Longer FVIII: the 4th generation

In this issue of Blood, Powell and colleagues present the first human data after the infusion of a new recombinant factor VIII (FVIII) product that when fused with the Fc fragment of IgG1 results in significantly prolonged half-life in the circulation.¹ 

The advent of safe and effective concentrates has meant that a person with hemophilia born today can expect an almost normal life expectancy and minimal morbidity. However, this depends on the early and lifelong use of prophylactic treatment with concentrate and the absence of an alloantibody to FVIII (inhibitor). Prophylaxis with FVIII is hindered by the inconvenience of frequent intravenous administration and cost. The half-life of FVIII is 8 to 12 hours so in hemophilia A prophylaxis is usually administered on alternate days or 3 times a week, which can be challenging especially in individuals with difficult venous access.

Although plasma-derived concentrates are safe and effective, recombinant products are preferred because of their perceived improved safety. March 2012 celebrates the 25th anniversary of the first infusion of recombinant FVIII into a human patient at the University of North Carolina at Chapel Hill.²  Initially, first-generation recombinant concentrates were formulated with plasma-derived human albumin. The second-generation products no longer contained albumin and the third-generation ones also eliminated human and animal proteins from the final preparation and the manufacturing process. Many manufacturers are now tackling the next step in development, to produce the fourth generation of recombinant FVIII products with a longer half-life. Among the techniques being employed to achieve this are pegylation, polysialylation, and coupling the FVIII to albumin or to the immunoglobulin Fc fragment.

Most serum proteins that are too large for renal filtration have a half-life of approximately 3 days. A notable exception, however, is immunoglobulin G (IgG), which has a half-life of 21 days in humans. This is achieved by binding of the IgG to the neonatal Fc receptor (FcRn) which, despite its name, is expressed throughout life in hepatocytes, the vascular endothelium, and many other tissues. IgG bound to the FcRn during pinocytosis and/or endocytosis is protected from degradation within the lysozomes because at low pH the IgG binds more avidly to the receptor. As the receptor is recirculated to the cell surface the IgG is released at the physiologically neutral pH of the circulation. This process has been exploited by several manufacturers that produced drugs fused to the Fc fragment of IgG1 including etanercept and romiplostim. Recently, Shapiro and colleagues showed that the monomeric rFIXFc fusion concentrate had a 3-fold longer half-life than the only licensed recombinant factor IX product.³ 

In this issue of Blood, Powell and colleagues demonstrate that a new recombinant FVIII Fc (rFVIIIFc) fusion product has a longer half-life than one of the licensed, full-length, third-generation products. The drug is a monomeric B-domain–deleted FVIII covalently linked via its carboxy-terminus to the N-terminus of an Fc monomer, which forms a disulfide bond with a second Fc monomer during synthesis and secretion.¹  In an earlier animal study in mice and dogs recently published in Blood, this rFVIIIFc product had a 2-fold longer half-life and this prolongation was dependent on the FcRn because it was abrogated in the FcRn knockout mice.⁴ 

In this trial, previously multiply treated adult patients with hemophilia A received 1 of 2 doses of the rFVIIIFc monomer and the same dose of a full-length recombinant FVIII (Advate). As expected, the studies were performed to the high standard required subsequent to submission for licensing. The rFVIIIFc product showed a 1.5- to 1.7-fold prolongation in half-life compared with the standard product when assayed using the 1-stage activated partial thromboplastin time assay and a 1.6- to 1.8-fold prolongation when using a 2-stage chromogenic assay. Concomitant with the prolongation in half-life, this product showed equivalent reduction in clearance and higher total systemic exposure.

An interesting observation is the lesser prolongation (1.5 to 1.7 ×) of the FVIII half-life in comparison to that seen with the factor IX Fc fusion product (3 ×) despite using the same technology. It is likely that this relates to the binding of FVIII to the von Willebrand factor (VWF) molecule that protects it from inactivation. In the circulation, approximately 98% of the FVIII is in complex with VWF, which is present in a 50-fold excess compared with FVIII.⁵  Evidence for this suggestion comes from the observation that the half-life of rFVIIIFc was directly proportional to the plasma concentration of VWF¹  and in the VWF knockout mice the half-life of rFVIIIFc was 5-fold longer than rFVIII.⁴  This suggests that the half-life of native VWF (16 to 17 hours)¹  is likely to limit the prolongation of the FVIII half-life to less than 2-fold irrespective of the approach used to extend it.

There are a number of unknowns about this molecule including the best method to measure its activity, its immunogenicity in previously untreated patients, as well as its exact role in treatment and prophylaxis. The 1.5-fold extension of the half-life suggests that twice-weekly prophylaxis maybe possible but trials with clinical end points are required to show this. In view of the dependence of the rFVIIIFc on the concentration of VWF, an intriguing possibility is whether it might be possible to administer the product together with subcutaneous desmopressin to achieve an even longer half-life.