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Recombinant Human Antithrombin Demonstrates Therapeutic Potential in Endotoxemia Model of Sepsis

Monday August 8, 9:05 am ET

FRAMINGHAM, Mass. and SYDNEY, Australia--(BUSINESS WIRE)--Aug. 8, 2005--Today, at the 20th Congress of the International Society of Thrombosis and Haemostasis in Sydney, Australia, Dr. Judith Leitner, working with Dr. Bernd Jilma's team at the Medical University of Vienna, presented the results of a study that described the therapeutic potential of recombinant human antithrombin, supplied by GTC Biotherapeutics, Inc. ("GTC", Nasdaq: GTCB), in a human model of sepsis. This physician-sponsored trial showed that supra-physiological levels of antithrombin without concomitant heparin have potent dose-dependent anticoagulant effects and anti-inflammatory properties in human experimental endotoxemia.

Severe sepsis still carries a high mortality rate despite advances in intensive care medicine and antimicrobial therapy. Every year, more than 750,000 people in the United States develop severe sepsis, a syndrome characterized by an overwhelming systemic response to infection, which can lead to organ dysfunction and ultimately death. Approximately 215,000 people in the US die from severe sepsis every year. The death rate can be as high as 60% for people with underlying medical problems.

Three natural anticoagulants have been tested in large phase III trials in sepsis: recombinant human activated Protein C, tissue factor pathway inhibitor and antithrombin. In all three trials, concomitant administration of heparin could have compromised clinical efficacy of the drugs under investigation. This study team hypothesized that antithrombin infused without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin induced cytokine production.

Results in Coagulation and Inflammation

Coagulation: In vivo thrombin formation decreased in a dose dependent fashion as measured by prothrombin fragment, thrombin antithrombin complexes (TAT) and D-dimer.

Inflammation: Infusion of recombinant human antithrombin rapidly decreased neutrophil and monocyte counts before endotoxin challenge, demonstrating a direct interaction with these leukocyte subsets. Antithrombin treatment significantly decreased peak interleukin-6 (IL-6) release by 40%.

Study Design

The study was a randomized, double-blind and placebo-controlled trial, consisting of three parallel groups totaling 30 healthy male subjects. Volunteers were randomly assigned to receive either a bolus primed continuous infusion of recombinant human antithrombin at 500% or 200% of normal antithrombin level or an equal volume of placebo (0.9% NaCl) over 4 hours. Immediately after the recombinant human antithrombin bolus infusion, an intravenous bolus of 2 ng/kg National Reference Endotoxin (LPS, Escherichia coli; USP, Rockville, MD) was given to all subjects.
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