Publication: A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A
Issued Date
2018-11-01
Resource Type
ISSN
15387836
15387933
15387933
Other identifier(s)
2-s2.0-85054175026
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Thrombosis and Haemostasis. Vol.16, No.11 (2018), 2184-2195
Suggested Citation
H. Eichler, P. Angchaisuksiri, K. Kavakli, P. Knoebl, J. Windyga, V. Jiménez-Yuste, A. Hyseni, U. Friedrich, P. Chowdary A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. Journal of Thrombosis and Haemostasis. Vol.16, No.11 (2018), 2184-2195. doi:10.1111/jth.14272 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46225
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A
Other Contributor(s)
Institute of Haematology and Transfusion Medicine, Warsaw
NHS Foundation Trust
Hospital Universitario La Paz
Universitätsklinikum des Saarlandes Medizinische Fakultät der Universität des Saarlandes
Ege Üniversitesi
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Medizinische Universitat Wien
Novo Nordisk A/S
NHS Foundation Trust
Hospital Universitario La Paz
Universitätsklinikum des Saarlandes Medizinische Fakultät der Universität des Saarlandes
Ege Üniversitesi
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Medizinische Universitat Wien
Novo Nordisk A/S
Abstract
© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. Essentials explorer™3 was a double-blinded, multiple-dose escalation trial of subcutaneous concizumab. A pharmacodynamic relationship for unbound TFPI and thrombin generation was confirmed. No serious adverse events and no anti-drug antibodies were observed. explorer™3 data support further clinical development of concizumab in people with hemophilia. Summary: Background Concizumab is a humanized mAb targeting tissue factor pathway inhibitor (TFPI), leading to enhanced thrombin generation (TG) potential. explorer™3 (NCT02490787) was a phase 1b, double-blind, multiple-dose escalation trial of subcutaneous concizumab in people with severe hemophilia A without inhibitors. Objectives The primary objective was to evaluate safety. Assessments of pharmacokinetics, pharmacodynamics and subcutaneous concizumab immunogenicity were secondary objectives. Patients/Methods Adverse events (AEs), clinical assessments and bleeding episodes were recorded. Plasma concizumab levels and unbound TFPI levels were measured with ELISAs; residual TFPI activity was measured with a chromogenic assay. Standardized assays were used to assess TG, D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels. explorer™3 was completed after investigation of three dose cohorts (0.25, 0.5 and 0.8 mg kg−1, once every 4 days) had been completed. Twenty-four patients received 12 doses of concizumab or placebo in a 3 : 1 randomization over a 42-day period. Results No serious AEs and no anti-drug antibodies were observed. Fifty-four mild and two moderate AEs were observed in 19 patients. Concizumab exposure increased with dose in a non-linear manner, confirming target-mediated drug disposition. D-dimer and F1 + 2 levels were increased mostly in the highest dose cohort, in line with previous observations. The level of unbound TFPI decreased in a dose-dependent manner, and was accompanied by a residual TFPI activity decrease and an increase in peak TG. Although the trial was not powered to evaluate efficacy, a trend towards lower bleeding rates was observed in patients in the highest dose cohort. Conclusion explorer™3 data support further clinical development of concizumab for use in people with hemophilia, with or without inhibitors.