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Review
. 2018 Jun;78(9):881-890.
doi: 10.1007/s40265-018-0922-6.

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Pratima Chowdary  1
Affiliations
Review

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Pratima Chowdary. Drugs. 2018 Jun.

Erratum in

Abstract

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly undetectable. A few haemophilia patients in the highest dose cohorts with complete inhibition of plasma TFPI showed a decreased fibrinogen concentration with normal levels of anti-thrombin and platelets and no evidence of thrombosis. Pharmacokinetic parameters were influenced by binding to the target (TFPI), demonstrating target mediated drug disposition. A trend towards decreasing bleeding tendency was observed and this preventative effect is being studied in Phase 2 studies with additional data gathered to improve our understanding of the therapeutic window and potential for thrombosis.

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Conflict of interest statement

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

PC reports, grants and personal fees from Pfizer, grants, personal fees and non-financial support from Bayer, personal fees and non-financial support from Baxalta (Shire), grants, personal fees and non-financial support from CSL Behring, grants, personal fees and non-financial support from NovoNordisk, grants, personal fees and non-financial support from Swedish Orphan Biovitrum AB (Sobi), personal fees from Freeline, personal fees from Roche, outside the submitted work.

Figures

Fig. 1
Fig. 1
TFPI mechanism of action and inhibition by anti-TFPI antibodies. a Tissue factor (TF) based initiation of coagulation and generation of FXa by the extrinsic tenase complex (FVIIa.TF.FX). b Inhibition of FXa and FVIIa by TFPI. c Binding of the different Kunitz (K) domains by the various anti-TFPI antibodies
See this image and copyright information in PMC

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