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].