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PHILADELPHIA — When his brother died of a heart attack in 2004, Michael Shawn Malloy worried he might be next. His father, grandfather and great-grandfather also died of heart-related illnesses. (Graphic: Turning back the clock) So Malloy, 48, a former Philadelphia police officer and father of two, got himself tested. The test found two partly blocked arteries. He volunteered for a trial of a drug, code-named D-4F, at the University of Pennsylvania hospital here. It is one of more than half a dozen pioneering methods being tested to see whether they can clear out arteries. If the research succeeds, any one of the treatments could turn back the clock on decades of cholesterol buildup, without bypass surgery or balloon angioplasty. (Related: Nine factors that affect your heart's health) "It's the next frontier," says Prediman Shah of Cedars Sinai Hospital in Los Angeles, who helped to develop one of the promising new drugs. It is a synthetic version of a protein called apoA-1 Milano, to be sold by Pfizer. Because it is the first drug known to reduce the amount of artery-clogging plaque, it has been likened to Drano drain cleaner. "The next frontier" also is probably the richest potential market in medicine. Seventy million people in the USA alone have heart disease. Heart disease is the nation's leading killer; it accounts for 900,000 heart attacks and strokes each year, the American Heart Association says. Drugs that lower cholesterol and other blood fats are the world's biggest sellers, with nearly $27 billion in sales in 2004, up 12% from the year before, according to the firm IMS Health, which tracks the drug industry. Lipitor leads the pack; it had sales of more than $10 billion and growth of 14% in 2004. Yet Lipitor and other statins, the blockbuster drugs that dramatically lower blood levels of bad cholesterol (LDL), cut heart attacks and strokes by just 30% to 40%. Even in high doses, statins alone can't undo artery disease. "That's the hard, cold reality of the last 15 years of research," says the Cleveland Clinic Foundation's Steven Nissen. "We need more." The new drugs either raise "good" cholesterol (HDL) or try to improve its effectiveness. That's because HDL is a kind of blood-borne barge that hauls fat from the artery wall to the liver for excretion. Studies show that people with high levels of HDL have cleaner arteries and less risk of heart attack. Until recently, only exercise and mega-doses of the vitamin niacin have been shown to boost HDL levels. A prescription form of niacin, Niaspan, by Kos Pharmaceuticals, raises HDL by 15% to 30%, depending on the dose. But many patients can't tolerate niacin's side effects, which include facial hot flashes. Research is on a rollDrug firms are racing to fill the treatment gap: • Pfizer plans to spend a record $800 million to develop an HDL booster called torceptrapib. The company is working separately on a synthetic apoA-1 that's simpler to make than apoA-1 Milano. • Roche is developing a drug, code-named JTT-705, that was discovered by the Japan Tobacco Co. Like Pfizer's torceptrapib, it boosts HDL levels, but it is in a far earlier stage of testing. • A company called Lipid Sciences has developed a method for extracting cholesterol from HDL so that the empty molecule can be reinfused into the bloodstream and reused. The company also is making synthetic apoA-1. • Merck is trying to reduce niacin's side effects. • Researchers also are working on drugs called PPAR and LXR agonists that they hope will pump cholesterol out of artery walls. With research gaining momentum, doctors are gearing up for studies involving thousands of patients. Many studies will rely on a new imaging technology called intravascular ultrasound, or IVUS, that allows researchers to measure the growth or shrinkage of deposits on artery walls. The University of Pennsylvania trial of D-4F, made by Bruin Pharmaceuticals and licensed to Novartis, involves 50 patients with heart disease or diabetes. The drug is easier to make than standard apoA-1 or apoA-1 Milano. And it was cleverly designed with a protein structure that is the mirror image of natural apoA-1. The transformation preserves its effectiveness but fools the digestive tract, which doesn't recognize it as a protein. That way it can be taken orally. Other versions of apoA-1 must be given intravenously or they'd be digested like beef. "When you give D-4F to animals, it dramatically reduces plaque buildup," says lead investigator Daniel Rader. "Now we're asking whether it works in humans." Malloy says he had ample reason to volunteer for the study. He describes himself as a "courageous person" who has shot two gunmen and taken four bullets himself — if not for a misfire, he says, a fifth bullet might have found his heart. But his brother's death from a heart attack terrified him. His brother, Francis, 47,had a wife and three children. "Shooting, being shot, was nothing compared to that," Malloy says. "I was scared to death." If D-4F lives up to its early promise, Malloy says, "I'll be the first Malloy in four generations to live to see his grandchildren." The Milano mystery
The apoA-1 Milano story illustrates how a chance observation can uncover a medical mystery and trigger an explosion of medical research. There's nothing dramatic about Chapter One: Three decades ago an ailing 49-year-old man visited a doctor in the northern Italian village of Limone sul Garda. The doctor found that the villager's HDL of 7 was dangerously low, well below the normal level of 40. His triglycerides, other blood fats linked to heart disease, were 319, more than twice the norm. Despite these ominous signs, his arteries were clear, says Cedars Sinai Hospital's Prediman Shah. Puzzled by the result, the doctor sent the villager to a specialist, Cesare Sirtori, in Milan. The case so intrigued Sirtori that he screened all 1,100 residents of Limone sul Garda to see whether he could find others with similar blood profiles. He found 40 people, all of whom could be traced to common ancestors born in the late 1700s. Their HDL averaged less than 20, half of normal for men and women. The doctor sent blood samples to the Gladstone Institute of Cardiovascular Disease at the University of California-San Francisco. Researchers there found that the villagers had a mutation in HDL's biggest protein, apoA-1. They dubbed the mutant version apoA-1 Milano. Shah infused synthetic apoA-1 Milano into rats and rabbits that were fed fatty food. Plaques in their arteries shrank. During a celebratory dinner in Milan, several researchers decided to form a company called Espirion to develop apoA-1 Milano for use in patients. Roger Newton, the company's new CEO and a developer of Lipitor, recruited the Cleveland Clinic's Nissen to test it. Nissen was picked because he had helped develop IVUS, which allows doctors to peek inside coronary arteries and measure the blockages they find. "I started out by telling my lab team it wouldn't work," Nissen says. "How do you take a disease that has taken decades to develop and reverse it?" Using IVUS in 47 heart patients, he found that just one infusion of apoA-1 Milano a week for five weeks shrank their artery-blocking plaques by more than 4%, the first time that any treatment has melted plaque away. "I just about fell off my chair," Nissen says. The study turned apoA-1 Milano into a billion-dollar molecule. Just days after Nissen published the results in the Journal of the American Medical Association in 2003, the drug goliath Pfizer bought Espirion Therapeutics and apoA-1 for $1.3 billion.
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