HEMOPHILIA: ADVANCES IN TREATMENTS

Hemophilia is an X-linked recessive disorder. It is divided into two different subtypes; hemophilia A (HA) and B (HB), which result from the deficiency or complete absence of clotting factors VIII (FVIII) and IX (FIX) respectively. Current management of HA and HB includes prophylactic factor replacement1. Neutralising antibodies, as inhibitors, can develop against the infused factor and that can complicate the management of hemophilia patients. If inhibitors develop, immune tolerance induction can potentially promote tolerance to exogenous FVIII or FIX, and bypassing agents (BPAs) such as recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC) can be used to circumvent factor use. Inhibitor development impacts negatively upon quality of life and treatment compliance, highlighting the need for improved therapies. Several novel pharmacological therapies developed for hemophilia aim to rebalance the clotting cascade. These therapies utilise a range of different mechanisms, namely: the extension of the circulating half-life of standard recombinant factors; the mimicking of factor VIII cofactor activity; rebalancing of coagulation through targeting of natural anticoagulants such as antithrombin and tissue factor pathway inhibitor; and inducing the production of endogenous factors with gene therapy. Extended half‐life products involves fusing FVIII or FIX to a protein with a long half-life. Albumin and the constant region (Fc) of IgG have long plasma half-lives as they bind to the neonatal Fc receptor, which is critical for the endogenous recycling of both IgG and albumin. Another method is PEGylation, where one or more PEG chains are covalently linked to rFVIII or rFIX. PEG chains interfere with the recombinant factors binding to their clearance receptors, thereby prolonging circulating half-life. Emicizumab, a recombinant humanised bispecific IgG antibody, mimics the cofactor function of the missing FVIII in HA. It simultaneously binds activated FIX (FIXa) and factor X (FX), bringing them into spatial proximity to promote FIXa-catalysed FX activation, thereby restoring haemostasis. Fitusiran, a novel therapy applicable to both HA and HB, consists of the amino acid, N-Acetyl- galactosamine, the ligand of the hepatic asialo-glycoprotein receptors, conjugated to a synthetic siRNA. It targets and degrades a region of the SERPINC1 gene mRNA, preventing antithrombin production and enhancing thrombin generation. Antithrombin is a potent