of cardiovascular research at Walter Reed Army Medical Center. "There have been very few interventions that actually reverse plaque buildup."

But Niaspan is far from the blockbuster the drug industry is seeking. Pfizer sold $11 billion worth of Lipitor last year. Niaspan, at a fraction of the price, brought in about $400 million. That's in part because some patients have a hard time tolerating the drug, which causes the face to flush. Coming up with an alternative HDL therapy has not been easy, however. Statins need only to block an enzyme responsible for cholesterol production, giving HDL a fighting chance to keep up with the excess. Boosting HDL productivity is much trickier.

The most advanced research focuses on a molecule that ferries cholesterol from the good HDL to the bad LDL, called cholesteryl ester transfer protein (CETP). Pfizer's HD candidate, which carries the tongue-twisting name torcetrapib, blocks CETP. Pfizer recently reported that its combination torcetrapib-Lipitor pill raised HDL by 44% to 66% in clinical trials involving 500 patients. But the drug also increased blood pressure, a potential problem for a heart drug. To ensure that the drug is both safe and effective, Pfizer says it will test it on a total of 25,000 people, and an approval likely won't be sought before 2007.

Pfizer has already alienated some cardiologists, however, by deciding to bundle torcetrapib with Lipitor. "A lot of people are looking at their decision not to market this as an independent agent as a way of extending their patent on Lipitor," which expires in 2011, complains Dr. Ira S. Nash, associate director of the cardiovascular institute at Mount Sinai Hospital in New York.

Long before that expiration date, other drugmakers will be pushing medicines that have at least some impact on HDL, though that may not be a primary target. Sanofi-Aventis (SNY ), for example, has started promoting the HDL benefits of its weight-loss drug, Acomplia, widely expected to win marketing approval early next year. Acomplia blocks cannabinoid receptors in the brain and fat cells that control appetite, among other things. In clinical trials, it helped obese patients achieve modest weight loss and raised HDL by an average of 20%.

The trial patients who benefited from improved HDL lost 15 pounds on average and reduced their waistlines by 2.7 inches. This loss of abdominal fat, which is loaded with cholesterol, is the likely reason HDL rose, says Jean-Pierre Després of the Quebec Heart Institute at Laval Hospital research center in Ste.-Foy, Que. "There is overwhelming evidence that abdominal fat in particular is a high risk factor with heart disease," he says.

Of course, abdominal fat, and LDL and HDL cholesterol can best be controlled with exercise and diet. But patients rarely comply with lifestyle prescriptives. They don't even comply with their drug prescriptions. As with any chronic disease, studies have found that 50% or more of patients either stop taking statins or don't take them as prescribed, making it difficult to control any kind of cholesterol.

To get around the compliance problem, Avant Immunotherapeutics Inc. (AVAN ), in Needham, Mass., has developed an HDL-boosting vaccine. It sets off an immune reaction to a specific region of CETP, the same protein targeted by Pfizer's drug, but it would be taken only twice a year.

Avant completed safety trials of the vaccine a year ago but does not have the resources to conduct the huge clinical trials needed to win approval. The company says it is talking to Big Pharma companies that would be willing to shoulder the costs, however. With statins as the template, shelling out $800 million to develop an HDL drug may turn out to be a bargain.

By Catherine Arnst

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