Cholesterol Study Offers Hope for a Bold Therapy. (National Desk)(new study injects new H.D.L. experimental drug and finds significant reductions in coronary-artery plaque) Gina Kolata.

Full Text: COPYRIGHT 2003 The New York Times Company

A small study of heart disease patients testing a hypothesis so improbable its principal investigator says he gave it a one-in-10,000 chance of succeeding has found that just a few treatments with an experimental drug reversed what may be the equivalent of years' worth of plaque in coronary arteries.

The results, published today in the Journal of the American Medical Association, involved just 47 heart attack patients. They were randomly assigned to be infused with one of two concentrations of a substance that mimics high density lipoprotein, or H.D.L., the substance that removes cholesterol from arteries, or to be infused with saline, which served as a control.

After five weekly infusions, those who got the experimental drug had a 4.2 percent decrease in the volume of plaque in their coronary arteries, while those who had saline infusions had if anything a slight increase in their plaque.

In contrast, said Dr. Steven E. Nissen, a Cleveland Clinic cardiologist, who directed the study, the most powerful statins take years to show more modest effects. Statins lower levels of low density lipoproteins, or L.D.L., which deliver cholesterol to the coronary arteries.

Dr. Daniel Rader, a lipid expert at the University of Pennsylvania, also expressed surprise, saying: ''It is amazing. The biggest and by far the most surprising thing is that it can happen so quickly. A weekly infusion? It is surprising enough that it makes us all want to see it replicated in a larger study.''

Dr. Bryan Brewer, chief of the molecular disease branch at the National Heart, Lung and Blood Institute, said, ''No one has ever seen anything like this in this amount of time.''

''Hardening of the arteries takes years and years to develop,'' Dr. Brewer said. ''It was thought that if we initiate therapy to decrease or prevent it, it would probably take years to have an effect. We thought H.D.L. therapy would work, but that it would work in six weeks was something no one anticipated.''

But all the investigators urged caution. This was a single small study that needs to be confirmed. And then there need to be large studies showing that the drug-induced reduction in plaque corresponds to a reduced risk of heart attacks.

Heart disease researchers have long wondered what would happen if they increased people's H.D.L. levels. Many thought it would prevent heart attacks because H.D.L. is associated with a reduced risk of heart disease in epidemiological studies. They were stymied, however, in going further. They knew how to treat L.D.L. and so prevent cholesterol from being delivered to arteries. That was with statins, drugs that lower L.D.L. levels and, studies showed, prevent heart attacks.

Companies tried, Dr. Rader said, looking for a pill to activate the H.D.L. genes. ''That's like a holy grail for the pharmaceutical industry,'' he said. ''It hasn't been found.''

A second, but obvious choice, would be to give people H.D.L., infusing it into their veins. But there was a problem. The idea of giving ordinary H.D.L. was in the public domain and not protected by patent and so companies were uninterested.

There was, however, one patented H.D.L., and Dr. Roger Newton, the president and chief executive of Esperion Therapeutics, of Ann Arbor, Mich., licensed the rights to develop it. Dr. Newton had developed a cholesterol-lowering drug; he was a discoverer of Lipitor, the most prescribed statin in the United States. His goal in forming Esperion in 1998 was to develop H.D.L. therapies.

The story of the patented H.D.L. began more than two decades ago, when Italian investigators reported that about 40 inhabitants of Limone sul Garde, a town in Northern Italy, had extraordinarily low H.D.L. levels, so low they were off the scale. Doctors expected that they would have high rates of heart disease, but, instead, it was reported, they actually seemed to be protected from heart disease and to live unusually long.

''It was one of the strangest paradoxes of medicine,'' Dr. Nissen said.

Eventually, researchers discovered that these people have a mutation in their H.D.L. gene. The H.D.L. they make simply breaks down quickly. They make plenty of it, but it disappears as soon as it is used.

Later, Dr. Rader says, investigators discovered that the villagers' life spans were average for the region.

But, in the meantime, Pharmacia, now owned by Pfizer, had obtained the patent rights to the H.D.L. they make, known as apoA-1Milano. Esperion licensed the rights from Pharmacia, and the research began.

One of the first to study apoA-1Milano was Dr. Prediman K. Shah, who directs the atherosclerosis research center at Cedars Sinai Medical Center. He reported it prevented plaque growth in arteries of rabbits and in mice. At higher doses, it even reversed the accumulation of plaque in mice. It took just six weeks.

''There was still skepticism at this point,'' Dr. Shah said. ''But we were convinced.''

Then he asked how quickly he could see an effect in the mice.

''Holy moly, to our big surprise, within 48 hours what these mice showed,'' he exclaimed. ''The cholesterol content of the plaques had dropped by almost 50 percent. Almost 50 percent of the lipid was gone. And the inflammation had dropped. The plaques had regressed.''

After conducting early tests of the H.D.L. in humans, looking for safety, Esperion approached Dr. Nissen. He had developed a technique, intravascular ultrasound, that involves threading a tiny ultrasound camera into arteries and directly observing plaques and precisely measuring their size. Would he direct a small study using that method to look for the drug's effects on plaque?

Dr. Nissen was dubious. Most studies he participates in go on for two or three years and involve 500 or more subjects to see an effect. This was to last just five weeks and involve about 50 people.

He agreed but the arrangement was that Dr. Newton at Esperion not even see the results until the paper was in press. He saw the data for the first time on Friday.

Dr. Nissen had no financial interests in the company.

When he saw the data, he was stunned. ''The plaques regressed. A lot. More than has been seen with any drug. I almost fell off my seat. This is just so bizarre and unusual.''

''Until now, the paradigm has been to prevent disease by lowering bad cholesterol,'' Dr. Nissen said, referring to L.D.L. lowering. ''If you get the bad cholesterol low enough, the plaques don't build up in the artery walls. This says you can also remove the disease in the wall of the artery.''

There are limitations, noted Dr. Alan R. Tall, an H.D.L. researcher at Columbia University. The main problem is the study's small size. ''It's not a watertight case by any means. But I basically believe it,'' he said. ''I think it's exciting.''

He and others see it as a harbinger of what might become a new heart disease prevention strategy that might involve pills to raise H.D.L. Or perhaps the therapy will remain an infusion, reserved for shrinking plaque in severe cases.

An infusion could have powerful effects, Dr. Rader said. ''You could use it like induction therapy with cancer, hit it real hard, shrink it as much as possible, and then use maintenance therapy to keep it from coming back,'' he noted. ''That's the idea and it's very attractive.''

Dr. Brewer sees it as a proof of principle.

''We've only decreased, roughly, thirty percent of heart attacks for people on statins,'' he said. ''Can we reduce it even further? Our goal would be to decrease it 95 percent, and that is one reason to pursue H.D.L therapy, and that is why the proof of principle is important.''

''We're clearly at the beginning of the field,'' Dr. Brewer said. ''But it's extremely encouraging.''