Phase I study of BAY 94-9027, a PEGylated B-domain-deleted  recombinant factor VIII with an extended half-life, in subjects  with hemophilia A.
BACKGROUND
BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia.


OBJECTIVE
To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.


METHODS
This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.


RESULTS
BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.


CONCLUSIONS
This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.
T E
TE
Coyle
M T
MT
Reding
J C
JC
Lin
L A
LA
Michaels
A
A
Shah
J
J
Powell
D000328:Adult; D000818:Animals; D005169:Factor VIII / Q000737:chemistry* / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry* / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
C451034:B-domain-deleted factor VIII; C000594952:BAY 94-9027; D010446:Peptide Fragments; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII