AtheroGenics Inc. saw its share value skyrocket on positive clinical trial results that revealed its lead drug candidate cut plaque buildup in heart disease patients.

Findings from the Phase IIb study showed a statistically significant plaque regression in those treated with AGI-1067, an oral compound designed to selectively block the inflammatory process in atherosclerosis, compared to the current standard of care. On that news, reported late Monday during the UBS Global Life Sciences conference in New York, the company's stock (NASDAQ:AGIX) gained 64.1 percent Tuesday, or $14.84, to close at $38.

The primary endpoint of the trial, called CART-2, was a change in coronary atherosclerosis as measured by total plaque volume after a 12-month treatment period compared to baseline values. Results of an interim analysis indicate that patients taking AGI-1067 on top of other medications showed a reduction in plaque volume by an average of 6.4 cubic millimeters, or 3.8 percent, which was a statistically significant difference (p<0.0003). By contrast, patients taking only standard-care medications did not show a statistically significant change from baseline.

"This is the first drug that's been developed to target inflammation in atherosclerosis, so it's a brand-new approach for the treatment of heart disease," AtheroGenics President and CEO Russell Medford told BioWorld Today. "We have no drugs on the market that deal with this major driver for atherosclerosis. The promise of AGI-1067 is that we may be able to break through the limitations that we see with the current standard of care - lipid-lowering agents, for example - and go beyond the inhibition of progression of the disease, to perhaps regression of atherosclerosis."

A secondary endpoint from the study's final analysis, to be released later this year, will examine whether there is a statistical significance between patients treated with AGI-1067 vs. those on standard care alone. The one-year study included 467 patients.

A secondary endpoint in the interim analysis, which measured the change in plaque volume in the most severely diseased subgroup of patients, also showed statistically significant regression from baseline by an average of 2.7 cubic millimeters, or 7.1 percent (p<0.0001). Overall adverse event rates were similar and AGI-1067 was generally well tolerated.

CART-2 originally was designed as a restenosis trial with change in atherosclerosis plaque volume as a secondary endpoint. As such, all of the randomized patient cardiac intravascular ultrasound scans independently analyzed by the Montreal Heart Institute would not ordinarily have been included. Medford noted that previously the restenosis endpoint represented the only regulatory pathway to approval with the mechanism of AGI-1067, which blocks signaling pathways within the endothelial cells that make up the inner lining of blood vessels to inhibit the production of VCAM-1 and other molecules involved in the inflammatory process.

But an end-of-Phase II meeting with the FDA produced a pathway to move the drug directly into testing for atherosclerosis. As a result, the Atlanta-based company began the ARISE study, an ongoing, 4,000-patient pivotal trial to test AGI-1067's ability to reduce clinical events in patients who have had a heart attack within the last year.

The regulatory pathway change also allowed for a change in CART-2's focus, and AtheroGenics and Montreal Heart then commissioned the Cleveland Clinic Foundation to read the entire set of intravascular ultrasound scans in a blinded manner to identify the patients who were most suitable for quantitative analysis in an atherosclerosis study. The 133 patients included in the interim analysis were identified as a result of the Cleveland Clinic review, and both Montreal Heart and the Cleveland Clinic concurred that those patients are appropriate subjects for the analysis.

The data analysis by both labs demonstrated that the reduction in plaque volume in the combined AGI-1067 treatment groups was greater than the standard-care group, although given the small number of patients in the interim analysis, the difference between the groups was not statistically significant.

"After you filter out all the patients who have technically adequate scans and come back for repeat ultrasounds, we're going to wind up at the end of the day with about 260 patients to evaluate," Medford said. "These 133 patients represent roughly half of the sample that we'll report out."

In the study, patients were randomized to placebo plus standard care or to one of three treatment groups. Starting 14 days prior to a scheduled angioplasty procedure, the first treatment group received AGI-1067 for the full 14 days, the second group received placebo for the first 11 days and AGI-1067 for the last three days, and the third group received placebo for all 14 days. Following the angioplasty, all three treatment groups continued receiving 280 mg of AGI-1067 daily for 12 consecutive months, plus standard of care. Plaque volume was measured at the time of angioplasty and again at the end of one year.

"The two leading labs in the world of intravascular ultrasound, Dr. Steven Nissen of the Cleveland Clinic and Dr. Jean-Claude Tardif of the Montreal Heart Institute, are both reporting out the same results from this data set," Medford noted. "They do their readings slightly different; they evaluate slightly different segments of the coronary artery, and it's two slightly different protocols. But this gives us tremendous encouragement on the strength and validity of the results. And it's never been done before."

He added that the key to examining the CART-2 findings is to view them as a link between the anatomy of the disease to its clinical events. The data, should they hold in the final analysis, point to another therapeutic signal that increases the likelihood of success in ARISE in reducing clinical events in heart disease patients. That trial is on track to complete enrollment by the end of the year, and AtheroGenics plans to evaluate and report the data, as well as submit a new drug application, by the end of next year. Looking further down the road, the company is beginning to explore commercialization strategies.

"We have all rights [to AGI-1067], and we are in active discussions with the large pharmaceutical companies that you would expect we'd be talking to if this drug hits its therapeutic profile," Medford said. "There are relatively few companies that have the experience and capability to launch and build this market for a major new class of anti- atherosclerosis drugs."

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