Intravenous administration of recombinant human
factor IX (rhFIX) acutely corrects the coagulopathy in
hemophilia B dogs. To date, 20 of 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. Our goal was to determine whether
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 historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized
hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX
antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by
enzyme-linked
immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized
hemophilia B dogs had 69% reduction in
bleeding frequency in year 1 compared with nontolerized
hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic
therapy in selected patients with
hemophilia B.