New developments in the management of moderate-to-severe hemophilia B

Abstract

Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the emerging FIX products possessing extended half-lives, and novel “rebalancing” approaches to hemophilia therapy.

Nonacog Beta Pegol: A Review in Haemophilia B

“…> 5 to < 40%, 1–5% and < 1% of normal levels) [ 1 , 2 ]. The mild form is characterized by rare spontaneous bleeding and severe bleeding during major trauma or surgery, the moderate form by occasional spontaneous bleeding and prolonged bleeding during minor trauma or surgery, and the severe form by spontaneous bleeding into joints and muscles [ 1 , 3 ]. According to the CHESS study, approximately one-third of the haemophilia B population in Europe have the severe form, which is associated with a high annual treatment cost [ 4 ].…”

“…Depending on bleeding sites, haemophilia B can be serious (joints, muscles, mucous membranes) or life-threatening (intracranial, neck/throat, gastrointestinal) [ 1 ]. Thus, haemophilia B is associated with frequent long-term disability, impaired health-related quality of life (HR-QOL) and substantial treatment cost [ 1 , 3 , 4 ].…”

“…Currently, prophylaxis is considered to be the standard of care for haemophilia B in developed countries [ 5 ]. In this approach, plasma FIX levels are maintained above 0.01 IU/mL (1%), thereby converting the disease severity phenotype from severe to moderate [ 1 , 3 , 5 , 6 ]; maintaining FIX levels > 1% may be useful in some patients [ 7 ]. Prophylaxis is associated with a few challenges, such as need for venous access, frequent FIX administrations, variable pharmacokinetics and increased initial cost; however, prophylaxis is considered superior to on-demand therapy as it prevents bleeding-related complications, particularly haemophilic arthropathy, in patients with severe disease [ 3 , 5 , 6 ].…”

“…Highly purified FIX concentrates [plasma-derived FIX (pdFIX) and recombinant FIX (rFIX)] are routinely used for the treatment of haemophilia B [ 1 , 3 ]. These preparations have showed haemostatic efficacy in on-demand, prophylaxis and perioperative settings and are associated with reduced thromboembolic complications relative to intermediate purity FIX concentrates, such as prothrombin complex concentrates (PCCs), which are rarely used now [ 3 ]. However, as pdFIX and rFIX have a relatively short plasma half-life (t 1/2 ; typically 16–19 h), they require frequent administration (2–3 times weekly) to maintain protective prophylaxis FIX levels [ 3 , 5 , 6 ].…”

“…These preparations have showed haemostatic efficacy in on-demand, prophylaxis and perioperative settings and are associated with reduced thromboembolic complications relative to intermediate purity FIX concentrates, such as prothrombin complex concentrates (PCCs), which are rarely used now [ 3 ]. However, as pdFIX and rFIX have a relatively short plasma half-life (t 1/2 ; typically 16–19 h), they require frequent administration (2–3 times weekly) to maintain protective prophylaxis FIX levels [ 3 , 5 , 6 ]. Therefore, current development efforts have focused on extending the t 1/2 of rFIX by modifying its physiological and pharmacokinetic properties with the aim of reducing treatment burden and thereby potentially improving treatment compliance and clinical outcomes [ 3 , 5 , 6 ].…”