Synergen Inc. on Monday said it has ended Phase III trials for Antril inthe treatment of severe sepsis, proving once again how elusive thedisease has been as a target for biotechnology drug developers.The Boulder, Colo.-based company discontinued its experimentshalfway through the clinical trials after interim results Friday showedstatistically insignificant reductions in the mortality of patients withorgan dysfunction and shock.Synergen's stock (NASDQ:SYGN) Monday dropped almost 50 percenton the news. It closed at $4.50 cents, down $4.37.The results spelled disappointment not only to the hundreds ofthousands of patients who suffer from the disease annually in the U.S.,but also Synergen, which said it would have to lay off about 50 percentof its personnel and shut down its manufacturing plant.Antril, an interleukin-1 receptor antagonist (IL-1ra), has been thecompany's lead product and it has spent in excess of $100 milliondeveloping the drug.George Abbott, Synergen's president and CEO, said the company plansno further development of Antril for sepsis and will re-evaluatecontinuing trials of the drug for rheumatoid arthritis.David Webber, an analyst with Alex, Brown & Sons Inc., of NewYork, said suspension of the Antril program ends Synergen's hopes ofbecoming a major independent drug company.Carol Werther, an analyst with Cowen & Co., of Boston, added that thefailure of Antril highlights, once again, the risks in drug development.Abbott said he expects to have a plan in place by the end of next weekto begin reducing the company's expenses. He added that Synergen has$135 million in cash and must begin reducing its burn rate of about $7million a month.Among the options the company will explore, he added, is a sale ofSynergen, a merger or some other form of joint venture. He would notsay if any negotiations already are under way."We do intend to maintain our focus on drug discovery and pre-clinicalresearch," Abbott said. "We have to find a balance. We have to cut theburn rate so we can operate independently, if we have to. But if thecompany is to be sold or if we are to enter into a collaboration, it wouldbe foolish of us to decimate our capabilities."Layoffs among Synergen's 630 employees are expected to begin withinthe next month. Kenneth Collins, the company's chief financial officer,said 60 percent of the staff are involved in research and development,25 percent are in administration and 15 percent are in manufacturing.He said no decisions have been made on staff reductions.Synergen also will discontinue attempts to seek regulatory approval ofAntril for sepsis in Europe.In discussing the interim Phase III analysis, Abbott said the resultsshowed there were no safety concerns with Antril. But he said he andhis researchers were surprised to discover that the study could notreproduce results from an earlier Phase III trial completed in February1993.The current study involved 700 patients and 499 of them were definedas severely ill with organ dysfunctions or shock. The primary end pointwas to increase survival and a secondary goal was reduction in 28-daymortality.The decision to target severe sepsis was based on a retrospectiveanalysis of the prior Phase III trial, which showed that 22 percent of themost severely ill patients experienced reduced mortality after treatmentwith Antril.The retrospective analysis was conducted after initial results revealedonly a 15 percent reduction in mortality among all patients whoparticipated in the trial. Those results were considered too low to bestatistically significant.Synergen's Robert Thompson, head of research and clinical science,blamed the poor findings on sepsis, describing it as a heterogeneousdisease that differs from patient group to patient group. Although nodetails were available, he said the interim results were significantlylower than the 22 percent patient response in the prior trial.Other sepsis drugs have had disappointing trial results as well.Centocor Inc., of Malvern, Pa., and Xoma Corp., of Berkeley, Calif.,have not had much success with their anti-endotoxin antibodies. AndImmunex Corp., of Seattle, has reported that its soluble tumor necrosisfactor receptor provided no clinical benefit in a Phase II study.Thompson said the failure of the trial does not reflect on thetechnology. He said inflammation is a cause as well as a consequenceof disease and he believes IL-1ra has a role in fighting it. He saidresults may prove more positive in treating chronic diseases, such asmultiple sclerosis and rheumatoid arthritis.Although Synergen was optimistic about the possibilities of Antril intreating sepsis, Webber said market analysts were not as enthusiasticafter the February 1993 trial results. For the year ending Dec. 31, 1993,Synergen posted losses of $86.6 million.Abbott said the company will continue with its phase II/III clinicaltrials of ciliary neurotrophic factor for Lou Gehrig's disease; Phase Iclinical trial of tumor necrosis factor binding protein for multiplesclerosis and rheumatoid arthritis; and pre-clinical trials of glial-derived neurotrophic factor for Parkinson's disease. n
-- Charles Craig
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