title: Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII.
abstract: BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects <16 years old, in two studies. A double-blind, randomized, pharmacokinetic (PK) crossover study, utilizing a central laboratory assay (one-stage (OS)) for both drug potency assignment and plasma FVIII-activity measurements, demonstrated that BDDrFVIII was PK-equivalent to a full-length rFVIII. Favourable efficacy and safety were observed: during defined routine prophylaxis in a patient population significant for preexisting target joints, nearly half (45.7%) of patients had no bleeding, and a low-annualized bleed rate (ABR) was achieved (median 1.9); 92.5% of haemorrhages (n = 187) required < or =2 infusions. Three subjects (1.5%, across both studies) developed de novo inhibitors (low-titre, transient), and the primary safety endpoint, based on a prospective Bayesian analysis, demonstrated the absence of neoantigenicity for BDDrFVIII. The PK-equivalence, based on central testing to align test and reference articles, and the novel Bayesian analysis of inhibitor safety in these investigations reflect robust experimental designs with relevance to future studies. This extensive dataset demonstrates the safety and efficacy of BDDrFVIII for haemophilia A.
authors.affiliation: Hemophilia Treatment Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. rechtm@ohsu.edu
authors.forename: M
authors.initials: M
authors.lastname: Recht
authors.forename: L
authors.initials: L
authors.lastname: Nemes
authors.forename: M
authors.initials: M
authors.lastname: Matysiak
authors.forename: M
authors.initials: M
authors.lastname: Manco-Johnson
authors.forename: J
authors.initials: J
authors.lastname: Lusher
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Mannucci
authors.forename: C
authors.initials: C
authors.lastname: Hay
authors.forename: T
authors.initials: T
authors.lastname: Abshire
authors.forename: A
authors.initials: A
authors.lastname: O'Brien
authors.forename: B
authors.initials: B
authors.lastname: Hayward
authors.forename: C
authors.initials: C
authors.lastname: Udata
authors.forename: D A
authors.initials: DA
authors.lastname: Roth
authors.forename: S
authors.initials: S
authors.lastname: Arkin
mesh_terms: D000293:Adolescent; D000328:Adult; D001499:Bayes Theorem; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics / Q000493:pharmacokinetics*; D002648:Child; D005169:Factor VIII / Q000235:genetics / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C451034:B-domain-deleted factor VIII; D019774:Blood Coagulation Factor Inhibitors; D010446:Peptide Fragments; C427184:recombinant factor VIII SQ; D005169:Factor VIII