Biological Rationale for New Drugs in the Bleeding Disorders Pipeline

Abstract

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

“…3 Extending FVIII half-life can reduce injection frequency, which may lessen treatment burden, improve compliance with prophylaxis, and positively impact therapeutic outcomes. 1,2,4,5 A protein composed of a single molecule of recombinant FVIII (rFVIII) covalently fused to the Fc domain of IgG 1 , recombinant FVIII Fc fusion protein (rFVIIIFc) (efraloctocog alfa), has been developed. 6 Fc fusion prolongs the half-life of rFVIIIFc by utilizing the neonatal Fc receptor and endogenous IgG recycling pathway, which delays lysosomal degradation of IgG and Fc fusion proteins, and cycles them back into the circulation.…”

Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

“…Several strategies for creating longer-acting replacement factors are in development, including modifications to the FVIII molecule, such as pegylation, glycopegylation, recombinant fusion to immunoglobulin (Ig) Fc, modification of the amino acid sequence to create sites for site-directed pegylation, and disulfide linkage between its light and heavy chains. [10][11][12] Chemical modification with pegylation is a well-established method of improving the PK profile by extending T 1/2 and circulation of therapeutic proteins. 13 With the goal of reducing the number of infusions required per week for prophylaxis, a pegylated recombinant FVIII-rurioctacog alfa pegol (BAX 855) was built to extend FVIII half-life on the manufacturing platform of Advate, a fulllength, unmodified rFVIII (Baxalta US Inc., Westlake Village, CA).…”

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

“…Thus, there is a strong medical need for rFVIII therapy that offers reduced potential for immunogenicity. In addition, research has focused on developing rFVIII products with an extended half-life to improve treatment convenience and standard of care for people with haemophilia A [10].…”