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Abstract nr. - FVIIa-CTP and FIX-CTP, a novel long-acting coagulation factors with prolonged haemostatic effect and improved recovery in FVIII-/- and FIX-/- mice

Background:

Prolor Biotech Inc. develops biobetter long acting versions of Factor VIIa and Factor IX utilizing a technology called CTP which involves fusion of the C terminus peptide of beta hCG to a target protein. The technology was clinically validated and proven as a safe and efficient way for increasing the half-life of several therapeutic proteins while maintaining their biological activity.

Aims:

To determine the pharmacokinetic, pharmacodynamic and haemostatic effect of FVIIa-CTP and FIX-CTP in FVIII-/- and FIX -/- mice.

Methods:

FVIIa-CTP and FIX-CTP were expressed in CHO cells transfected with the proper genes and purified. FVIIa-CTP and FIX-CTP were administered to FVIII-/- and FIX-/- mice, PK and PD profiles were determined and the long acting homeostasis effect was evaluated and compared to the commercial products following bleeding challenge.

Results:

FVIIa-CTP pharmacokinetic parameters, as assessed by a clotting assay(Staclot), were superior to those of rFVIIa. Its half-life and AUC were 5 and 3.5 fold higher, respectively, in FVIII-/- mice and recovery was 2 times higher as compared to rFVIIa. In a TVT study, FVIIa-CTP had a profound survival effect, which was maintained for more than 48 hours. Following CTP fusion, FVIIa specific activity was only slightly reduced. FIX-CTP half life (as measured by aPTT) was 4 times longer than rFIX and a significant reduction in bleeding duration and intensity following a tail vein bleeding challenge in FIX -/-mice was observed 48 hr post dosing. Fusion of CTP significantly improved rFIX recovery in 2 folds, while its specific activity was slightly reduced.

Conclusion:

Fusion of CTP to FVIIa and FIX was well tolerated, markedly enhanced pharmacokinetics, increased exposure, increased recovery and prolonged hemostatic effect in hemophilic mice. Our data suggest that CTP fused coagulation factors have the potential to significantly improve the prophylactic and on demand treatment in patients with hemophilia.

 © Copyright 2012 5th Annual Congress EAHAD. All rights reserved. Sunday 27th of November 2011 11:56:40

Author(s)

G. Hart

M. Zakar

O. Hershkovitz

A. Bar-Ilan

E. Fima

Institute(s)

Prolor Biotech Inc. ; 7 Golda Meir, Nes- Ziona ,Israel 74140 (1)

Prolor Biotech Inc. ; 7 Golda Meir, Nes- Ziona, Israel 74140 (2)

Prolor Biotech Inc. ; 7 Golda Meir ,Nes- Ziona Israel 74140 (3)

Prolor Biotech Inc. ; 7 Golda Meir ,Nes- Ziona Israel 74140 (4)

Prolor Biotech Inc. ; 7 Golda Meir ,Nes- Ziona Israel 74140 (5)

© Copyright 2012 5th Annual Congress EAHAD. All rights reserved. Sunday 27th of November 2011 11:56:40 AM