A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A
Makaleler > Tam Makale · 2018
Yazarlar: H. Eichler, P. Angchaisuksiri, K. Kavakli, P. Knoebl, J. Windyga, V. Jiménez‐Yuste, A. Hyseni, U. Friedrich, P. Chowdary
Journal of Thrombosis and Haemostasis, Uluslararası, 2018, cilt 16, ss 2184-2195
DOI: 10.1111/jth.14272
Özet
Unlabelled Box •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. The authors would like to thank the patients who participated in the trial and their families. The authors would like to acknowledge the contribution of all investigators (see below), co‐investigators and study nurses who were involved in the explorer™3 trial and screened patients for the trial. The authors would also like to thank J. Haaning, L. Jacobsen, M. T. Kveiborg, J. Rasmussen, K. Wahlander and R. Wirz from Novo Nordisk for their review of and input to the manuscript. Medical writing support was provided by Physicians World Europe GmbH, Mannheim, Germany, and was financially supported by Novo Nordisk A/S, Denmark. The explorer™3 study was sponsored by Novo Nordisk, A/S, Denmark. The explorer™3 investigators were: P. Angchaisuksiri, P. Chowdary, H. Eichler, S. Halimeh, V. Jiménez‐Yuste, K. Kavakli, R. Kazmi, G. Kenet, R. Klamroth, P. Knoebl, J. Lasky, O. Stasyshyn, M. Trossaert, J. Windyga, and S. Zupancic‐Salek. Novo Nordisk, A/S 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 (F 1 + 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 F 1 + 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.