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

Background: Concizumab is a humanized mAb targeting tissue factor pathway inhibitor (TFPI), leading to enhanced thrombin generation (TG) potential. explorer (TM) 3 (NCT02490787) was a phase lb, double-blind, multipledose 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 (TM) 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 (TM) 3 data support further clinical development of concizumab for use in people with hemophilia, with or without inhibitors.