Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs.
BACKGROUND
Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor (F)IX concentrates per week. A FIX molecule with a prolonged half-life has the potential to greatly improve the convenience of, and adherence to, prophylaxis.


OBJECTIVE
The aim of our studies was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of a recombinant fusion protein linking coagulation FIX 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 ELISA 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
The 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 after rIX-FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed the observed superior profile. Prolonged PDs of rIX-FP were demonstrated with APTT<60 s 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 PK profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half-life extension in patients with hemophilia B.
Preclinical Research and Development, CSL Behring GmbH, Marburg, Germany. marc.nolte@cslbehring.com
M W
MW
Nolte
T C
TC
Nichols
J
J
Mueller-Cohrs
E P
EP
Merricks
I
I
Pragst
S
S
Zollner
G
G
Dickneite
D000818:Animals; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D002836:Hemophilia B / Q000097:blood / Q000188:drug therapy*; D006490:Hemostatics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010314:Partial Thromboplastin Time; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000075462:Serum Albumin, Human
C422455:ALB protein, human; D006490:Hemostatics; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D005164:Factor IX; D000075462:Serum Albumin, Human