Go long! A touchdown for factor VIII?

The recurrent hemarthroses and resultant crippling hemophilic arthropathy of hemophilia have almost been completely eradicated through aggressive prophylactic therapy with clotting concentrates in the developed world. Quality of life measures now track similar to their unaffected peers and patients engage regularly in sporting activities unimagined in previous generations.1 Prophylaxis for severe hemophilia is now recognized as the standard of care with optimal initiation very early in life before the onset of repeated hemarthroses, typically between ages 1 to 3 years.2 Nevertheless, barriers remain to realizing the benefits of prophylaxis universally.3 The costs for prophylactic replacement therapy are much greater than $100 000 USD per patient per year. Repeated venous access (typically 3 times per week to every other day) is still a barrier for many with frequent need for central venous access devices in the youngest boys. Suboptimal adherence to a prophylactic regimen also compromises outcomes.4 Recombinant FVIII (rFVIII) has proven to be a remarkable facsimile of its plasma-derived counterpart. The broad adoption of rFVIII throughout the developed world has increased the worldwide supply of FVIII concentrates and helped advance the implementation of prophylaxis. However, at the heart of recombinant DNA technology is not just the ability to mimic native proteins, but to exploit insights gleaned from their structure and function to engineer targeted modifications to enhance their functional properties. A number of bioengineering strategies have led to rFVIII variants with improved efficiency of expression, increased potency and resistance to inactivation, and resistance to inhibitors.3 A major emphasis of current bioengineering efforts has been on half-life extension.5 A longer-acting FVIII holds promise to overcome some of the barriers to adoption of and adherence to prophylaxis. The primary determinant of FVIII residence time in plasma is interaction with von Willebrand factor (VWF), which protects it from proteolysis and cellular uptake. Clearance of FVIII has only recently begun to be elucidated. FVIII is too large in molecular weight to be cleared by the kidney. Cellular clearance, primarily in the liver, occurs through interaction with a family of lowdensity lipoprotein receptor–related proteins (LRP) and heparan sulfate proteoglycan receptors among others (see figure).6 Some of the halflife extension strategies under investigation include sustained delivery, first attempted through association of rFVIII with PEGylated liposomes, chemical modification (eg, direct PEGylation) and bioengineering rFVIII itself through mutagenesis or the generation of fusion proteins After intravenous infusion, factor VIII (FVIII) is stabilized in plasma through noncovalent association with von Willebrand factor (VWF) protecting it from proteolysis and cellular uptake. With a hemostatic challenge, thrombin activation releases FVIII from VWF so that it can exert its procoagulant function. The majority of infused FVIII is cleared in the liver through interaction with the low-density lipoprotein receptor–related protein (LRP) family of cell-surface receptors. A PEGylated form of FVIII would have reduced cellular uptake and a resultant prolongation of plasma half-life. The elimination of PEG-FVIII that is internalized in the hepatocyte has not been fully characterized but may follow urinary and fecal excretion routes limiting intracellular accumulation.