title: Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.
abstract: OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.
authors.affiliation: Aflac Cancer Center and Blood Disorders Service and Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA. christine.kempton@emory.edu
authors.forename: C L
authors.initials: CL
authors.lastname: Kempton
authors.forename: T C
authors.initials: TC
authors.lastname: Abshire
authors.forename: R A
authors.initials: RA
authors.lastname: Deveras
authors.forename: W K
authors.initials: WK
authors.lastname: Hoots
authors.forename: J C
authors.initials: JC
authors.lastname: Gill
authors.forename: C M
authors.initials: CM
authors.lastname: Kessler
authors.forename: N S
authors.initials: NS
authors.lastname: Key
authors.forename: B A
authors.initials: BA
authors.lastname: Konkle
authors.forename: P
authors.initials: P
authors.lastname: Kuriakose
authors.forename: D E
authors.initials: DE
authors.lastname: Macfarlane
authors.forename: G
authors.initials: G
authors.lastname: Bergman
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood; D005169:Factor VIII / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000097:blood / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013552:Swine; D055815:Young Adult
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005169:Factor VIII