Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients

Jerry S Powell, Neil C. Josephson, Doris Quon, Margaret V. Ragni, Gregory Cheng, Ella Li, Haiyan Jiang, Lian Li, Jennifer A. Dumont, Jaya Goyal, Xin Zhang, Jurg Sommer, Justin McCue, Margaret Barbetti, Alvin Luk, Glenn F. Pierce

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149 Scopus citations

Abstract

Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t 1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.

Original languageEnglish (US)
Pages (from-to)3031-3037
Number of pages7
JournalBlood
Volume119
Issue number13
DOIs
StatePublished - Mar 29 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Powell, J. S., Josephson, N. C., Quon, D., Ragni, M. V., Cheng, G., Li, E., Jiang, H., Li, L., Dumont, J. A., Goyal, J., Zhang, X., Sommer, J., McCue, J., Barbetti, M., Luk, A., & Pierce, G. F. (2012). Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood, 119(13), 3031-3037. https://doi.org/10.1182/blood-2011-09-382846