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

Abstract

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 concentrationdependent 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 lg kg À1 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 â 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.

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

“…As with emicizumab, potential benefits of these other non‐factor therapies include improved compliance due to more convenient subcutaneous (rather than intravenous) administration. Promising early results have been demonstrated with concizumab, a humanised monoclonal antibody targeting anti‐tissue factor pathway inhibitor (TFPI): there were no serious AEs in concizumab‐treated patients with haemophilia A or B; improved thrombin generation was observed in patients with haemophilia A and B and in plasma samples from patients with haemophilia A and inhibitors . Two other monoclonal antibodies targeting TFPI (BAY 1093884 and PF‐06741086) are in development.…”

Global coagulation assays in hemophilia A: A comparison to conventional assays

“…Novel nonreplacement therapies such as FVIII‐mimetic bispecific antibodies and tissue factor (TF) pathway inhibitor antibodies may be difficult to measure using conventional assays. Researchers have explored the use of global assays to measure coagulation potential with these products . Furthermore, evidence suggests that global assays are a useful tool to detect bleeding tendency in people with HA, might facilitate individualized treatment of patients with HA, and help monitor bypassing agents in patients with inhibitors …”

“…Researchers have explored the use of global assays to measure coagulation potential with these products. 19,20 Furthermore, evidence suggests that global assays are a useful tool to detect bleeding tendency in people with HA, 2,21-25 might facilitate individualized treatment of patients with HA, 26,27 and help monitor bypassing agents in patients with inhibitors. 28,29 To investigate and understand differences in global and conventional laboratory assays in the diagnosis and management of HA, we measured the coagulation potential of patients with severe, moderate, and mild HA using thromboelastometry, TGA, and clot waveform analysis and compared the parameters to conventional APTT tests and FVIII levels.…”

The Potential Close Future of Hemophilia Treatment - Gene Therapy, TFPI Inhibition, Antithrombin Silencing, and Mimicking Factor VIII with an Engineered Antibody

“…Antibodies to Inhibit TFPI Antibodies to TFPI have long been known to shorten clotting times [6], and they were shown to enhance generation of both FXa and thrombin [14,19]. TFPI levels in patients with hemophilia do not seem different from those without [20].…”

“…A dose-dependent procoagulant effect was evidenced by D-dimers and Prothrombin Fragments F1 + F2 [23]. Concizumab was shown to augment results of a thrombin generation assay in vitro in plasma of hemophilia patients as well as ex vivo after s.c. injections in healthy volunteers [19]. A phase 2 study is underway to assess the efficacy and safety of concizumab administered s.c. once daily in preventing bleeding episodes in hemophilia A and B patients with inhibitors.…”