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

• Published in: Blood Vol. 119; no. 13; pp. 3031 - 3037
• Main Authors: Powell, Jerry S., Josephson, Neil C., Quon, Doris, Ragni, Margaret V., Cheng, Gregory, Li, Ella, Jiang, Haiyan, Li, Lian, Dumont, Jennifer A., Goyal, Jaya, Zhang, Xin, Sommer, Jurg, McCue, Justin, Barbetti, Margaret, Luk, Alvin, Pierce, Glenn F.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 29.03.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Adult; Biological and medical sciences; Clinical Trials and Observations; Dose-Response Relationship, Drug; Factor VIII - administration & dosage; Factor VIII - adverse effects; Factor VIII - pharmacokinetics; Factor VIII - therapeutic use; Half-Life; Hematologic and hematopoietic diseases; Hemophilia A - blood; Hemophilia A - drug therapy; Hemophilia A - metabolism; Humans; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - adverse effects; Immunoglobulin Fc Fragments - therapeutic use; Infusion Pumps; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Platelet diseases and coagulopathies; Receptors, Fc - administration & dosage; Receptors, Fc - metabolism; Receptors, Fc - therapeutic use; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - therapeutic use; Time Factors; von Willebrand Factor - analysis; Young Adult; Human; Hematology; Factor VIII; Hemopathy; Protein A; Biological activity; Hemophilia A; Genetic disease; Recombinant protein; Fusion protein; Coagulation factor; Coagulopathy; Prolonged
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-09-382846

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 t1/2, 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.