Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia

Abstract

Novel approaches to the treatment of haemophilia are needed due to the limitations of the current standard of care, factor replacement therapy. Aspirations include lessening the treatment burden and effectively preventing joint damage. Treating haemophilia by restoring thrombin generation may be an effective approach. A promising target for restoring thrombin generation is tissue factor pathway inhibitor (TFPI), a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor-induced coagulation via factor Xa-dependent feedback inhibition of the tissue factor-factor VIIa complex. Inhibition of TFPI reverts the coagulation process to a more primitive state evolutionarily, whilst regulation by other natural inhibitors is preserved. An aptamer and three monoclonal antibodies directed against TFPI have been investigated in clinical trials. As well as improving thrombin generation in the range associated with mild haemophilia, anti-TFPI therapies have the advantage of subcutaneous administration. However, the therapeutic window needs to be defined along with the potential for complications due to the novel mechanism of action. This review provides an overview of TFPI, its role in normal coagulation, the rationale for TFPI inhibition, and a summary of anti-TFPI therapies, previously or currently in development.

The German Hemophilia Registry: Growing with Its Tasks

“…Also, the first non-factor-based medicinal product was authorized for the European market for treatment of HA patients with FVIII inhibitors in 2018 with Emicizumab (Hemlibra) [35], a bispecific monoclonal antibody which mimics FVIII function [36,37]. Other non-factor products undergoing clinical trials include Fitusiran, a small interfering RNA (siRNA) that blocks the synthesis of the blood coagulation inhibitor Antithrombin [38][39][40], and the monoclonal antibodies Concizumab [41,42] and Marstacimab (PF-06741086) [43], which target TFPI, an inhibitor of the tissue factor pathway [44,45]. To facilitate data capture for new therapies, EHL products and Emicizumab were included as separate classes of therapeutics in the dhr.…”

Current progress and future direction in the treatment for hemophilia

“…One healthy subject developed thrombophlebitis. The findings of the early EXPLORER trials have been concisely summarized by the same authors [11]. More recently, the results of a Phase 2 study were published [17].…”

“…K1 and K2 are responsible for inhibition of FVIIa and FXa, respectively. The biochemical properties of TFPI are summarized elegantly by Chowdary [11]. Neutralization of TFPI can restore disordered thrombin generation, and therefore, TFPI inhibition is an attractive concept for hemostatic control in hemophilia.…”

Comparative Analysis of Thrombin Calibration Algorithms and Correction for Thrombin-α2macroglobulin Activity

“…The clinical application of the thrombin generation (TG) assay has been suggested by multiple research studies, and it is often used for bionanalytical assessment in clinical trials [ 1 , 2 ]. The TG assay, while uniquely sensitive to the mechanism of action of numerous drugs developed for treatment of bleeding and thrombotic diseases [ 3 , 4 , 5 , 6 , 7 ], remains hard to standardize and validate for routine use outside of the expert central laboratories [ 8 , 9 , 10 , 11 , 12 , 13 ]. Modern automated TG assays are based on fluorogenic peptide substrates which release fluorophore in a relatively slow reaction with thrombin [ 11 , 14 , 15 , 16 , 17 , 18 ].…”