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Executive Summary

SYNERGEN WILL DELAY ANTRIL PLA UNTIL COMPLETION OF SECOND PHASE III TRIAL, the company announced March 23. While Synergen still plans to file for registration of the interleukin-1 receptor antagonists for sepsis in Europe later this year based on one Phase III study, the firm said it "does not currently expect to file for marketing approval in the U.S. until completion of this next study." In February, following a preliminary analysis of the company's first Phase III trial, Synergen asserted that its time frame for filing the Antril PLA in the third quarter of this year was unchanged ("The Pink Sheet" March 1, T&G-7). Now, the earliest the company could file is in 1994. Synergen CEO Jon Saxe told a March 23 teleconference that the decision to conduct the new study was made "shortly" after seeing the initial Phase III trial results. Synergen hopes to begin enrollment of the follow-up Phase III study this summer. The new double-blind, placebo-controlled trial would enroll sepsis patients who are at high risk of dying. The company maintains that results of its recently completed Phase III trial demonstrate that Antril reduces mortality in the high-risk patient group. Patients in the new study would be screened using an algorithm combining APACHE III scores and other high-risk criteria to determine which patients would receive therapy, the company said. The believe that Antril treatment will be of benefit to high- risk sepsis patients is based on a retrospective analysis of Synergen's first Phase III study that showed patients treated with high-dose Antril had a 22% reduction in mortality compared to placebo, from 45% to 35%. The high-risk group, who made up two- thirds of those enrolled, were defined as patients with a predicted 28-day mortality of greater than 24%. The preliminary results of the trial were presented on March 23 at the International Symposium on Intensive Care and Emergency medicine in Brussels. The analysis of the 893-patient trial presented by Charles Fisher, MD, The Cleveland Clinic, did not show any statistically significant reduction in mortality among prospectively defined patient groups. Patients were treated with a 100 mg bolus dose of Antril followed by a 72-hour infusion of either 1 mg/hr or 2 mg/hr. The prospectively defined groups of all patients and shock patients had nonstatistically significant reductions in mortality of 15% to 14%, respectively. Fisher explained that the marginal overall results could be due to a less than expected mortality in the placebo group. Prior sepsis studies consistently showed a placebo mortality rate of 40%- 45%, whereas the placebo group in the Antril Phase III trial had a mortality rate of 34%. Fisher said the power calculation for the study was based on an expected 40% mortality rate in the placebo group. He could not explain why the mortality rate in this study was lower than previous trials. Synergen refuted a suggestion by one British investigator involved in the Antril trial that the "atypical" payment arrangement to physicians participating in the study may have affected the mortality outcomes. Instead of being paid per patient, he said, physicians were paid a certain amount if they entered a patient into the trial and received subsequent payments if the patient survived 48 hours, 72 hours, etc. The physicians received close to $5,000 for every patient that survived to the 28-day endpoint, he said, suggesting that this system may have led to a selection bias in that physicians might be more likely to enroll patients who would survive. Synergen said the payments were a regular reimbursement scheme for the clinicians' services.

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