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Executive Summary

CENTOCOR's CENTORX REDUCES BY 35% HEART ATTACKS AND REPEAT ANGIOPLASTY on an emergency basis in patients following balloon angioplasty, according to results of the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial reported March 16 at the American College of Cardiology annual meeting in Anaheim. The results were presented by Neil Kleinman, MD, Baylor College of Medicine, one of the investigators in the 56-center study. In a press briefing following the presentation, Eric Topol, MD, The Cleveland Clinic, one of the EPIC study directors, called the effects of CentoRx (7E3) a "meaningful and important reduction in the serious events" following percutaneous transluminal coronary angioplasty (PTCA). Compared to aspirin, which causes a 20% reduction in such events, "this is a pretty substantial difference," Topol commented. Centocor issued a same-day press release stating that the company would submit a product license application (PLA) in 1993 for the chimeric monoclonal antibody fragment inhibitor of the platelet glycoprotein GPIIb/IIIa receptor based on the data. Centocor received the data from the trial about a week prior to the meeting and is still analyzing the results. Lilly has marketing rights to CentoRx under a $100 mil. 1992 licensing agreement, which also included rights to Centocor's anti-sepsis MAb Centoxin (HA-1A). Centocor's decision to terminate its second Phase III trial of Centoxin appears to ensure that Lilly will assume rights to CentoRx without further payment. The company would have owed an additional $25 mil for CentoRx if Centoxin was approved in 1993 (see preceding T&G). In the double-blind, placebo-controlled EPIC trial, 2,099 patients were enrolled who were considered high risk for complications during balloon angioplasty. Patients were considered at high risk if they recently had had a myocardial infarction, had unstable angina, were in the acute phase of an infarction or had an angiogram identified as high risk. Patients were randomized to placebo, a .25 mg/kg bolus injection of CentoRx plus a placebo infusion, or a CentoRx .25 mg/kg bolus dose plus 10 microgram/minute infusion of the drug over 12 hours. The bolus injections were administered 10 minutes prior to balloon angioplasty. All patients received aspirin and heparin. The percentage of patients experiencing death, a myocardial infarction, or emergency repeat angioplasty in the following 30 days post-PTCA was reduced from 12.8% in the placebo group to 8.3% in the patients treated with the CentoRx bolus dose plus 12-hour infusion. The 11.4% incidence of complications in the patients receiving a CentoRx bolus dose just prior to therapy was not statistically significantly different from placebo. The major side effect of CentoRx therapy, as expected, was a two-fold increase in the incidence in major bleeding over placebo. Fourteen percent of patients treated with the bolus plus infusion dose of CentoRx experienced major bleeds, as defined by a greater than 5 gm/dl decrease in hemoglobin, compared to 7% of placebo- treated patients. Patients treated with the CentoRx bolus dose had an 11% incidence of major bleeds. There were no additional intracranial hemorrhages in the CentoRx treated groups. Kleinman said the incidence of bleeds represents an increase of five events per 1,000 patients undergoing angioplasty, requiring eight additional patients to receive transfusions. Most of the bleeds were at the puncture site of the femoral artery. Better clinical management of patients and a reduction in aspirin or heparin dose may reduce the number of bleeds, Kleinman suggested. Because of the bleeding complications, study co-director Robert Califf, MD, Duke University Medical Center, recommended that CentoRx only be used in patients at high risk of reocclusion of blood vessels following angioplasty. The researchers estimate that 10% to 20% of all angioplasty patients are considered high risk, or 40,000-60,000 patients. Califf called CentoRx the first agent to significantly reduce myocardial infarction in angioplasty. Califf emphasized the independence of the study from Centocor involvement. "Centocor provided the support for the trial, but the trial was conducted by our study group," he said. In addition, Califf maintained that "no one at Centocor and no one who was treating a patient at the trial knew which treatment the patient was getting to avoid any bias or any opportunity of people coming to the wrong conclusion." Analyses of the data were conducted independently by the Duke researchers and separately by Centocor, he said. A six-month follow up of the patients treated with CentoRx may yield data on whether the agent prevents restenosis compared to placebo, study co-director Topol said. Additional studies are being considered investigating CentoRx in conjunction with thrombolytic agents, Califf noted. Centocor has completed Phase II studies in myocardial infarction and unstable angina. The Phase II results in angina, although not statistically significant, showed a trend in reduction of myocardial infarctions in the CentoRx treated patients.

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