40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors
R Ljung, F A Karim, K Saxena, T Suzuki, P Arkhammar, A Rosholm, P Giangrande, Pioneer™1 Investigators, Chantal Rothschild, Midori Shima, Satoshi Higasa, Takashi Suzuki, Michio Sakai, Faraizah Abdul Karim, Ivo Elezovic, Rolf Ljung, Bülent Zülfikar, Paediatric Haematology, Türkiz Gürsel, Paul Giangrande, David Bevan, Kapil Saxena, Michael Recht, M Elaine Eyster, Milton S Hershey, Tung Thanh Wynn, Guy Young, Johnny Mahlangu, Nadine Rapiti, R Ljung, F A Karim, K Saxena, T Suzuki, P Arkhammar, A Rosholm, P Giangrande, Pioneer™1 Investigators, Chantal Rothschild, Midori Shima, Satoshi Higasa, Takashi Suzuki, Michio Sakai, Faraizah Abdul Karim, Ivo Elezovic, Rolf Ljung, Bülent Zülfikar, Paediatric Haematology, Türkiz Gürsel, Paul Giangrande, David Bevan, Kapil Saxena, Michael Recht, M Elaine Eyster, Milton S Hershey, Tung Thanh Wynn, Guy Young, Johnny Mahlangu, Nadine Rapiti
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.
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).
Keywords: Factor VII; Factor VIII; hemophilia; inhibitors; safety.
© 2013 International Society on Thrombosis and Haemostasis.
Source: PubMed