Abstract | INTRODUCTION: rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII. MATERIALS AND METHODS: Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate(®)) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl3-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200-250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice. RESULTS: rVIII-SingleChain displayed a high affinity for von Willebrand factor (KD=44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl3-induced arterial occlusion model. CONCLUSIONS: rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.
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Authors | Sabine Zollner, Elmar Raquet, Philipp Claar, Jochen Müller-Cohrs, Hubert J Metzner, Thomas Weimer, Ingo Pragst, Gerhard Dickneite, Stefan Schulte |
Journal | Thrombosis research
(Thromb Res)
Vol. 134
Issue 1
Pg. 125-31
(Jul 2014)
ISSN: 1879-2472 [Electronic] United States |
PMID | 24814969
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014. Published by Elsevier Ltd. |
Chemical References |
- von Willebrand Factor
- recombinant factor VIII SQ
- Factor VIII
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Topics |
- Animals
- Disease Models, Animal
- Factor VIII
(pharmacokinetics, pharmacology)
- Hemophilia A
(metabolism)
- Macaca fascicularis
- Mice
- Rabbits
- Rats
- Surface Plasmon Resonance
- von Willebrand Factor
(metabolism)
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