Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors

Chai‐Adisaksopha, Chatree; Nevitt, Sarah J; Simpson, Mindy L.; Janbain, Maissaa; Konkle, Barbara A.

doi:10.1002/14651858.cd011441.pub2

Cited by 19 publications

(23 citation statements)

References 44 publications

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“…Individuals treated for prophylaxis have less bleeding, but experience heavy treatment that remind them their disease. This hypothesis is confirmed by results of the NIS BH28768 study, 9 the COCHRANE systematic revue 26 and the EQOFIX study 10 …”

Section: Methodsmentioning

confidence: 70%

Cost‐effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti‐FVIII inhibitors in France

Polack

Trossaërt²,

Cousin

et al. 2020

Haemophilia

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Introduction The development of an anti‐FVIII inhibitor is the most serious complication of haemophilia A occurring in up to 30% of severe haemophilic patients. The current management of haemophilia A with inhibitor uses bypassing agents (BPA) and represents a significant therapeutic burden together with a limited adherence to prophylactic treatment. Emicizumab is the first monoclonal antibody developed in haemophilia A approved for the prevention of bleeding episodes in patients with anti‐FVIII inhibitor. Aim The purpose of this study is to evaluate the incremental cost‐effectiveness ratio (ICER) of emicizumab versus BPAs. Methods A Markov model was developed over a five‐year time horizon to estimate the comparative costs and benefits of the different therapeutic approaches in this rare disease. Model inputs were clinical, including annual bleeding rate and quality of life, and economical including mainly costs of prophylaxis, bleeds and adverse events. Results Emicizumab treatment is dominant, ie lest costly and more effective, in the base‐case analysis saving 234 191 € for a gain of 0.88 QALY. This is confirmed by both the deterministic and probabilistic sensitivity analyses. The main limit of the study remains the absence of long‐term clinical data allowing to relate treatment consumption to clinical benefit, especially in the progression of haemophilic arthropathy. Conclusion Our results show that emicizumab is a cost‐effective treatment allowing to consider an easy to implement prophylactic treatment for haemophilia A patients with anti‐FVIII inhibitors.

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Section: Methodsmentioning

confidence: 70%

Cost‐effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti‐FVIII inhibitors in France

Polack

Trossaërt²,

Cousin

et al. 2020

Haemophilia

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“…The mechanisms underpinning their haemostatic efficacy are based on restoration of thrombin generation through pathways that potentially contribute a minimal amount of thrombin under normal conditions [ 15 – 17 ]. Besides bleed management, they are used for secondary and tertiary prophylaxis, but they are less effective when compared to FVIII and FIX prophylaxis in non-inhibitor patients and have been associated with occasional episodes of thrombosis [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

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

Chowdary

2018

Drugs

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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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“…These bypassing agents restore thrombin generation to achieve haemostatic efficacy via pathways that, in normal haemostasis, may contribute only a limited amount of thrombin [24][25][26]. In addition to on-demand therapy, they have also been used for prophylaxis, but provide less effective bleed control when compared to prophylaxis in non-inhibitor patients [27][28][29][30].…”

Section: Current Haemophilia Care: Challenges and Limitationsmentioning

confidence: 99%

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

Chowdary

2018

Int J Hematol

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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.

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Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors

Cited by 19 publications

References 44 publications

Cost‐effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti‐FVIII inhibitors in France

Cost‐effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti‐FVIII inhibitors in France

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

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

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