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Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs.


J Thromb Haemost. 2012 Jun 22;


Authors: Nolte MW, Nichols TC, Mueller-Cohrs J, Merricks EP, Pragst I, Zollner S, Dickneite G


Abstract

Background: Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor IX (FIX) concentrates per week. A FIX molecule with a prolonged half-life has the potential to greatly improve convenience of, and adherence to, prophylaxis. Objectives: The aim of our studies was to investigate the pharmacokinetic and pharmacodynamic profile of a recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP). Methods: Cynomolgus monkeys and hemophilia B dogs received single intravenous doses of rIX-FP (50-500 IU kg(-1) ). rIX-FP plasma levels were determined by an activity-based assay (dogs only) and anti-FIX enzyme-linked immunosorbent assay methods. Additionally, activated partial thromboplastin time (aPTT) was determined in hemophilia B dogs. Data were compared with a direct study comparator (recombinant FIX [rFIX]) or previously published data. Results: Terminal half-life of rIX-FP was prolonged in both species compared with FIX reference data. In hemophilia B dogs, human FIX antigen levels remained above 0.05 IU mL(-1) more than three times longer following rIX-FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed observed superior profile. Prolonged pharmacodynamics of rIX-FP was demonstrated with aPTT <60 seconds sustained around four times longer with rIX-FP (5.9 days) than rFIX (1.5 days). Conclusions: These studies indicate that the recombinant albumin fusion technology successfully improves the pharmacokinetic profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half-life extension in patients with hemophilia B. © 2012 International Society on Thrombosis and Haemostasis.

PMID: 22726310 [PubMed - as supplied by publisher]