title: Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa.
abstract: BACKGROUND
  Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors.
  
  
  OBJECTIVE
  To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors.
  
  
  METHODS
  In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept(™) 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg(-1) ) or rFVIIa (one to three doses at 90 μg kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care.
  
  
  RESULTS
  In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa.
  
  
  CONCLUSIONS
  This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Lentz
authors.forename: S
authors.initials: S
authors.lastname: Ehrenforth
authors.forename: F Abdul
authors.initials: FA
authors.lastname: Karim
authors.forename: T
authors.initials: T
authors.lastname: Matsushita
authors.forename: K N
authors.initials: KN
authors.lastname: Weldingh
authors.forename: J
authors.initials: J
authors.lastname: Windyga
authors.forename: J N
authors.initials: JN
authors.lastname: Mahlangu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015942:Factor VIIa / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C000596433:vatreptacog alfa; D015942:Factor VIIa
keywords: antibodies; clinical trial, phase III; hemophilia; inhibitors; recombinant factor VIIa