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


CONCLUSIONS
Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A.
Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
G
G
Young
University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa.
J
J
Mahlangu
Michigan State University, East Lansing, MI, USA.
R
R
Kulkarni
Our Lady's Children's Hospital, Dublin, Ireland.
B
B
Nolan
Great Ormond Street Hospital for Children, London, UK.
R
R
Liesner
Barts and the London Comprehensive Care Centre, London, UK.
J
J
Pasi
Royal Children's Hospital, Melbourne, Victoria, Australia.
C
C
Barnes
Biogen, Cambridge, MA, USA.
S
S
Neelakantan
Biogen, Cambridge, MA, USA.
G
G
Gambino
Biogen, Cambridge, MA, USA.
L M
LM
Cristiano
Biogen, Cambridge, MA, USA.
G F
GF
Pierce
Biogen, Cambridge, MA, USA.
G
G
Allen
D000367:Age Factors; D057134:Antibodies, Neutralizing / Q000097:blood; D001315:Australia; D002648:Child; D002675:Child, Preschool; D002681:China; D003029:Coagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005060:Europe; D005169:Factor VIII / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006395:Hemarthrosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control*; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007262:Infusions, Intravenous; D008297:Male; D009656:North America; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D012307:Risk Factors; D012720:Severity of Illness Index; D013019:South Africa; D016896:Treatment Outcome
D057134:Antibodies, Neutralizing; D003029:Coagulants; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII
children; coagulation factor VIII; hemophilia A; prophylaxis; recombinant fusion proteins