Swelling Hope for a Heart Drug


By Catherine Arnst In the 17 years since statins first reached the market, they have had a huge impact on heart disease. Statins block a liver enzyme that's key to producing so-called bad (LDL) cholesterol, and they can lower the risk of a heart attack or stroke in an individual patient by as much as 40%. It's no wonder that the five statins now on the market are the best-selling drugs in the world. But to cardiologists, they still aren't good enough.

Heart disease remains the No. 1 killer in the industrialized world and is responsible for 1 in every 2.6 deaths, despite doctors having written hundreds of millions of statin prescriptions. Some 64.4 million Americans, or 23% of the population, suffer from cardiovascular disease. About half of these patients don't have high cholesterol, so they would never have been prescribed a statin in the first place. Even the large numbers of patients who are asympomatic and have normal cholesterol suffer a heart attack or stroke each year.

IDENTIFYING TRIGGERS. Scientists now know it's not the cholesterol killing patients, but their own immune systems. Atherosclerosis, the underlying disease that causes most heart attacks and strokes, occurs when the fatty deposits of cholesterol, called plaque, build up in the arteries. Researchers discovered about a decade ago that these deposits set off inflammation -- the immune system's major weapon against foreign invaders in the body -- and that's when things turn dangerous.

The inflamed arteries swell up around the plaque and eventually squeeze the plaque until it bursts, sending out a deadly particle, called a clot, that can block the flow of blood to the heart. Consequently, a great deal of recent drug development in cardiovascular disease has centered on stopping inflammation. To do that, scientists have to identify the cellular triggers that prompt the immune system to go after the plaque in the first place.

One of the more promising of these triggers is Lp-PLA2, an enzyme believed to activate a cascade of inflammatory reactions. Lp-PLA2 processes LDL cholesterol into plaque and then produces cellular signals within the plaque that prompts inflammation. GlaxoSmithkline (GSK) discovered the enzyme in collaboration with Human Genome Sciences (HGSI), and now has a promising drug in development, called 480848, that blocks the enzyme before it can do any damage. Glaxo plans to start Phase III clinical trials of this drug next year and may be ready to seek Food & Drug Administration approval by 2009, according to Dr. Lawson Macartney, head of cardiovascular medicine development for Glaxo.

STROKE ALARMS. In the meantime, the presence of Lp-PLA2 may become a widely used early warning signal of stroke. At the American Heart Assn., Scientific Sessions, an important medical meeting held Nov. 7-10 in New Orleans, researchers presented a study showing that elevated levels of Lp-PLA2 in the blood significantly indicate an increased risk of stroke. Indeed, the enzyme was a far better predictor of stroke than cholesterol levels.

The trial followed 15,592 participants between the ages of 45 and 64 for six years, regularly measuring their blood levels of Lp-PLA2, cholesterol, and C-reactive protein, another enzyme that's implicated in heart disease. They found that those with high levels of Lp-PLA2 had a significantly increased risk of stroke, even if their cholesterol and C-reactive levels weren't elevated. Higher Lp-PLA2 blood levels could predict stroke better than traditional risk factors as blood pressure, smoking status, and the presence of diabetes.

Dr. Christie M. Ballantyne, director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine and lead investigator of the study, says these most recent results confirm earlier studies and lend support to making a test for Lp-PLA2 levels routine for patients who might be at risk of stroke by virtue of age, lifestyle, or family history.

"COMPELLING" DATA. A blood test for the enzyme already exists. Called PLAC, it's made by diaDexus, a privately held company in San Francisco, and won FDA approval in July, 2003. The procedure isn't widely used right now, says Ballantyne, in part because doctors already conduct many tests for heart disease. But he notes the new study's "very compelling" data linking Lp-PLA2 to stroke could help popularize the test.

The data also bolster efforts to develop drugs that target not only Lp-PLA2 but other inflammatory triggers as well. The healthcare consultancy Medtech Insight recently issued a report predicting that promising anti-atherosclerosis drugs could start to emerge by 2006 and will eventually match the success of the current statins. At that point, heart disease might finally lose its place as the nation's top killer. Arnst is BusinessWeek's medical writer


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