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.

Keywords: bleeding disorders; factor IX; hemophilia B; plasma half-life; therapy.

Figure 1

rFIX forms with extended terminal half-lives. Notes: (A) rFIXFc fusion protein with IgG1 Fc domain directly attached to C-terminus (no linker region), (B) rIX-FP fusion protein with albumin attached via linker peptide containing a proteolytic cleavage site, (C) N9-GP rFIX modified in a site-selective manner with a 40 kDa PEG moiety attached to one or both N-glycosylation sites in the activation peptide. The domain structure of the mature FIX protein is shown for each form with activation cleavage sites and posttranslational modifications as indicated. Abbreviations: rFIX, recombinant FIX; FIX, factor IX; EGF, epidermal growth factor; GLA, gamma-carboxylation; PEG, polyethylene glycol.

Figure 2

Cross section of blood vessel indicating location of extravascular FIX pool. Notes: Intravascular compartment consists of circulating FIX protein, extravascular compartment is represented by the endothelial monolayer plus the basement membrane that is enriched with collagen IV binding sites for FIX. The extravascular pool contributes to the in vivo hemostatic function of FIX in the hemophilia B mouse. The majority (∼80%) of injected FIX is sequestered rapidly in the liver, likely involving the sinusoidal endothelium. Other vascular organs show later peaks of FIX localization. Abbreviation: FIX, factor IX.