Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A

• Published in: Journal of thrombosis and haemostasis Vol. 13; no. 6; pp. 967 - 977
• Main Authors: Young, G., Mahlangu, J., Kulkarni, R., Nolan, B., Liesner, R., Pasi, J., Barnes, C., Neelakantan, S., Gambino, G., Cristiano, L. M., Pierce, G. F., Allen, G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.06.2015
• Subjects: Age Factors; Antibodies, Neutralizing - blood; Australia; Child; Child, Preschool; children; China; Coagulants - administration & dosage; Coagulants - adverse effects; Coagulants - immunology; Coagulants - pharmacokinetics; coagulation factor VIII; Drug Administration Schedule; Europe; Factor VIII - administration & dosage; Factor VIII - adverse effects; Factor VIII - immunology; Factor VIII - pharmacokinetics; Female; Half-Life; Hemarthrosis - blood; Hemarthrosis - diagnosis; Hemarthrosis - drug therapy; Hemarthrosis - prevention & control; Hemophilia A - blood; Hemophilia A - diagnosis; Hemophilia A - drug therapy; Hemophilia A - prevention & control; hemophilia A; Humans; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - adverse effects; Immunoglobulin Fc Fragments - immunology; Infusions, Intravenous; Male; North America; prophylaxis; recombinant fusion proteins; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacokinetics; Risk Factors; Severity of Illness Index; South Africa; Treatment Outcome; South Africa; Australia; North America; China; Europe; hemophilia A; recombinant fusion proteins; coagulation factor VIII; children; prophylaxis
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.12911

Summary Background Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Objective Kids A‐LONG was a phase 3 open‐label study evaluating the safety, efficacy and pharmacokinetics of a longer‐acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL−1 [< 1%]). Methods The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice‐weekly prophylaxis (Day 1, 25 IU kg−1; Day 4, 50 IU kg−1); dose (≤ 80 IU kg−1) and dosing interval (≥ 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. Results No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half‐life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety‐three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg−1. At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. Conclusion Twice‐weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A.