Biotech Tracker - Tifacogin Program for Sepsis Unlikely to Move Forward

BiotechTracker - Tifacogin Program for Sepsis Unlikely to Move Forward

July 10, 2003 Chiron (NASDAQ: CHIR) and Pfizer’s (NYSE: PFE) tifacogin is a recombinant tissue factor pathway inhibitor (TFPI) formulation. In late 2001, tifacogin failed to meet its primary efficacy endpoint in its phase III OPTIMIST (optimized phase II tifacogin in multicenter international sepsis trial) program in patients with sepsis. Although primary data were unavailable, it was revealed that recipients of tifacogin did not experience a significant reduction in 28-day, all-cause mortality in the high-powered, prospective, double-blind, placebo-controlled OPTIMIST program. At that time, we indicated that the unfavorable early termination of the trial boded extremely poorly for the agent.

Now, the July 9, 2003 issue of The Journal of the American Medical Association reveals both the primary data and subgroup analyses. Tifacogin did not reduce all-cause mortality in patients with severe sepsis and a high international normalized ratio (INR, a measure of anticoagulation and bleeding propensity often elevated in advanced systemic inflammatory response syndrome [SIRS], a body’s response to overwhelming inflammation). Though benefit may be observed for patients low INRs, as is the case for all recipients, tifacogin administration was associated with an increased risk of serious bleeding. Tifacogin’s proven biochemical ability to inhibit thrombin generation and fibrin formation associated with the septic phenomena of tissue factor release and aberrant coagulation did not translate into clinically relevant therapy. Probability of the tifacogin program moving forward is now nearly zero.

Dr. Edward Abraham and colleagues assessed outcomes of 1,955 severely septic patients who were randomized to receive intravenous tifacogin or placebo for 96 hours. 1,754 study subjects had high INRs (at least 1.2) and 201 had low INRs (<1.2). Insignificant differences in the therapeutic effects of tifacogin and placebo were observed in terms of overall mortality at 28 days for those with high INRs, with a 34.2% rate for tifacogin recipients (n = 880) and a 33.9% rate for placebo recipients (n = 874). Overall mortality at 28 days for those with low INRs was significantly lower for tifacogin recipients (12%; n = 83) compared to placebo recipients (22.9%; n = 118; p = .03 by a logistic regression model). However, there was an increase in serious adverse events associated with bleeding in the tifacogin group in both INR-based cohorts – 6.5% for tifacogin recipients versus 4.8% placebo recipients in the high INR cohort, and 6.0% for tifacogin recipients versus 3.3% for placebo recipients in the low INR cohort.

A related editorial by Angus and Crowther, from the evidence-based medicine cradles University of Pittsburgh and McMaster University (Hamilton, Ontario), outlined multiple confounding factors and trial design inadequacies that may have contributed to the unacceptable outcomes of the tifacogin program. They lament that overcoming these obstacles is extremely unlikely to resurrect tifacogin or any other anticoagulant in trials for sepsis, with the possible exception of low-dose heparin. Molecular targets they identify as most appropriate for future development in sepsis pharmacology include high-mobility group B1 protein, microphage, migration inhibitory factor, complement C5a, and apoptosis inhibitors.

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