Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia 2019-09, Vol.25 (5), p.797-806
• Main Authors: Patel‐Hett, Sunita, Martin, Erika J., Mohammed, Bassem M., Rakhe, Swapnil, Sun, Pengling, Barrett, John C., Nolte, Melinda E., Kuhn, Janice, Pittman, Debra D., Murphy, John E., Brophy, Donald F.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Blood; Blood Coagulation - drug effects; Clotting; coagulation; Coagulation factors; Female; global haemostatic assays; haemophilia; Hemophilia; Hemophilia A - drug therapy; Hemophilia A - pathology; Humans; Male; Plasma - metabolism; Prothrombin; Recombination; Thrombin; thrombin generation assay; Thromboplastin - antagonists & inhibitors; Tissue factor; tissue factor pathway inhibitor; whole blood clotting
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.13820

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.