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40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics, and preliminary efficacy in hemophilia patients with inhibitors.

Ljung, Rolf LU ; Karim, F A; Saxena, K; Suzuki, Toru LU ; Arkhammar, P; Rosholm, A and Giangrande, P (2013) In Journal of Thrombosis and Haemostasis 11(7). p.1260-1268
Abstract
BACKGROUND: A 40K glycoPEGylated, recombinant Factor VIIa (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared to rFVIIa was developed as a potential candidate for bleed preventive regimens in patients with hemophilia and inhibitors. OBJECTIVES: 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. PATIENTS/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... (More)
BACKGROUND: A 40K glycoPEGylated, recombinant Factor VIIa (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared to rFVIIa was developed as a potential candidate for bleed preventive regimens in patients with hemophilia and inhibitors. OBJECTIVES: 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. PATIENTS/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. RESULTS AND 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 (Registration Number: NCT00951405). This article is protected by copyright. All rights reserved. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Thrombosis and Haemostasis
volume
11
issue
7
pages
1260 - 1268
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000321763500006
  • pmid:23578227
  • scopus:84880198215
ISSN
1538-7933
DOI
10.1111/jth.12237
language
English
LU publication?
yes
id
7762a304-9a42-4058-833c-34bc2380c751 (old id 3733870)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23578227?dopt=Abstract
date added to LUP
2013-05-04 18:00:22
date last changed
2019-04-10 01:23:02
@article{7762a304-9a42-4058-833c-34bc2380c751,
  abstract     = {BACKGROUND: A 40K glycoPEGylated, recombinant Factor VIIa (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared to rFVIIa was developed as a potential candidate for bleed preventive regimens in patients with hemophilia and inhibitors. OBJECTIVES: 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. PATIENTS/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. RESULTS AND 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 (Registration Number: NCT00951405). This article is protected by copyright. All rights reserved.},
  author       = {Ljung, Rolf and Karim, F A and Saxena, K and Suzuki, Toru and Arkhammar, P and Rosholm, A and Giangrande, P},
  issn         = {1538-7933},
  language     = {eng},
  number       = {7},
  pages        = {1260--1268},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics, and preliminary efficacy in hemophilia patients with inhibitors.},
  url          = {http://dx.doi.org/10.1111/jth.12237},
  volume       = {11},
  year         = {2013},
}