Hamostaseologie 2019; 39(S 01): S1-S92
DOI: 10.1055/s-0039-1680220
Poster
P08 Haemophilia 2
Georg Thieme Verlag KG Stuttgart · New York

Improving the FVIII Binding Affinity of a Recombinant VWF D'D3-albumin Fusion Molecule Translates to Dosing Benefits with Respect to the Half-life Extension of Co-administered FVIII

S. Pestel
1   CSL Behring, Research, Marburg, Germany
,
E. Raquet
1   CSL Behring, Research, Marburg, Germany
,
M. Mischnik
1   CSL Behring, Research, Marburg, Germany
,
P. Claar
1   CSL Behring, Research, Marburg, Germany
,
M. Wilson
2   CSL Limited, Research, Bio21 Institute, Melbourne, Australia
,
S. Dower
2   CSL Limited, Research, Bio21 Institute, Melbourne, Australia
,
E. Herzog
1   CSL Behring, Research, Marburg, Germany
,
T. Weimer
1   CSL Behring, Research, Marburg, Germany
,
A. Andrews
2   CSL Limited, Research, Bio21 Institute, Melbourne, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
13 February 2019 (online)

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    Scientific Research Question: A recombinant VWF D'D3 albumin fusion protein (rD'D3-FP) has been developed to extend the half-life of co-administered coagulation factor VIII (FVIII), for the treatment of hemophilia A. Pharmacokinetic (PK) studies in rats, rabbits, cynomolgus monkeys and FVIII knockout mice have demonstrated a significant improvement in rVIII-SingleChain PK parameters upon co-administration with rD'D3-FP. Interestingly the half-life of rVIII-SingleChain, although increased, remained less than that of the co-administered rD'D3-FP. It is hypothesized that FVIII exchange between rD'D3-FP and endogenous VWF in circulation combined with a reduced recycling efficiency for FVIII contribute to this shorter half-life. To overcome these issues, novel rD'D3-FP variants with reduced dissociation for FVIII under both neutral and acidic conditions have been generated. This study aimed to investigate if rD'D3-FP variants with enhanced FVIII binding are more effective at improving the PK of co-administered FVIII than wild-type rD'D3-FP.

    Methodology: rD'D3-FP (wild-type and variants) were administered intravenously at a dose range of 0.086-10 mg/kg, alone or in combination with rVIII-SingleChain (200 IU/kg). Plasma PK of rD'D3-FP molecules and FVIII (antigen and/or activity levels) was monitored for up to 96 h.

    Findings: All rD'D3-FP species displayed comparable PK. The rD'D3-FP variants with improved FVIII binding properties showed enhanced potency, with the dose levels required for equivalent FVIII half-life extension, correlating to the off-rate improvements. At potential clinical doses, the rD'D3-FP variants provide benefits with respect to dose levels and half-life extension of co-administered FVIII.

    Conclusions: Our results support the development of an enhanced FVIII affinity variant of rD'D3-FP to further improve the treatment of hemophilia A.


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    No conflict of interest has been declared by the author(s).