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Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas.
Haemophilia 2019; 25(5):797-806H

Abstract

INTRODUCTION

Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting.

AIM

We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF-06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas. We compared the effects of marstacimab to the effects of recombinant coagulation factors and investigated the reproducibility of marstacimab in restoring haemostasis by comparing its effect in whole blood collected from the same study participants on differing days.

METHODS

Citrated whole blood and plasmas obtained from haemophilia participants were supplemented ex vivo with vehicle, marstacimab, recombinant FVIII (rFVIII) or recombinant factor IX (rFIX) and analysed in ROTEM, TGA and the dPT assay using low tissue factor concentrations to trigger coagulation.

RESULTS

Marstacimab induced pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in angle. Similarly, participant plasmas supplemented with marstacimab exhibited improvements in TGA parameters, including reduced lag times, increased peak thrombin concentrations and reductions in dPT clotting time. Concentrations of marstacimab tested showed activity comparable to addition of rFVIII or rFIX and were reproducible.

CONCLUSIONS

These studies show the ex vivo potency of marstacimab in restoring haemostasis in whole blood and plasmas from haemophilia participants and comparability to ex vivo reconstitution with recombination coagulation factors.

Authors+Show Affiliations

Rare Disease Research Unit, Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, VA, USA.Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, VA, USA. Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.Rare Disease Research Unit, Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.Rare Disease Research Unit, Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.Division of Hematology/Oncology, Department of Internal Medicine, VCU, Richmond, VA, USA.Division of Hematology/Oncology, Department of Internal Medicine, VCU, Richmond, VA, USA.Division of Hematology/Oncology, Department of Internal Medicine, VCU, Richmond, VA, USA.Rare Disease Research Unit, Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.Rare Disease Research Unit, Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, VA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31336410

Citation

Patel-Hett, Sunita, et al. "Marstacimab, a Tissue Factor Pathway Inhibitor Neutralizing Antibody, Improves Coagulation Parameters of Ex Vivo Dosed Haemophilic Blood and Plasmas." Haemophilia : the Official Journal of the World Federation of Hemophilia, vol. 25, no. 5, 2019, pp. 797-806.
Patel-Hett S, Martin EJ, Mohammed BM, et al. Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. Haemophilia. 2019;25(5):797-806.
Patel-Hett, S., Martin, E. J., Mohammed, B. M., Rakhe, S., Sun, P., Barrett, J. C., ... Brophy, D. F. (2019). Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. Haemophilia : the Official Journal of the World Federation of Hemophilia, 25(5), pp. 797-806. doi:10.1111/hae.13820.
Patel-Hett S, et al. Marstacimab, a Tissue Factor Pathway Inhibitor Neutralizing Antibody, Improves Coagulation Parameters of Ex Vivo Dosed Haemophilic Blood and Plasmas. Haemophilia. 2019;25(5):797-806. PubMed PMID: 31336410.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. AU - Patel-Hett,Sunita, AU - Martin,Erika J, AU - Mohammed,Bassem M, AU - Rakhe,Swapnil, AU - Sun,Pengling, AU - Barrett,John C, AU - Nolte,Melinda E, AU - Kuhn,Janice, AU - Pittman,Debra D, AU - Murphy,John E, AU - Brophy,Donald F, Y1 - 2019/07/23/ PY - 2019/02/20/received PY - 2019/06/18/revised PY - 2019/06/21/accepted PY - 2019/7/25/pubmed PY - 2019/7/25/medline PY - 2019/7/24/entrez KW - coagulation KW - global haemostatic assays KW - haemophilia KW - thrombin generation assay KW - tissue factor pathway inhibitor KW - whole blood clotting SP - 797 EP - 806 JF - Haemophilia : the official journal of the World Federation of Hemophilia JO - Haemophilia VL - 25 IS - 5 N2 - INTRODUCTION: Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting. AIM: We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF-06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas. We compared the effects of marstacimab to the effects of recombinant coagulation factors and investigated the reproducibility of marstacimab in restoring haemostasis by comparing its effect in whole blood collected from the same study participants on differing days. METHODS: Citrated whole blood and plasmas obtained from haemophilia participants were supplemented ex vivo with vehicle, marstacimab, recombinant FVIII (rFVIII) or recombinant factor IX (rFIX) and analysed in ROTEM, TGA and the dPT assay using low tissue factor concentrations to trigger coagulation. RESULTS: Marstacimab induced pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in angle. Similarly, participant plasmas supplemented with marstacimab exhibited improvements in TGA parameters, including reduced lag times, increased peak thrombin concentrations and reductions in dPT clotting time. Concentrations of marstacimab tested showed activity comparable to addition of rFVIII or rFIX and were reproducible. CONCLUSIONS: These studies show the ex vivo potency of marstacimab in restoring haemostasis in whole blood and plasmas from haemophilia participants and comparability to ex vivo reconstitution with recombination coagulation factors. SN - 1365-2516 UR - https://www.unboundmedicine.com/medline/citation/31336410/Marstacimab,_a_tissue_factor_pathway_inhibitor_neutralizing_antibody,_improves_coagulation_parameters_of_ex_vivo_dosed_haemophilic_blood_and_plasmas L2 - https://doi.org/10.1111/hae.13820 DB - PRIME DP - Unbound Medicine ER -