Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management

Abstract

The unprecedented progress in addressing unmet needs in haemophilia care to date includes developing several novel therapies that rebalance haemostasis by restoring thrombin generation in patients with haemophilia A or B with and without inhibitors. These novel therapies are FVIII mimetics, antithrombin interference RNA therapy and several monoclonal antibodies directed against the tissue factor pathway inhibitor (anti-TFPI). In this review, we provide an update on the progress made in developing anti-TFPI therapie. Phase 1 data from the three anti-TFPI studies showed acceptable safety profiles, and currently, available phase 2 data are encouraging. While these data support these molecules' further development progression, there is uncertainty on several aspects of their evolution. Two of the three anti-TFPIs have shown drug-related thrombosis, with one study consequently terminated. None of the thrombotic events is predictable with current monitoring tools, and none correlate with known coagulation parameters. All three anti-TFPIs undergo target mediated drug disposition, which impacts the formulation of dosing regimen fo these therapies. They would require more frequent dosing than some of the extended half-life clotting factor products and antithrombin RNAi therapy. There is no assay to measure the TFPI as the physiological levels are very low, which makes monitoring the impact of the anti-TFPI a challenge. The anti-TFPIs have several advantages, including their bioavailability when administered subcutaneously, their stable pharmacokinetics and their ability to prevent bleeds in haemophilia A or B patients with and without inhibitors. Whether these advantages can be realized will depend on the outcome of the currently ongoing studies.

Updates on Novel Non-Replacement Drugs for Hemophilia

“…Concizumab is a monoclonal, humanized IgG4 antibody specifically binding to the Kunitz-2 domain. Preclinical studies in vitro or in animal models have described its action in restoring thrombin generation and favoring the onset of a procoagulant action [ 30 , 31 , 32 , 33 ].…”

“…Two other anti-TFPIs developed for the treatment of patients with hemophilia deserve a brief mention: befovacimab (BAY 1093884) and MG1113 [ 33 ]. Befovacimab is a human IgG2 monoclonal antibody created to bind both to the Kunitz domain 1 and 2.…”

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

“…Studies on the evaluation of these novel molecules, including befovacimab, concizumab, and marstacimab, have been ongoing in participants with HA or HB, regardless of the presence of inhibitors. Of these, befovacimab also targets the K1 domain of the TFPI ( 113 ). While favorable results were obtained from the preclinical in vivo studies and phase 1 clinical trials, the phase 2 study was terminated early due to three befovacimab-related thrombotic serious adverse events (SAEs) ( 114 ).…”

Hemostatic efficacy of marstacimab alone or in combination with bypassing agents in hemophilia plasmas and a mouse bleeding model

“…Nonfatal thrombotic events were also observed in two studies with anti‐TFPI monoclonal antibodies in development, resulting in either termination or interruption of the study. 18 Patients with inhibitors receiving treatment with marstacimab may concomitantly receive treatment with rFVIIa or aPCC after a breakthrough bleeding event. 19 Therefore, there is a potential concern for excessive thrombin generation with the use of marstacimab in combination with rFVIIa or aPCC.…”

“…Thrombotic events have been associated with concomitant use of a bypass agent (an aPCC: FEIBA) for treatment of breakthrough bleeding episodes during prophylaxis of patients with inhibitors with the nonfactor treatment emicizumab. Nonfatal thrombotic events were also observed in two studies with anti‐TFPI monoclonal antibodies in development, resulting in either termination or interruption of the study 18 19 …”