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Evaluation of the toxicology, pharmacokinetics, and local tolerance of recombinant factor IX Fc fusion protein in animals.

Authors :
Dumont JA
Loveday KS
Light DR
Pierce GF
Jiang H
Source :
Thrombosis research [Thromb Res] 2015 Aug; Vol. 136 (2), pp. 371-8. Date of Electronic Publication: 2015 Jan 23.
Publication Year :
2015

Abstract

Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) is a recombinant coagulation factor composed of a single molecule of recombinant factor IX (rFIX) covalently fused to the Fc domain of human immunoglobulin G1 (IgG1) with no intervening sequence. An extensive nonclinical program was performed to support the clinical development of rFIXFc for treatment of people with hemophilia B.<br />Materials and Methods: Repeat-dose toxicology studies of rFIXFc were performed in 2 relevant species: Sprague Dawley rats (4-week study) and cynomolgus monkeys (5- and 27-week studies). Assessments included in-life observations, electrocardiograms (monkeys only), laboratory evaluations (including hematology and blood chemistry), postmortem analyses, local tolerance, and pharmacokinetics (PK). Allometric scaling was performed with PK data from multiple species, including humans. Local tolerance (single-dose study) and thrombogenic potential (Wessler stasis model) of rFIXFc were tested in New Zealand White rabbits.<br />Results: There were no significant local or systemic toxicity findings in the repeat-dose studies. Allometric scaling data suggested that animal rFIXFc PK results are predictive of human PK parameters. There were no findings from the local tolerance study in rabbits; thrombogenic activity was less than that elicited by rFIX and a prothrombin complex concentrate, and similar to vehicle control.<br />Conclusions: rFIXFc was well tolerated in toxicology studies and demonstrated a low thrombogenic potential. These results are consistent with phase 1/2a and phase 3 clinical studies of rFIXFc in people with hemophilia B.<br /> (Copyright © 2015. Published by Elsevier Ltd.)

Details

Language :
English
ISSN :
1879-2472
Volume :
136
Issue :
2
Database :
MEDLINE
Journal :
Thrombosis research
Publication Type :
Academic Journal
Accession number :
25840744
Full Text :
https://doi.org/10.1016/j.thromres.2015.01.020