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doi:10.22028/D291-44279
Titel: | A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A |
VerfasserIn: | Eichler, Hermann Angchaisuksiri, P. Kavakli, Kaan Knoebl, P. Windyga, J. Jiménez-Yuste, Victor Hyseni, A. Friedrich, U. Chowdary, P. |
Sprache: | Englisch |
Titel: | Journal of thrombosis and haemostasis : the official journal of the International Society on Thrombosis and Haemostasis |
Bandnummer: | 16 |
Heft: | 11 |
Seiten: | 2184-2195 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2018 |
Freie Schlagwörter: | clinical trial factor VIII hemophilia A pharmacokinetics safety |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | 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. |
DOI der Erstveröffentlichung: | 10.1111/jth.14272 |
URL der Erstveröffentlichung: | https://www.sciencedirect.com/science/article/pii/S1538783622029142 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-442792 hdl:20.500.11880/39715 http://dx.doi.org/10.22028/D291-44279 |
ISSN: | 1538-7836 1538-7933 |
Datum des Eintrags: | 24-Feb-2025 |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Chirurgie |
Professur: | M - Prof. Dr. Hermann Eichler |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S1538783622029142-main.pdf | 673,66 kB | Adobe PDF | Öffnen/Anzeigen |
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