3.3. Novel therapeutic opportunities in haemophilia care
Novel therapeutic opportunities to improve treatment of haemophilia patients are rapidly evolving. These include: novel FVIII/FIX products, substitution therapies, haemostatic rebalancing therapy and gene therapy/editing. Figure 3 provides an overview of the coagulation cascade and the site of action of novel therapeutics in haemophilia care.
3.3.1. Recombinant and modified release FVIII and FIX products
The short half-life of the standard therapies for haemophilia requires frequent administration within prophylaxis regimens. Extended half-life FVIII/FIX recombinant concentrates have been obtained by fusion to polyethylene glycol (FVIII & FIX), IgG1-Fc (FVIII & FIX) or albumin. These modifications have provided prominent decrease in injection frequency – every 1 to 2 weeks for prophylaxis [4]. EHL clotting factors increase treatment adherence, improve clinical outcomes and provide an opportunity for improved individualised treatment for haemophilia. Elocta and Alprolix, for haemophilia A and B respectively, are examples of EHL which have been recently authorised for the use in the European Union.
3.3.2. Substitution therapy
A subcutaneously administered bispecific monoclonal antibody (Emicizumab) has recently been developed. It bridges FX and FIXa and acts as a partial functional mimic to FVIIIa, to restore the missing function of FVIIIa. Because of its unique structure, Emicizumab is not expected to induce or be affected by factor VIII inhibitors. HAVEN 1, a phase 3 non interventional study in severe haemophilia A patients with inhibitors, showed an 87% reduction in bleed rates compared with no prophylaxis, and a 79% reduction compared with prior BPA prophylaxis [13]. HAVEN 3 study evaluated Emicizumab prophylaxis in haemophilia A patients without inhibitors, using weekly dosing, and demonstrated a 68% reduction in treated bleeds compared with prior factor VIII prophylaxis [14]. These results support the hypothesis that the level of steady-state maintenance of haemostasis achieved with Emicizumab prophylaxis can result in superior efficacy with respect to traditional prophylaxis.
3.3.3. Rebalancing therapy
Haemostasis is a complex physiological process that maintains a balance between the normal blood flow within the vasculature and the induction of blood clot formation following injury [15]. In the presence of a coagulation factor deficiency, such as Haemophilia, this delicate balance is shifted toward bleeding. In contrast, derangements in the natural anticoagulant pathways can lead to thrombosis. Evidences from current knowledge demonstrate that targeting these natural anticoagulant pathways (anti-thrombin and tissue factor pathway inhibitors, protein S and protein C) can restore the haemostatic equilibrium in the presence of a bleeding disorder [16]. Fitusiran is an RNA interference (RNAi) therapy which targets antithrombin (AT) in the liver and interferes with AT translation by binding and degrading messenger RNA-AT to prevent AT synthesis and promote haemostasis. In both preclinical and clinical studies, AT knockdown led to dose-dependent lowering of AT levels and reduced the bleeding phenotypes in haemophilia patients. [17-18].