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Executive Summary

GENSIA ARASINE STUDY SECONDARY ANALYSIS SHOWS HEART ATTACK DECREASE in patients undergoing coronary artery bypass surgery (CABG). The Phase III trial results were reported March 16 at the American College of Cardiology annual meeting by Dennis Mangano, MD, University of California-San Francisco. The analysis found that high dose Arasine (acadesine) reduced myocardial infarctions by 72%. Acadesine acts by increasing local concentrations of adenosine in heart tissue in the presence of ischemia, Mangano said. Adenosine in turn increases vasodilation and release of oxygen free radicals and prevents neutrophil activation. The significance of the results is unclear due to the use of two different analyses. The study's primary analysis failed to show a statistically significant benefit for Arasine. In the double-blind, placebo-controlled study, 633 bypass surgery patients were randomized to placebo, high-dose or low-dose acadesine. The two primary endpoints in the study were myocardial infarction and all cardiovascular outcomes. Myocardial infarction was defined in the first analysis as changes in electrocardiogram, or the presence of creatinine kinase (CK-MB), or the presence of MI at autopsy. The preliminary analysis using these criteria for myocardial infarction showed no difference between high-dose and low-dose acadesine and placebo. The incidences of MI were 24%, 26% and 21%, respectively. However, when the additional analysis was conducted to include a more "clinically rigorous" definition of MI (ECG changes and CK- MB presence, or MI at autopsy), the difference between high-dose acadesine and placebo was significant. Myocardial infarctions were reduced from 5.2% to 1.4%. There was no statistical difference between the high and low doses of acadesine, 5.2% compared to 4.2%. Gensia VP-Medical and Pharmaceutical Development Walter Singleton, MD, maintained at a same-day press briefing that FDA was aware that the company would conduct two different analyses of the data. "It was clear in our discussions with the agencies that both of these definitions were being considered," he said. Singleton explained that although the firm and FDA agreed that the first definition of MI was "less rigorous," Gensia decided to use it "because the incidence of endpoints was projected to be larger using this definition than the more stringent one." Therefore, the company used the first definition "to power the study [and] calculate the sample size," he said. The second endpoint of cardiovascular outcomes -- which included myocardial infarction, cardiac death, stroke, heart failure and life-threatening arrhythmias -- was not statistically significantly different for acadesine compared to placebo when myocardial infarction was defined by the broader criteria. When the more stringent definition of myocardial infarction was used, high-dose acadesine significantly reduced combined cardiovascular events from 14% to 5% compared to placebo. The only individual cardiovascular event other than MI that was reduced was the incidence of stroke, which occured in 4.2% of placebo patients compared to .5% of Arasine patients. An international Phase III study of high-dose Arasine compared to placebo in 821 patients presented at the meeting by Eric Jamieson, MD, University of British Columbia, showed no statistically significant benefit overall of high-dose Arasine. Gensia's Singleton asserted that there were problems in the international study involving the plasma samples. "This issue we believe has confounded the analysis of all those results that depend on CK-MB levels," Singleton said. Gensia "is conducting an additional post submission study of bypass graft surgery to provide additional evidence in case we should need it," Singleton said. The 50-center study "is underway and is scheduled for completion with approximately 1,000 patients about the end of 1993 to mid-1994," Singleton said. The study focuses on the most specific definition of myocardial infarction requiring both ECG and enzyme changes. The other identified endpoint is a combined cardiovascular outcome including myocardial infarction, cardiac death and stroke. Gensia filed its Arasine NDA in December 1992 and a computer- assisted NDA (CANDA) earlier this month. The company filed for registration in Europe in January. The company said that FDA has "accepted the submission" for review. Singleton said Gensia also is conducting a study with Arasine "in patients who are at high risk of developing cardiovascular complications undergoing major noncardiac surgery."

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