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

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 23; no. 5; pp. 769 - 776
• Main Authors: Waters, E. K., Sigh, J., Friedrich, U., Hilden, I., Sørensen, B. B.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2017
• Subjects: Adolescent; Adult; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Blood Coagulation Tests; Case-Control Studies; concizumab; Drug Monitoring; haemophilia; Hemophilia; Hemophilia A - blood; Hemophilia A - diagnosis; Hemophilia A - drug therapy; Hemophilia B - blood; Hemophilia B - diagnosis; Hemophilia B - drug therapy; Humans; mAb 2021; Male; Middle Aged; Plasma; Thrombin; Thrombin - biosynthesis; thrombin generation; thrombin generation assay; Thrombin Time; Tissue factor; tissue factor pathway inhibitor; Treatment Outcome; Young Adult; haemophilia; tissue factor pathway inhibitor; thrombin generation assay; concizumab; thrombin generation; mAb 2021
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.13260

Aims Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration‐dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. Methods For the ex vivo spiking study, platelet‐poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001–500 nm concizumab. For the multiple‐dosing study, four healthy males received concizumab 250 μg kg−1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram® system with 1 pm tissue factor. Results In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near‐normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. Conclusions Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy.