New Developments in Factor Replacement Therapy in the Treatment of Hemophilia

Introduction

Significant progress has been made over the past several years towards increasing the use of prophylaxis for hemophilia, yet there is still substantial room for improvement. Prophylaxis has allowed patients to be much more active, but for some this has resulted in an increased risk of injury and bleeding. In certain cases, patients who have been on long-term prophylaxis are not able to easily recognize when bleeds occur, particularly those that are subclinical (ie, microbleeds). Small bleeds into joint spaces can initiate the process of hemophilic arthropathy, causing pain and diminished range of motion.

One important limitation of current prophylaxis is that factors are administered intravenously. This can be especially challenging for toddlers and adolescents who may require administration of factor 2 to 3 times a week, causing stress and inconvenience for patients and their families. Additionally, due to the short half-life and rapid clearance of many recombinant factors, plasma trough levels fall rapidly after infusion, leading to levels that may not provide adequate protection against bleeding. Administration of a 50-U/kg dose of recombinant or plasma-derived factor VIII in a child, for example, will provide a 100% correction of factor levels (Figure 1).1-3 Assuming a typical half-life of 8 to 12 hours, this results in a level of approximately 1% after 48 hours. To maintain factor VIII trough greater than 1% at all times, prophylaxis dosing frequency should be every other day or 3 days per week. There is therefore a need for factors with longer half-lives that could be administered less often but provide similar or improved time spent above the 1% level.

Figure 1. Current Standard Half-Life Factor VIII Challenge in a Child3
figure 1
For some long-acting factors that have a longer pharmacokinetic “tail,” dosing may depend on length of time under a critical trough factor level, which can differ from patient to patient.

To decrease the need for such frequent administration, various methods have been developed to alter the chemical nature of the factor and/or its pharmacokinetics (PK) and improve stability. Bioengineering strategies and fusion protein technologies have resulted in the development of extended half-life (EHL) and next-generation factors that increase factor circulation time, prolong half-life, and extend the duration of time spent above the 1% trough level. These may also reduce the frequency of administration, thus increasing patient convenience. Ideally, such factors should not increase immunogenicity and should be relatively easy to assay for PK monitoring.

To begin, please answer the following polling question about your practice.

What types of extended half-life factors are available for patients with hemophilia, and how do these differ from one another?                         

Meeks