Washington Editor

Final heart study results continued to prove the ability of AtheroGenics Inc.'s product to reverse atherosclerotic plaque, but shares in the company dropped by 15.5 percent, as the findings weren't as positive as strong interim data seen in September.

Called CART-2, the Phase IIb trial met its primary endpoint, a measure of the change in coronary atherosclerosis as demonstrated by total plaque volume after a 12-month treatment period with AGI-1067 compared to baseline values. Combined results of the final analysis, conducted by the Montreal Heart Institute and the Cleveland Clinic Foundation, indicated that the drug reduced plaque volume by an average of 3.9 cubic millimeters, or 2.3 percent (p=0.0015). The findings stem from testing in 233 patients.

But AGI-1067's regression figures aren't as high as corresponding data reported two months ago following an interim analysis, in which patients taking AGI-1067 with other medications had a reduction in plaque volume by an average of 6.4 cubic millimeters, or 3.8 percent (p<0.0003). Those data, which stem from testing in fewer patients, sent the company's stock up 64 percent on the day they were released. (See BioWorld Today, Sept. 29, 2004.)

In contrast, on Monday the Atlanta-based company's stock (NASDAQ:AGIX) dropped $4.87 to close at $26.50.

"I really was a little surprised and disappointed to see that," said Mark Colonnese, AtheroGenics' chief financial officer. Colonnese said the data "validate the company's technology platform," and are "positive news that enhances the probability of success with our Phase III program."

He added that the final data line up in a similar fashion to the interim data set.

For example, results in another endpoint, while not statistically significant, showed that the use of AGI-1067 produced a minor reduction in plaque volume of 1.5 cubic millimeters, or 0.8 percent, compared to the standard of care (p=0.45). Also in the final analysis, while the plaque regression observed in the AGI-1067 group exceeded that observed in the standard-of-care group numerically, the difference did not reach statistical significance (p=0.29). But a trend toward significance (p=0.12) was seen in analysis by the Montreal Heart Institute.

Like the AGI-1067 vs. baseline comparison, the AGI-1067 vs. standard-of-care plaque volume data were less than what was reported two months ago. At that time, the interim data revealed a reduction in plaque volume of 3.5 cubic millimeters, or 2 percent, compared to the standard of care.

That also was the case in the most severely diseased 5 mm subsegment, in which patients' plaque volume regressed from baseline by a statistically significant average of 1.8 cubic millimeters, or 4.8 percent (p<0.0001). But again, those figures were lower than the data reported two months ago that showed a regression from baseline by an average of 2.7 cubic millimeters, or 7.1 percent.

"The numbers are lower, but this was a randomized sample," Colonnese said. "When we presented the interim analysis, that was the random sample set that was available at that time. This is the final analysis, so I think that's just indicative that everything is done randomly."

Treatment with AGI-1067 also produced a statistically significant reduction in levels of myeloperoxidase, an inflammatory biomarker that correlates with future cardiovascular events. All AGI-1067 patients received a 280-mg dose once per day, plus standard of care. Plaque volume was measured at the time of angioplasty and again at the end of one year using intravascular ultrasound.

"This is the first anti-inflammatory drug designed to treat coronary disease," Colonnese said. "No other drugs out there today have that mechanism."

He added that a number of other recent trials with widely prescribed cardiology drugs, such as Lipitor, Zocor and Norvasc, showed that they managed to halt or slow the progression of plaque volume, but were unable to reverse it.

The oral compound is designed to selectively block signaling pathways within endothelial cells that make up the inner lining of blood vessels, which in turn inhibits the production of VCAM-1 and other molecules involved in the inflammatory process.

AGI-1067 already has entered pivotal testing in the ARISE study, an ongoing, 4,000-patient trial, to test its ability to reduce clinical events such as cardiac deaths, heart attacks and strokes in patients who have had a heart attack within the last year. The trial is about a year into enrollment, and Colonnese said the company hopes to complete it and report data by the end of next year. The company said the study reached its target of 4,000 patients, though it plans to continue enrollment so as to accelerate the accumulation of patient years of exposure on the drug.

It is evaluating a 300-mg dose, which would be used commercially should the product receive FDA approval down the road. With an eye toward such prospects, AtheroGenics continues to discuss potential partnerships.

"Yes, those discussions are active," Colonnese said.