title: 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors.
abstract: BACKGROUND
  A 40K glycoPEGylated, recombinant activated factor VII (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared with rFVIIa was developed as a potential candidate for bleed-preventive regimens in patients with hemophilia and inhibitors.
  
  
  OBJECTIVE
  To evaluate the safety, pharmacokinetics and preliminary efficacy of multiple doses of N7-GP in congenital hemophilia A and B patients with high-titer inhibitors.
  
  
  METHODS
  In this global, prospective, randomized, double-blinded, phase 2 trial, 25, 100 or 200 μg kg(-1)  N7-GP was administered intravenously once every second day during a 3-month, bleed-preventive regimen and compared with a preceding 3-month observation period with on-demand treatment of bleeds with rFVIIa. The primary endpoint was adverse events; secondary endpoints were evaluation of immunogenicity, pharmacokinetics and efficacy.
  
  
  CONCLUSIONS
  Overall, 23 patients were randomized and dosed (n = 8/7/8 for 25/100/200 μg kg(-1) ). N7-GP was well tolerated, with a low frequency of adverse events. No serious adverse events, immunogenic or thromboembolic events related to N7-GP were reported. The pharmacokinetic properties of N7-GP were similar to those reported in phase 1. The annualized bleeding rate (ABR) decreased in the treatment period vs. the observation period at all N7-GP dose levels. However, a dose-response relationship in the reduction could not be established in the N7-GP dose range evaluated. The ABR was also reduced at two dose levels during the last part of the observation period, and increased notably in the follow-up period irrespective of previous N7-GP dose. The trial was registered at ClinicalTrials.gov (
  
  
  BACKGROUND
  NCT00951405).
authors.affiliation: Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden. rolf.ljung@med.lu.se
authors.forename: R
authors.initials: R
authors.lastname: Ljung
authors.forename: F A
authors.initials: FA
authors.lastname: Karim
authors.forename: K
authors.initials: K
authors.lastname: Saxena
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: P
authors.initials: P
authors.lastname: Arkhammar
authors.forename: A
authors.initials: A
authors.lastname: Rosholm
authors.forename: P
authors.initials: P
authors.lastname: Giangrande
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood*; D002648:Child; D003029:Coagulants / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D015942:Factor VIIa / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000906:Antibodies; D003029:Coagulants; C533779:glycoPEGylated factor VIIa; D015942:Factor VIIa
keywords: Factor VII; Factor VIII; hemophilia; inhibitors; safety