Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients.
Current factor VIII (FVIII) products display a half-life (t(1/2)) 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 IgG(1) to extend circulating rFVIII t(1/2). 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.
University of California, Davis, Sacramento, CA, USA. jspowell@ucdavis.edu
Jerry S
JS
Powell
Neil C
NC
Josephson
Doris
D
Quon
Margaret V
MV
Ragni
Gregory
G
Cheng
Ella
E
Li
Haiyan
H
Jiang
Lian
L
Li
Jennifer A
JA
Dumont
Jaya
J
Goyal
Xin
X
Zhang
Jurg
J
Sommer
Justin
J
McCue
Margaret
M
Barbetti
Alvin
A
Luk
Glenn F
GF
Pierce
D000328:Adult; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007260:Infusion Pumps; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011961:Receptors, Fc / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013997:Time Factors; D055815:Young Adult; D014841:von Willebrand Factor / Q000032:analysis
D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D014841:von Willebrand Factor; D005169:Factor VIII