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Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-05-1498.
Submitted May 12, 2003
Accepted August 15, 2003
Reduced bleeding events with subcutaneous administration of recombinant human factor IX (BeneFixTM) in immune tolerant hemophilia B dogs
Karen E Russell, Eva H Olsen, Robin A Raymer, Elizabeth P Merricks, Dwight A Bellinger, Marjorie S Read, Bonita J Rup, James C Keith Jr, Kyle P McCarthy, Robert G Schaub, and Timothy C Nichols*
Pathology and Laboratory Medicine, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
Wyeth Reasearch, Cambridge, MA, USA
* Corresponding author; email: tnichols{at}med.unc.edu.
Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20/20 dogs developed inhibitory antibodies to the xenoprotein making it impossible to determine if new human FIX products, formulations or methods of chronic administration can reduce bleeding frequency (Blood 1996;88:2603-2610). Our goal was to determine if hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs resulting in a significant reduction in the development of inhibitors relative to the historical controls cited above (5/12 vs. 20/20, p < 0.001). The 7/12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCT), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable anti-human FIX antibody titers by ELISA, and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in Year 1 compared to non-tolerized hemophilia B dogs (P = 0.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected hemophilia B patients.
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