A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A

• Published in: Journal of thrombosis and haemostasis 2018-11, Vol.16 (11), p.2184-2195
• Main Authors: Eichler, H., Angchaisuksiri, P., Kavakli, K., Knoebl, P., Windyga, J., Jiménez‐Yuste, V., Hyseni, A., Friedrich, U., Chowdary, P.
• Format: Article
• Language: English
• Subjects: Antiplatelet therapy; Bleeding; clinical trial; Drug dosages; factor VIII; Hemophilia; hemophilia A; Immunogenicity; Monoclonal antibodies; Pharmacodynamics; Pharmacokinetics; Prothrombin; safety; Thrombin; Tissue factor
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.14272

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.