European principles of inhibitor management in patients with haemophilia: implications of new treatment options
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(2020) 15:219
LETTER TO THE EDITOR
Open Access
European principles of inhibitor management in patients with haemophilia: implications of new treatment options C. Hermans1* , P. L. F. Giangrande2,3, B. O’Mahony2,4, P. de Kleijn5, M. Bedford6, A. Batorova7, J. Blatný8, K. Jansone2 and on behalf of the European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD)
Keywords: Haemophilia, Guidelines, Inhibitors, Factor VIII, Factor IX, Bypassing agents, Emicizumab, Immune tolerance In light of the rapidly changing landscape of haemophilia treatment, the authors of the position paper on the “European Principles of Inhibitor Management” published in 2018 (Table 1) [1] now provide an update on the major impact of novel therapies that bypass and/or substitute clotting factor VIII (FVIII) and IX (FIX) in the care of haemophilia patients with FVIII- or FIXneutralizing allo-inhibitory antibodies (inhibitors). The most advanced novel agent is undoubtedly emicizumab (Hemlibra®, Roche), a bispecific antibody that mimics the function of FVIII and facilitates the coagulation cascade in haemophilia A patients both with and without inhibitors as it is not recognized by FVIII-neutralizing allo-inhibitory antibodies. Phase III clinical trials in adults (HAVEN 1) and children (HAVEN 2) have shown significant overall bleed reduction compared to prophylaxis with classical bypassing agents such as recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrate (aPCC) in patients with haemophilia A and inhibitors [2, 3]. This molecule is administered subcutaneously, once a week or less frequently, greatly alleviating the burden of intravenous injections, especially in paediatric patients with inhibitors. Emicizumab is currently the only novel marketed agent and
is increasingly accessible for people with haemophilia A with and without inhibitors [4]. In many developed countries, emicizumab has become the prophylactic agent of choice for patients with persistent inhibitors against FVIII with major reported benefits [5]. Several other novel agents are in different stages of development and will probably also have a major impact on the care of haemophilia patients. A new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions (marzeptacog alfa (activated) (MarzAA)), has increased catalytic activity and prolonged half-life which allows subcutaneous dosing [6]. Other new agents which downregulate natural anticoagulants, thereby rebalancing haemostasis, are currently under study in patients with haemophilia A and B. These agents work either by blocking tissue factor pathway inhibitor (TFPI) using subcutaneous monoclonal antibodies (concizumab, NovoNordisk; marstacimab, Pfizer) or knocking down antithrombin synthesis through a subcutaneous double-stranded small interfering RNA (Alnylam) [7]. Haemophilia B patients with inhibitors, who have been clinically the most underserved subpopulation, may benefit the most from these new agents.
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