Evaluation of Factor VIII Polysialylation: Identification of a Longer-Acting Experimental Therapy in Mice and Monkeys
| Autor: | Alexandra Kopic, Tanja Ruthsatz, Hanspeter Rottensteiner, Frank M. Horling, Friedrich Scheiflinger, Werner Höllriegl, Alexander Bauer, Gerald Schrenk, Peter Leidenmühler, Martin J. Wolfsegger, Gerald Höbarth, Alfred Weber, Herbert Gritsch, Birgit M. Reipert, Helmut Glantschnig, Karima Benamara, Veronika Ehrlich, Michael Dockal, Maria Schuster, Peter Turecek |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Drug Evaluation Preclinical Pharmacology Hemophilia A 03 medical and health sciences 0302 clinical medicine Von Willebrand factor Pharmacokinetics von Willebrand Factor Animals Humans Medicine Scavenger receptor Receptor Receptors Scavenger Clinical Trials as Topic Factor VIII biology business.industry Immunogenicity Area under the curve N-Acetylneuraminic Acid Absorption Physiological Rats Macaca fascicularis 030104 developmental biology Toxicity biology.protein Molecular Medicine Female business 030217 neurology & neurosurgery Half-Life Protein Binding Lipoprotein |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 371:95-105 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.119.260067 |
| Popis: | Extended half-life (EHL) factor therapies are needed to reduce the burden of prophylaxis and improve treatment adherence in patients with hemophilia. BAX 826 is a novel polysialylated full-length recombinant factor VIII [polysialyic acid (PSA) rFVIII] with improved pharmacokinetics (PK), prolonged pharmacology, and maintained safety attributes to enable longer-acting rFVIII therapy. In factor VIII (FVIII)-deficient hemophilic mice, PSArFVIII showed a substantially higher mean residence time (>2-fold) and exposure (>3-fold), and prolonged efficacy in tail-bleeding experiments (48 vs. 30 hours) compared with unmodified recombinant FVIII (rFVIII), as well as a potentially favorable immunogenicity profile. Reduced binding to a scavenger receptor (low-density lipoprotein receptor-related protein 1) and von Willebrand factor (VWF) as well as a largely VWF-independent circulation time in mice provide a rationale for prolonged BAX 826 activity. The significantly improved PK profile versus rFVIII was confirmed in cynomolgus monkeys [mean residence time: 23.4 vs. 10.1 hours; exposure (area under the curve from time 0 to infinity): 206 vs. 48.2 IU/ml⋅h] and is in line with results from rodent studies. Finally, safety and toxicity evaluations did not indicate increased thrombogenic potential, and repeated administration of BAX 826 to monkeys and rats was well tolerated. The favorable profile and mechanism of this novel experimental therapeutic demonstrated all of the requirements for an EHL-rFVIII candidate, and thus BAX 826 was entered into clinical assessment for the treatment of hemophilia A. SIGNIFICANCE STATEMENT: Prolongation of FVIII half-life aims to reduce the burden of prophylaxis and improve treatment outcomes in patients with hemophilia. This study shows that polysialylation of PSArFVIII resulted in prolongations of rFVIII circulation time and procoagulant activity, together with a favorable nonclinical safety profile of the experimental therapeutic. |
| Databáze: | OpenAIRE |
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