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SYNERGEN’s ANTRIL EFFECT LIMITED TO MOST SERIOUSLY ILL SEPSIS PATIENTS

Executive Summary

SYNERGEN's ANTRIL EFFECT LIMITED TO MOST SERIOUSLY ILL SEPSIS PATIENTS based on preliminary results of the company's Phase III trial with the interleukin-1 receptor antagonist. "Antril appears to benefit those patients who have the highest risk of death from sepsis," Synergen said Feb. 22. The Boulder, Colo.-based biopharmaceutical firm reported that preliminary analyses from the trial, which was unblinded on Feb. 20, show that "one-half to two-thirds of the patients assessed as being most seriously ill showed a 20%-25% reduction in mortality in the groups treated with Antril." Mortality among seriously ill patients in the placebo group was 44%. Synergen called the reduction in deaths among seriously ill sepsis patients "meaningful," but declined to say whether it was statistically significant. The preliminary results from the 60-center, 893- patient trial will be presented in full March 23 at the International Symposium on Intensive Care and Emergency Medicine in Brussels. In the double-blind, randomized, placebo-controlled Phase III trial, two-thirds of the patients were treated with Antril and one-third received placebo plus standard antibiotic therapy. Patients treated with Antril received either 67 mg/kg or 133 mg/kg of the drug over three days. The study endpoint was 28-day mortality. While Antril showed some reduction in mortality in the seriously ill patients, a subgroup that was not prospectively defined in the Phase III protocol, the drug had little effect in reducing mortality among all sepsis patients. Patients treated with low-dose Antril had a mortality rate of 31% compared to 34% for patients receiving placebo. The mortality rate for patients treated with high-dose Antril was slightly less at 29%. Mortality for placebo patients was less than that seen in Phase II studies of Antril. In a same-day teleconference, CEO Jon Saxe said the company was "disappointed" that the results did not match those of the Antril Phase II trial. Those data on 99 patients, presented at the American College of Chest Physicians meeting in November 1991, showed a reduction in mortality among all sepsis patients of 40%- 60%, from 44% in the placebo group to 25% and 16%, in the low and high-dose Antril groups, respectively. Because Antril seemed to work for all patients in the Phase II study, Synergen did not consider it necessary to prospectively define a subgroup in which the drug might be effective in Phase III trial, Saxe explained. The lesser magnitude of effect seen in the preliminary Phase III results will not alter Synergen's time frame for a PLA filing for Antril, Saxe asserted. The company still intends to submit an application to FDA by the third quarter, he noted, although the indication may be narrower in scope. Synergen believes the trial will be sufficient to obtain FDA approval. However, based on the agency's reaction to marginal results from sepsis studies for Centocor's Centoxin and Xoma's E5, an additional Phase III trial may be required before FDA will approve Antril. Centoxin received another blow when a second trial requested by FDA was halted after analyses found that the mortality rate for patients without gram-negative bacteremia was greater in the Centoxin group than the placebo group ("The Pink Sheet" Jan. 25, T&G-2). Centocor is expected to announce its plans for Centoxin imminently upon completion of analyses by Bio-Pharm Clinical Services. Xoma and its marketing partner Pfizer continue to plan another Phase III trial for E5, to begin within a month or two. Saxe asserted that the Phase III trial results will not appreciably alter the market size for Antril since market analysis shows that physicians' preference would be to use the drug in the most severely ill patients anyway. He added that the Antril data showing an effect in a specific population of sepsis patients will allow hospital and formulary committees to determine which patients are most likely to benefit from Antril therapy, which is expected to cost close to $3,000. The Phase III data will also allow Synergen to design follow-up studies in septic shock and hemorrhagic shock as well as pediatric trials, Saxe maintained. Saxe said the company is not planning to lay off any personnel at this time and has $240 mil. in cash on hand.

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