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Rare Endocrine Disorders


Eichler H, Angchaisuksiri P, Kavakli K, Knoebl K, Windyga J, Jiménez-Yuste V, Hyseni A, Friedrich U, Chowdary P



Eichler H, Angchaisuksiri P, Kavakli K, Knoebl K, Windyga J, Jiménez-Yuste V, Hyseni A, Friedrich U, Chowdary P. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. J Thromb Haemost. 2018;16(11):2184-2195.




Date of Publication: 

8th October 2018



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.