NEW ORLEANS -- Succinobucol (AGI-1067), a novel potent antioxidant for acute coronary syndrome, missed the primary endpoint in a phase III trial, researchers reported here. But it outperformed placebo in secondary endpoints.
NEW ORLEANS, March 29 -- Succinobucol (AGI-1067), a novel potent antioxidant for acute coronary syndrome, missed the primary endpoint in a phase III trial, researchers reported here.
But the investigational drug, a monosuccinic ester of probucol, outperformed placebo in some secondary endpoints, reported an undaunted Marc A. Pfeffer, M.D., Ph.D., of Harvard Medical School, at the American College of Cardiology meeting.
Studied with more than 6,000 acute coronary syndrome patients succinobucol failed to meet the primary combined endpoint of cardiovascular death, resuscitated arrest, myocardial infarction, stroke, unstable angina, or coronary revascularization.
The drug was superior to placebo for the secondary endpoint of reducing cardiovascular death, MI, and stroke,
"When we do the next trial with succinobucol, I think we will be able to have a better idea of how to do this study," Dr. Pfeffer said after reporting results of the international ARISE (Aggressive Reduction of Inflammation Stops Events trial. "I really think we have a good product here. If we do not go forward with it we will have missed an opportunity."
In the phase III study, 17.3% of 3,066 patients assigned to placebo experienced one of the endpoints in the study compared with 17.2% of the 3,078 patients taking succinobucol.
When the ARISE team analyzed the secondary endpoints, it found that 6.7% or 207 patients on succinobucol experienced the composite endpoint of cardiovascular death, cardiac arrest, heart attack or stroke compared with 8.2% or 252 patients taking placebo (P=0.028) said co-investigator Jean-Claude Tardif, M.D., of the Montreal Heart Institute at the University of Montreal.
ARISE was a double-blind, placebo-controlled trial in 6,144 patients with a history of hospitalization for acute myocardial infarction or unstable angina 14 to 365 days before screening. They had to be older than 60 year or have a history of diabetes. The trial was conducted in 259 cardiac centers in the United States, United Kingdom, Canada, and South Africa. All patients in the study were well treated with the appropriate standard of care.
After a two-week run-in of placebo on top of optimal medical therapy, patients were randomized to succinobucol at 300 mg a day or placebo. They were on the study drug for a planned 24 months.
Dr. Tardif said a higher number of revascularization procedures in the succinobucol cohort - although not a significant difference - tipped the balance in the primary endpoint to a non-significant finding.
"The highest bar in clinical research is to improve the prognosis of patients who are already receiving optimal care," said Dr. Pfeffer. "Although the formal primary composite endpoint in ARISE was not met, we believe that the trial generated strong evidence that use of AGI-1067 will produce tangible clinical benefits for patients with coronary artery disease."
Patients taking succinobucol were also markedly less likely to develop new onset diabetes, with the study researchers observing a 64% reduced risk (P
Dr. Tuzcu disclosed possible financial conflicts of interest with Pfizer, AstraZeneca, Takeda, sanofi-aventis and Sankyo. Dr. Tardif disclosed possible financial conflicts of interest with Pfizer and with the Canadian Institutes of Health Research. Dr. Pfeffer disclosed possible financial conflicts of interest with Alza, Amgen, AtheroGenics, Cytokinetics, Daiichi Sankyo, Genzyme, GlaxoSmithKline, Novartis, Via Pharmaceuticals, AstraZeneca and Sanofi-Synthelabo/Bristol-Myers Squibb.