Novel rIX-FP product may offer hemophilia B patients prophylaxis with fewer IV injections

Bruce Furie, MD, MD

The holy grail for the treatment of hemophilia has been the replacement, forever, of the missing Factor VIII or Factor IX. We have made stepwise progress over the years, from whole blood to fresh frozen plasma (to cryoprecipitate for Factor VIII — but not for Factor IX replacement!) to intermediate purity factor concentrates to pure plasma-derived or recombinantly produced Factor VIII and Factor IX. The ultimate goal has been gene therapy, an approach that is yet to be fully realized (Roth DA. N Engl J Med. 2001;344:1735-1742. Nathwani AC. New Engl J Med. 2011;365:2357-2365).

One of the most attractive features of the treatment of these genetic disorders is that the severe form of hemophilia, which is associated with a severe bleeding phenotype, is characterized by levels of Factor VIII or Factor IX that are 1% of normal or lower. Raising this level by just a couple of percent dramatically improves the phenotype. For these reasons, prophylactic treatment of hemophilia B — Factor IX deficiency — usually involves infusion of Factor IX three times per week, with significant improvement in the reduction of bleeding events and improvement in the hemarthrosis so often complicating severe hemophilia. However, with a half-life of about 18 hours, annual Factor IX infusions are costly, inconvenient and sometimes difficult. The current struggle, short of gene therapy, is to generate a form of Factor IX with a longer half-life than Factor IX. Several approaches have been taken. The fusion of Factor IX to a single chain immunoglobulin Fc shows increased half-life in humans of about 56 hours (Shapiro AD. Blood. 2012;119:666-672). GlycoPEGylated recombinant Factor IX demonstrated a half-life of 93 hours in humans.

In the current work, a novel fusion protein involving Factor IX linked to albumin through a cleavable linker susceptible to Factor XIa has been shown to be safe and to have favorable pharmacokinetic properties. The half-life of this fusion protein is 92 hours. This fusion protein is considerably different than other experimental agents in that Factor IX is not only fused to a protein, albumin, with a long plasma half-life, but requires cleavage and release from the fusion protein. It is important to emphasize that this published study limits its conclusions to safety and fusion protein half-life. We know nothing about the efficacy of this agent for the treatment of hemophilia B yet. For one, the cleavage and activation of the fusion protein in vitro during Factor IX assay is performed with Factor XIa, whereas in vivo the complex of Factor VIIa-tissue factor is likely the dominate activator of Factor IX. Further studies of this and other second-generation Factor IX replacement products hopefully will lead to inexpensive new products that require only occasional infusion for effective prophylactic therapy.

Katherine A. High, MD

This paper by Santagostino and colleagues presents the results of a first-in-human study of a long-acting Factor IX product. Like FIX-Fc, the Biogen-Idec product in late-stage testing, this product also achieves a longer half-life by fusing the Factor IX gene sequence to a sequence encoding a protein with a much longer half-life, in this case albumin. Although this study is small (25 subjects with severe hemophilia B), the results are encouraging, documenting a half-life of 92 hours — five times longer than current Factor IX products — after a dose of 50 IU/kg. Larger studies will be required to establish efficacy, but there were no spontaneous bleeding events in the 14-day period of observation after infusion of doses of 50 IU/kg or 75 IU/kg.

Along with N9-F9, the Novo-Nordisk long-acting product that also exhibits a 5-fold increase in half-life through a different mechanism (targeted PEGylation of N-linked glycans in the activation peptide of Factor IX), this new bioengineered Factor IX adds to the pipeline of products in development that may allow dosing regimens closer to twice a month, rather than the current twice-a-week regimen. Similar efforts to produce long-acting Factor VIII products have been less successful, and more work is needed to reach a similar improvement in treatment for hemophilia A.