Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice.
FIX binds tightly to collagen IV. Furthermore, a FIX mutant, FIXK5R, which binds better than wild-type FIX to collagen IV, provides better hemostasis than wild-type FIX, long after both are undetectable in the plasma. There is also credible evidence of extravascular FIX. Here, we use the saphenous vein bleeding model to compare the efficacy of recombinant FIXFc (Alprolix) and wild-type FIX (BeneFIX) in hemophilia B mice 7 days postinfusion. Although the terminal half-life of Alprolix is significantly longer than that of BeneFIX, at equal doses Alprolix is not better at controlling bleeding 7 days postinfusion, presumably because of the extravascular FIX. Both BeneFIX and Alprolix exhibit a linear response in clotting efficacy up to 150 IU/kg, where they appear to saturate an extravascular compartment, because there is no additional prophylactic benefit from higher doses. A robust pool of extravascular FIX is clearly observed surrounding blood vessels, localized to the same region as collagen IV, in 2 representative human tissues: liver and skeletal muscle. We see no increased risk for thrombosis at 250 IU/kg FIX at 6 hours postinfusion. In summary, 7 days postinfusion into hemophilia B mice, BeneFIX and Alprolix are hemostatically indistinguishable despite the latter's increased half-life. We predict that doses of FIX ∼3 times higher than the currently recommended 40 to 50 IU/kg will, because of FIX's large extravascular compartment, efficiently prolong prophylactic hemostasis without thrombotic risk.
Department of Pathology and Laboratory Medicine, McAlister Heart Institute Core Laboratory.
Brian
B
Cooley
Department of Pathology and Laboratory Medicine.
William
W
Funkhouser
Department of Medicine-Hematology, and.
Dougald
D
Monroe
Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC;
Ashley
A
Ezzell
Mann BioConsulting, Gaithersburg, MD;
David M
DM
Mann
Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, NC;
Feng-Chang
FC
Lin
Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC; and.
Paul E
PE
Monahan
Department of Biology, University of North Carolina-Chapel Hill, Chapel Hill, NC.
Darrel W
DW
Stafford
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000493:pharmacokinetics / Q000494:pharmacology; D002836:Hemophilia B / Q000097:blood / Q000188:drug therapy; D006470:Hemorrhage / Q000097:blood / Q000517:prevention & control; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology
D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C000599709:factor IX Fc fusion protein; D005164:Factor IX