Synergen Inc. announced Thursday that it has filed formarketing approval in Europe of its sepsis drug Antril. Thecompany's marketing authorization application (MAA) fortreatment of severe sepsis was submitted to the member statesof the European Union for consideration by the Committee forProprietary Medicinal Products (CPMP).

The application is based on data from the Boulder, Colo.,company's initial Phase III U.S. study, which found nosignificant difference in survival times among all treatmentgroups. In two-thirds of the patients with severe sepsis whoreceived Antril, however, there was a 22 percent reduction inrisk of mortality compared with placebo. Patients with a 24percent or greater risk of mortality were considered to havesevere sepsis.

When Synergen announced results of the U.S. trial lastFebruary, the company said it would discuss with regulatoryagencies in Europe, Canada and the U.S. its plans to submit aproduct license application (PLA) for Antril. In March,Synergen said it would conduct a second Phase III trial of therecombinant interleukin-1 receptor before filing an applicationwith FDA.

The second trial, which began in August, has the same entrycriteria as the first study; it includes patients regardless of riskof mortality. The difference between the trials is that Synergenhas prospectively defined the patient population in which thedrug will be effective. The company did a retrospective subsetanalysis after the first trial.

Analyst Carol Werther of Cowen & Co. said the European filingwas expected; Cowen & Co., which makes a market in Synergen,has a model for Antril sales in Europe for next year. Werthernoted that Europe "is a little less strict" than the U.S. inconsidering whether a patient population is prospectivelydefined.

Jay Silverman, an analyst with Wertheim Schroder, saidSynergen might have to supplement the European filing withresults from the second trial. Over the long run, he said, filingon the basis of the current data could shorten the approvaltime.

European experience with Centocor Inc.'s sepsis drug, Centoxin,may make the CPMP more wary of approving a drug based onless data than FDA will receive. Centoxin was approved inEurope before being considered by FDA. FDA subsequentlyrequested that the company do a second Phase III trial, andwhen an excessive mortality rate was observed in one arm ofthe study, Centocor pulled Centoxin from the market in Europeand halted development of the monoclonal antibody for sepsis(see BioWorld, Jan. 19, 1993).

Synergen (NASDAQ:SYGN) has taken a course of action similarto that of Xoma Corp. FDA denied approval of Xoma's anti-endotoxin monoclonal antibody, E5, for sepsis in April 1992,concluding that the company's first two Phase III trials did notdemonstrate sufficient efficacy. Xoma then undertook a thirdPhase III trial in a narrower population -- patients withdocumented Gram-negative sepsis who experienced organfailure. The company also filed for marketing approval of E5 inJapan based on Phase III trials conducted in Japan with included as supplemental information (see BioWorld, Oct.21, 1993). In addition, Xoma has filed for E5 approval inEurope through the CPMP.

Synergen said the CPMP will review its Antril application andthe committee's advisory opinion will apply to all of themember states of the European Union, including Belgium,Denmark, France, Germany, Greece, Ireland, Italy, Luxembourg,the Netherlands, Portugal, Spain and the United Kingdom. "Ifthe opinion is favorable, country marketing authorizations aregenerally granted individually upon compliance with localregulations," Synergen said.

The company said it also plans to submit similar regulatoryfilings in the next several months in the countries of theEuropean Free Trade Association -- Austria, Finland, Norway,Sweden and Switzerland -- and in Canada, Australia and NewZealand. Synergen plans to file a PLA in the U.S. uponcompletion of the company's second Phase III trial, which isexpected by the end of the year.

Synergen's stock closed Thursday at $14 a share, up 75 cents.

-- Brenda Sandburg News Editor

(c) 1997 American Health Consultants. All rights reserved.