Phase I study of BAY 94‐9027, a PEGylated B‐domain‐deleted recombinant factor VIII with an extended half‐life, in subjects with hemophilia A
| Autor: | Mark T. Reding, J. C. Lin, Jerry S. Powell, L. A. Michaels, A. Shah, T. E. Coyle |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Treatment outcome Pharmacology Hemophilia A recombinant proteins Recombinant factor viii Polyethylene Glycols Clinical Haemostasis and Thrombosis law.invention Young Adult chemistry.chemical_compound law hemic and lymphatic diseases Animals Humans Medicine Prospective Studies Factor VIII business.industry Half-life Hematology Middle Aged Virology Peptide Fragments Phase i study Treatment Outcome Multicenter study chemistry Recombinant DNA clinical trial Phase 1 Original Article business pharmacokinetics Bay Ethylene glycol |
| Zdroj: | Journal of Thrombosis and Haemostasis |
| ISSN: | 1538-7836 |
| DOI: | 10.1111/jth.12506 |
| Popis: | Background BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. Objectives To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. Patients/Methods This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. Results BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ∼ 19 h (vs. ∼ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. Conclusions This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia. |
| Databáze: | OpenAIRE |
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