Synergen Inc. may well be leading the race for an effectivetreatment for sepsis after it reported that trials of its sepsisdrug, Antril, are 80 percent complete.

The company said at last week's Cowen & Co. conference in SanFrancisco that it expects to complete the pivotal efficacytrials by the end of the year. Once results are analyzed,Synergen will be ready to submit a product license application,according Paul Laland, spokesman for the Boulder, Colo.,company.

About 20 companies have taken up the challenge of finding aneffective therapy for sepsis syndrome, a chronic diseaseaffecting between 300,000 and 500,000 Americans annually.

Industry experts agree that there is a need for therapies thatact broadly in both gram-negative and gram-positive sepsis,since a conclusive method to diagnose the difference betweenthe two diseases has not yet been developed.

Cytokines TNF and IL-1 have played a strong role in slowingdown sepsis after it begins. Brandon Fradd, an analyst withMontgomery Securities in San Francisco, has noted a trend inthe use of cytokine blockers among companies developingtreatments.

Synergen's Antril is a recombinant interleukin-1 receptorantagonist (IL-1ra), a cytokine produced by the body inresponse to infection or injury, and is an important mediatorof inflammation. Overproduction of IL-1 has been implicated inseptic shock. However, IL-1ra is a naturally occurring humanprotein that blocks its action.

TNF receptor intercepts and neutralizes the cytokine tumornecrosis factor, and an excess of TNF has been identified as aharmful influence in the inflammatory response of septicshock, an often fatal over-reaction of the body to severebacterial infection.

"In the near term, cytokines appear to have a clear impact inthe most severe patients, if not all," said Fradd.

Immunex Corp. of Seattle is simultaneously developing IL-1and TNF receptors, and Joyce Lonergan, an analyst withBoston-based Cowen & Co., said Immunex will be the onlycompany in a position to be able to compare how both drugswork.

According to Lonergan, other companies -- including CentocorInc., Xoma Corp., Chiron Corp., Genentech Inc. and IncytePharmaceuticals Inc. -- that are working on only blockers ofgram-negative sepsis with roughly the same 1996 markettimetable face tough competition. "It may be easier to treat apatient with a broader-use drug," she said.

Cynthia Robbins-Roth, editor of BioVenture View, said evenSynergen's IL-1ra won't be the sole answer to treating sepsisbecause of the complex interaction of different networks inthe body. She said that the manipulation of only one cytokinewill not have a reproducable clinical effect, and that acombination therapy to chase an effect at multiple levels isneeded for an effective therapy.

Robbins-Roth said she sees a similarity between the flawedapproaches to treating sepsis and early cancer researchbecause both conditions involve a range of slightly differentdisease levels in patients.

Robbins-Roth said clinical researchers are now beginning toidentify molecular mechanisms that give a better set oftargets to treat the disease than just cytokines.

"The future is a combination of therapeutic efforts ofmicrobial derived mediators, such as anti endotoxins incombination with host-derived inflammatory mediators suchas TNF (tumor and IL-1," said Steven Opal of Brown UniversitySchool of Medicine. He added that it is essential that a singleagent work before adding a combination therapy.

-- Michelle Slade Associate Editor

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

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