Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A.
This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week.
Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa;
Johnny
J
Mahlangu
Jerry S
JS
Powell
Margaret V
MV
Ragni
Pratima
P
Chowdary
Neil C
NC
Josephson
Ingrid
I
Pabinger
Hideji
H
Hanabusa
Naresh
N
Gupta
Roshni
R
Kulkarni
Patrick
P
Fogarty
David
D
Perry
Amy
A
Shapiro
K John
KJ
Pasi
Shashikant
S
Apte
Ivan
I
Nestorov
Haiyan
H
Jiang
Shuanglian
S
Li
Srividya
S
Neelakantan
Lynda M
LM
Cristiano
Jaya
J
Goyal
Jurg M
JM
Sommer
Jennifer A
JA
Dumont
Nigel
N
Dodd
Karen
K
Nugent
Gloria
G
Vigliani
Alvin
A
Luk
Aoife
A
Brennan
Glenn F
GF
Pierce
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004334:Drug Administration Schedule; D005169:Factor VIII / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy*; D006470:Hemorrhage / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII