AtheroGenics Inc. continues its push to forge a new path in the treatment of heart disease.

The Atlanta-based company began a pivotal Phase III trial of AGI-1067, its oral anti-inflammatory drug candidate to treat atherosclerosis in coronary heart disease patients.

"This is the hot ticket," Russell Medford, AtheroGenics' president and CEO, as well as a cardiologist, told BioWorld Today. "In the field of cardiology and in new therapies for heart disease, inflammation is front and center. Our ability to treat this disease as an inflammatory disease is an exciting possibility. It's exciting to have potentially a new class of therapy to treat the major killer in the U.S."

AGI-1067 is the first in a new class of drugs known as vascular protectants designed to block the expression of VCAM-1, or vascular cell adhesion molecule-1. The compound works to reduce inflammation in blood vessel walls - a direct cause of atherosclerosis.

The ARISE (Aggressive Reduction of Inflammation Stops Events) trial will be conducted in 160 U.S., Canadian and South African cardiac centers to evaluate AGI-1067's impact on a variety of outcomes, such as death due to coronary disease, myocardial infarction, stroke, coronary revascularization and unstable angina in coronary heart disease patients. The study is designed to assess the incremental benefits of AGI-1067 to standards of care, meaning all 4,000 patients in the trial, including those on placebo, also will receive additional heart disease medications - statins and other cholesterol-lowering therapies, high blood pressure medications and anti-clotting agents. ARISE will follow its patients for an average of 18 months or until a minimum of 1,160 primary events have occurred.

"This trial looks at a number of clinical events that one would expect to have as complications of a patient with active coronary disease," Medford said. "If one has a diagnosis of coronary artery disease, one is at an increased risk of developing a series of events such as another heart attack within a year, dying within a year, having to undergo revascularization and being hospitalized. Also, because of the tight association of atherosclerosis in the coronary and cerebral circulation, your risk of a stroke is higher as well."

AtheroGenics said no medications exist to directly treat the underlying chronic inflammation of atherosclerosis. Likening the inflammation associated with coronary disease to arthritis of the blood vessel, Medford said the benefits of such therapy could have wide-reaching effects on the nearly 14 million coronary heart disease patients in the U.S. He said a similar number of Europeans also suffer from the disease.

"For the first time we're going to be targeting the underlying cause of atherosclerosis in coronary disease, which would be an important new type of therapeutic approach that initially would be very complementary to everything we're doing now - the use of statins to lower cholesterol, the use of antihypertensives to lower blood pressure," Medford said. "All of these things are important in reducing your risk of coronary disease and progression of disease. But we've learned that these risk factors all share a final common pathway - they all induce this inflammatory response in the blood vessel that leads to growth of atherosclerotic plaque, its destabilization and the cause of myocardial infarction."

Results from AtheroGenics' Phase II trial called CART-1 (Canadian Antioxidant Restenosis Trial-1) suggested that AGI-1067 had a direct anti-atherosclerotic effect on the coronary blood vessels, which included improvements in lumen volume, plaque volume and total vessel volume. CART-1 also demonstrated that AGI-1067 was well tolerated with no increase in adverse effects vs. placebo.

The compound had been developed in collaboration with Kenilworth, N.J.-based Schering-Plough Corp. until a little more than a year ago. AtheroGenics, which reacquired the small molecule's full rights, said the move was designed to allow it to more rapidly develop AGI-1067. (See BioWorld Today, Oct. 8, 2001.)

AtheroGenics originally projected the deal could generate $198 million. Schering-Plough had assumed development costs and received worldwide rights to develop, manufacture and market the compound to treat and prevent restenosis in patients following angioplasty. Schering-Plough also gained rights to the drug for all indications, as well as other agents in a library of vascular protectant compounds. (See BioWorld Today, Oct. 29, 1999.)

AtheroGenics continues to seek partnership opportunities for AGI-1067.

AtheroGenics features three other drug programs in clinical development, all of which have been discovered and developed internally. AGIX-4207, the second clinical compound derived from its vascular protectant technology platform, is an oral agent being tested in a Phase II program to treat rheumatoid arthritis. AGIX-4207 IV is an intravenous rheumatoid arthritis treatment that has completed a Phase I study. AGI-1096 is an oral agent that has completed a Phase I trial to prevent organ transplant rejection.

Medford said the coming year also would bring news of a second-generation vascular protectant, an oral chronic asthma therapy still in preclinical development.

AtheroGenics' stock (NASDAQ:AGIX) closed Tuesday at $7.62, up 22 cents.