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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.
Haemophilia 2017; 23(5):769-776H

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 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.

Authors+Show Affiliations

Haemophilia Biology, Novo Nordisk A/S, Måløv, Denmark.Haemophilia Biology, Novo Nordisk A/S, Måløv, Denmark.Haemophilia Biology, Novo Nordisk A/S, Måløv, Denmark.Haemophilia Biology, Novo Nordisk A/S, Måløv, Denmark.Haemophilia Biology, Novo Nordisk A/S, Måløv, Denmark.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28594458

Citation

Waters, E K., et al. "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." Haemophilia : the Official Journal of the World Federation of Hemophilia, vol. 23, no. 5, 2017, pp. 769-776.
Waters EK, Sigh J, Friedrich U, et al. 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. Haemophilia. 2017;23(5):769-776.
Waters, E. K., Sigh, J., Friedrich, U., Hilden, I., & Sørensen, B. B. (2017). 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. Haemophilia : the Official Journal of the World Federation of Hemophilia, 23(5), pp. 769-776. doi:10.1111/hae.13260.
Waters EK, et al. 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. Haemophilia. 2017;23(5):769-776. PubMed PMID: 28594458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Waters,E K, AU - Sigh,J, AU - Friedrich,U, AU - Hilden,I, AU - Sørensen,B B, Y1 - 2017/06/08/ PY - 2017/03/29/accepted PY - 2017/6/9/pubmed PY - 2018/5/22/medline PY - 2017/6/9/entrez KW - concizumab KW - haemophilia KW - mAb 2021 KW - thrombin generation KW - thrombin generation assay KW - tissue factor pathway inhibitor SP - 769 EP - 776 JF - Haemophilia : the official journal of the World Federation of Hemophilia JO - Haemophilia VL - 23 IS - 5 N2 - 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. SN - 1365-2516 UR - https://www.unboundmedicine.com/medline/citation/28594458/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_ L2 - https://doi.org/10.1111/hae.13260 DB - PRIME DP - Unbound Medicine ER -