Long-lasting recombinant factor VIII proteins for hemophilia A

Abstract

In the past 50 years, the lifespan of an individual affected with severe hemophilia A has increased from a mere 20 years to near that of the general unaffected population. These advances are the result of and parallel advances in the development and manufacture of replacement therapies. We are now poised to witness further technologic leaps with the development of longer-lasting replacement therapies, some of which are likely to be approved for market shortly. Prophylactic therapy is currently the standard of care for young children with severe hemophilia A, yet requires frequent infusion to achieve optimal results. Longer-lasting products will transform our ability to deliver prophylaxis, especially in very young children. Longer-lasting replacement therapies will require changes to our current treatment plans including those for acute bleeding, prophylaxis, surgical interventions, and even perhaps immunotolerance induction. Ongoing observation will be required to determine the full clinical impact of this new class of products.

Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A

“…Surprisingly, we did not find an association between the concentrations of LRP1 and FVIII PK. The main mechanism for half-life prolongation using pegylated FVIII is the interference of the clearance through receptors like LRP1 [33,34]. Prolongation of FVIII half-life has been achieved by pegylation, fusion with albumin or a component of immunoglobulin G [33].…”

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

“…Despite the various reported half-lives found in the product brochures of FVIII products, it is commonly understood that the half-life of standard FVIII products is between 8 and 12 hours with individual variation seen with different brands. There have been several strategies for extending FVIII half-life such as attaching a PEG moiety, albumin, or the Fc fragment of immunoglobulin to the FVIII protein 6,19. PEGylation protects FVIII from proteolytic degradation, while both Fc fragment and albumin conjugation use the recycling of the endocytosed fusion protein through the neonatal Fc receptor pathway 6.…”

“…There have been several strategies for extending FVIII half-life such as attaching a PEG moiety, albumin, or the Fc fragment of immunoglobulin to the FVIII protein 6,19. PEGylation protects FVIII from proteolytic degradation, while both Fc fragment and albumin conjugation use the recycling of the endocytosed fusion protein through the neonatal Fc receptor pathway 6. Although both immunoglobulins and albumin normally have very long half-lives, these approaches have only resulted in a modest increase in the half-life of FVIII, likely due to the dependence on VWF that stabilizes FVIII 5.…”

“…Conjugation with albumin takes advantage of the natural half-life of albumin, whereas PEGylation protects FVIII from proteolytic enzymes. Fc conjugation takes advantage of the existence of the neonatal Fc receptor that allows protection and recirculation of the FVIII via this receptor pathway 5,6. Recently, a novel single-chain recombinant FVIII (Afstyla ® ) has been approved by the US Food and Drug Administration (US FDA) in May 2016.…”

FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity

“…Future experiments will test for reduced immunogenicity and antigenicity of sequencemodified FVIII proteins using human PBMCs and animal models. Some recently introduced therapeutic FVIII proteins have extended half-lives achieved through conjugation to Fc 67 or polyethylene glycol, 67,68 or sequence modifications to generate a single-chain FVIII, 69 etc. The effects of these modifications on immunogenicity are subjects of ongoing research.…”