Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII.
Thromb Res
; 132(2): 280-7, 2013 Aug.
Article
en En
| MEDLINE
| ID: mdl-23830969
ABSTRACT
INTRODUCTION:
The preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII, was assessed in a series of animal studies. MATERIALS ANDMETHODS:
In the tail-clip bleeding model, hemophilia A mice were injected with escalating doses (1-150 IU/kg) of rVIII-SingleChain, B-domain deleted (BDD) rFVIII (ReFacto AF(®)), or full-length rFVIII products (Advate(®), Helixate(®)). Total blood loss and the percentage of animals in which hemostasis occurred were assessed in this observer-blinded, randomized study. In a second non-randomized study in hemophilia A mice, thromboelastographic analysis, thrombin generation, and activated partial thromboplastin time assays were performed. General safety and toxicity were assessed in three animal species, including determination of the prothrombotic potential of rVIII-SingleChain in a rabbit venous thrombosis model.RESULTS:
Under acute bleeding conditions, the effect of rVIII-SingleChain on total blood loss and hemostasis was indistinguishable from BDD and full-length rFVIII. rVIII-SingleChain and full-length rFVIII (both 20 IU/kg) corrected thromboelastographic parameters, activated partial thromboplastin time, and thrombin generation to a similar degree in hemophilia A mice. In a thrombosis model, the effect of rVIII-SingleChain on thrombus incidence was non-significant and comparable to BDD rFVIII at doses up to 500 IU/kg. Treatment with rVIII-SingleChain did not cause anaphylactic reaction or local intolerance in safety and toxicity studies, and demonstrated an excellent overall safety profile.CONCLUSIONS:
rVIII-SingleChain showed convincing hemostatic efficacy and excellent tolerability in animal studies, warranting continued investigation in human Phase I/III trials (AFFINITY).Palabras clave
ADA; AUC; AUC from 0 to 24hours; AUC from 0 to last timepoint; AUC(0-last); AUC(024h); B-domain deleted; BDD; C(max); CFT; CHO; CI; CT; Chinese hamster ovary; ELISA; ETP; FVIII; GLP; PTF; TGA; VWF; aPCC; aPTT; activated partial thromboplastin time; activated prothrombin complex concentrate; activated recombinant factor VIII; anti-drug antibody; area under the curve; clot formation time; clotting time; confidence interval; endogenous thrombin potential; enzyme-linked immunosorbent assay; factor VIII; good laboratory practice; half-life; hemostasis; maximum concentration; potentiation of thrombus formation; preclinical; rFVIII; rFVIIIa; rVIII-SingleChain; recombinant; recombinant factor VIII; t(1/2); t(max); thrombin generation assay; time taken to achieve C(max); von Willebrand factor
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor VIII
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Hemofilia A
Tipo de estudio:
Clinical_trials
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Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Thromb Res
Año:
2013
Tipo del documento:
Article
Pais de publicación:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA