Succinobucol Misses Primary End Point, but Investigators Say Drug Still Has Potential

March 27, 2007

March 27, 2007 (New Orleans, LA) - Full data from the Aggressive Reduction of Inflammation Stops Events (ARISE) study, a phase 3, double-blind, placebo-controlled trial with succinobucol (AGI-1067, AtheroGenics Inc), were presented today at the American College of Cardiology 2007 Scientific Sessions, and although the study missed its primary end point, investigators say they remain "bullish" on the compound.

The study, designed to assess the incremental benefits of succinobucol over current standard of care in coronary-artery-disease (CAD) patients, showed that the novel compound did not reduce the length of time to the first occurrence of cardiovascular mortality, resuscitated cardiac arrest, nonfatal MI, nonfatal stroke, hospitalization for angina pectoris, or use of coronary revascularization, findings that were previously reported by heartwire . There was, however, a significant 19% reduction in cardiovascular death, cardiac arrest, MI, and stroke, a prespecified secondary end point, as well as a significant reduction in new-onset diabetes.

Dr Jean-Claude Tardif, the coprincipal investigator who presented the ARISE findings during the late-breaking clinical-trials session, told the press he was cautiously optimistic about the results and that the positive secondary findings could be used to direct future research.

"Reductions in heart attacks and strokes are certainly something that is very clinically relevant," Tardif said. "Yes, we have to confirm these findings because our primary end point was not achieved, but if you have a drug, irrespective of things you can measure in the blood, that is reducing MI, stroke, and new-onset diabetes, on top of standard of care, and we can confirm that in the next trial, I think this is a very promising therapy.

During the clinical-trials session, however, Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) expressed concern about interpreting the results too positively, especially in light of the fact that succinobucol increased LDL-cholesterol levels, decreased HDL-cholesterol levels, and was associated with a trend toward more heart-failure hospitalizations.

"Perhaps we should be a little more cautious here," said Harrington. "You have some good things going in one direction, some bad things going in another, some good metabolic parameters with glucose control, some bad metabolic parameters with LDL and HDL, so I'm really not sure what to make of this other than things going in both directions. Overall, I'd say it's probably pretty neutral."

Some signals going in strange directions

AGI-1067 was the first in a new class of drugs, known as vascular protectants, that aimed to reduce inflammation in blood-vessel walls and to provide antioxidant protection. Investigators sought to test whether the agent would provide additional protection on top of standard care in patients with CAD. In total, 6144 patients with acute coronary syndrome were randomized to succinobucol or placebo, and all patients were well treated, with 90% of patients taking statins and aspirin, as well as ACE inhibitors, beta blockers, or other lipid-lowering therapies.

Results showed no difference in the primary end point, with the Kaplan-Meier curves for placebo and succinobucol virtually identical. Regarding the prespecified secondary end points, there was no significant difference in the composite of cardiovascular death, cardiac arrest, MI, stroke, or unstable angina. However, when unstable angina was removed, there was a significant 19% reduction in cardiovascular death, cardiac arrest, MI, or stroke. In addition, investigators also reported a significant 64% reduction in new-onset diabetes mellitus.

Tardif said that he did not believe this to be chance finding and that he remains "pretty upbeat" about the drug.

However, as noted by Harrington, the agent moved lipid levels in an atherogenic fashion, increasing LDL cholesterol and decreasing HDL cholesterol. Although the drug was safe and well tolerated, there was an increase in heart-failure hospitalizations observed with the drug. Addressing the lipid findings, Tardif pointed to the late-breaking torcetrapib studies, in which he participated, that showed significant decreases in LDL cholesterol and dramatic increases in HDL cholesterol but also an increased risk of cardiovascular mortality and clinical events. Reducing hard cardiovascular events, as observed in ARISE, is "more important than an LDL number," he said.

Results hopeful

Commenting on the study, Dr E Murat Tuzcu (Cleveland Clinic, OH), who chaired the media briefing, said he believed that further study of the drug is warranted.

"The results do not tell us to give credence to these therapies," said Tuzcu. "But they also tell us that we shouldn't lose hope with this because there are positive signals. Now, this is an arduous and slow process but it will allow us to go forward more intelligently and with more information."

AtheroGenics has previously said it would continue to develop the drug, based on these positive secondary end points, and prepare for discussions with the US Food and Drug Administration (FDA) on how to proceed further. In December 2005, AstraZeneca agreed to pay AtheroGenics up to $1 billion for exclusive rights to the drug, although payment was contingent upon the drug's approval by the FDA. AstraZeneca currently has a limited time window to decide if it wishes continue its involvement with the drug program.

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