possible new heart drug

Cleveland Clinic Foundation Heart Center - Print version
November 5 , 2003

BREAKING NEWS: "Super HDL" Reverses Atherosclerois
Extraordinary results of Cleveland Clinic-led study may be a "paradigm shift" in treatment of America's most deadly ailment.

Do 40 people in a small village in rural Italy hold the key to reversing plaque buildup in coronary arteries? A new study appearing in the Nov. 5 edition of the Journal of the American Medical Association* provides strong evidence that five weekly infusions of a synthetic form of “good cholesterol,” or HDL, can remove significant amounts of plaque from these arteries.

“This is an extraordinary and unprecedented finding,” said Cleveland Clinic cardiologist Steven E. Nissen, M.D., who directed the 10-center nationwide study. “This is the first convincing demonstration that targeting HDL, good cholesterol, can benefit patients with heart disease, the leading cause of death in the United States.”

The development of this investigational drug is an unusual story. About 30 years ago, researchers discovered 40 individuals in Limone Sul Garda in Northern Italy who appeared perfectly healthy, despite having very low levels of good cholesterol. Ordinarily, such people would have a high risk of heart disease, but these people did not. Intrigued, researchers wanted to find out why. Their studies revealed a variant in a protein known as Apolipoprotein A-I, which is a component of HDL. This variant was named ApoA-I Milano after the city of Milan, where the initial laboratory work was done.

ApoA-I Milano is being developed into a potential treatment for heart disease by Esperion Therapeutics Inc., an Ann Arbor, Mich.-based biopharmaceutical company. Esperion’s investigational treatment, designated ETC-216, is a recombinant version of ApoA-I Milano combined with a phospholipid. After pre-clinical studies showed rapid removal of plaques from diseased arteries, scientists at Esperion came to Dr. Nissen to help them design a study to determine whether infusions of the ApoA-I Milano/phospholipid complex could reverse coronary plaque buildup in patients with heart disease.

The Cleveland Clinic-directed study administered the ApoA-I Milano/phospholipid complex intravenously over a five-week period to a randomized group of patients initially hospitalized for acute chest pain. Researchers measured arterial plaques using intravascular ultrasound (IVUS) before and after the six-week study. Patients who were given the synthetic protein showed a dramatic decrease in arterial plaques, whereas a comparison group given saline showed no change in plaques.

Atherosclerosis, sometimes known as “hardening of the arteries,” is the process by which fatty deposits build up on the inner lining of artery walls, creating plaques. These plaques can grow large enough to significantly reduce blood flow. If the plaques rupture, they can cut off blood flow to vital organs, including the heart, causing heart attacks.

Traditional therapies for atherosclerosis focus on lowering levels of “bad” cholesterol, known as LDL. Although high levels of HDL have been shown to be beneficial, the clinical significance of targeting HDL therapeutically was unknown. This trial sought to test that possibility.

Dr. Nissen cautions that, “Much more testing needs to be performed to determine whether this unique form of HDL can be used routinely to treat patients with atherosclerosis.” He emphasized that the current clinical trial was a small “proof of concept” study, designed only to demonstrate the potential of this new therapy.

“People should not view new therapies as a ‘magic-bullet’ cure. For most of us, medicines will never replace the need to make healthy lifestyle choices,” Nissen said.

“Nonetheless, this study represents a paradigm shift,” he continued, “offering new hope for a devastating and common disease. We now know that it is possible to actively remove cholesterol plaques from the coronary arteries with drugs. I am confident that eventually this approach will make a significant difference in the care of patients with coronary heart disease.”

Study Details

The ApoA-I Milano trial involved 57 acute coronary syndrome patients in a randomized, prospective, double-blind, multicenter clinical trial conducted from November 2001 to March 2003. All patients had experienced an acute coronary syndrome, either unstable angina (severe chest pain) or heart attack. Each patient had a single coronary artery examined using IVUS within two weeks following the cardiac event.

IVUS technology gives doctors the ability to visualize coronary plaques using high-frequency sound waves. The procedure is performed along with cardiac catheterization. Doctors are able to see detailed images of the interior walls of the arteries and precisely measure the size of the plaques inside the artery.

Patients were randomized to three treatment groups — placebo, low dose or high dose of intravenous recombinant ApoA-I Milano/phospholipid complex. The study drug was administered as a weekly intravenous infusion for a total of five weeks. Patients underwent IVUS of the originally imaged coronary artery for a second time within two weeks following the final infusion. The second images then were compared with baseline images to compare plaque levels. Researchers found a statistically significant change in volume of the thickened, fatty lining inside the arteries of patients who had received either the high or the low dose of intravenous recombinant ApoA-I Milano/phospholipid complex.

The trial was conducted in 10 community and tertiary care hospitals throughout the United States. Researchers at The Cleveland Clinic reviewed all IVUS examinations without knowing which patients had received which type of infusion. Esperion Therapeutics* funded this study.


*a new browser window will open with this link. The inclusion of links to other web sites does not imply any endorsement of the material on the web sites or any association with their operators

©Cleveland Clinic Foundation 11/03


Original article: [www.clevelandclinic.org]

Jerry:
Thanks! Very interesting. I had heard vague descriptions of this trial, but nothing concrete. Sounds very hopeful.

Pam