Safety and pharmacokinetics of anti‐TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

Abstract

) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). Results: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC 0-∞ of 33 960 h lg mL À1 and a maximum mean concentration of 247 lg mL À1 was measured at the highest dose. Conclusions: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

Concizumab, an anti‐tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay

“…Concizumab can be administered subcutaneously (s.c.); therefore, it may represent a novel approach for prophylaxis [1].…”

“…One potential target for alternative treatment strategies is tissue factor pathway inhibitor (TFPI), the primary inhibitor of the initiation of coagulation. It binds and inhibits factor VIIa (FVIIa) in complex with tissue factor (TF), and factor Xa (FXa), with the overall effect of reduced thrombin generation and decreased blood coagulation [1,6].…”

“…Primary prophylaxis with infusions of coagulation factor VIII (FVIII; haemophilia A) or factor IX (FIX; haemophilia B) is the gold standard of care for haemophilia patients today, with the aim of preventing bleeds, slowing the progression of joint destruction and preserving musculoskeletal function [1,2,4,5].…”

“…Severe haemophilia A and B are characterized by recurrent bleeding into joints, muscles and soft tissues [1][2][3].…”

“…In addition to preventing FXa binding to TFPI, concizumab also blocks TFPI inhibition of TF-FVIIa, resulting in increased FXa and thrombin generation in vitro [1].…”