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Update to Chapter 123: Hemophilia A and B

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Several methods have been developed to extend the half-life of recombinant factor VIII. PEGylation is one of these methods; it consists of covalent binding of polyethylene glycol (PEG) polymers to therapeutic agents through site-specific binding to free cysteine residues or via protein engineering (site-specific PEGylation and glycoPEGylation). PEGylated recombinant FVIII (rFVIII) products (BAY 94-9027, N8-GP, and BAX 855) showed a half-life that was approximately 1.5–1.6-fold longer than that of standard rFVIII products (Konkle et al, 2015; Peyvandi et al, 2016). The first full-length extended half-life (EHL) rFVIII produced by coupling PEG polymer (BAX 855, Adynovate) was approved by the U.S. Food and Drug Administration (FDA) for hemophilia A treatment, excluding surgical procedures.

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Another method used to extend the half-life of factor concentrates is fusion with the fragment crystallizable (Fc) region of IgG. This strategy was shown to result in a half-life for rFVIII-Fc that was 1.5-fold that of standard rFVIII concentrate (Mahlangu et al, 2014). The rFVIII-Fc (Eloctate) was approved for hemophilia A treatment by the FDA and recently also by the European Medicines Agency (EMA).

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An additional novel recombinant FVIII molecule has been developed with a specific single-chain design (rVIII-SingleChain, CSL627), which increases the intrinsic stability of the FVIII molecule by reducing the potential for dissociation of the heavy and light chains of FVIII. In addition, rVIII-SingleChain shows much stronger affinity for its natural carrier protein, von Willebrand factor (VWF). This translates into pharmacokinetics that are superior to those of standard rFVIII .

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For the treatment of hemophilia B, new recombinant FIX (rFIX) products obtained by PEGylation and Fc-fusion technologies have been developed, and the results were more promising than those for other modified recombinant coagulation proteins (Negrier et al, 2011; Powell et al, 2013). Clinical trials of the glycoPEGylated (N9-GP) and Fc-fusion (rFIX-Fc, Alprolix) rFIX products showed half-lives of up to 93 h and 82 h, respectively, which are remarkably longer than the standard rFIX half-life. The times needed to reach 1% of FIX activity were 22 days and 11.2 days, respectively, for N9-GP and rFIX–Fc.

References +
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Konkle  BA, Stasyshyn  O, Chowdary  P, Bevan  DH, Mant  T, Shima  M,  et al: Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A.. Blood 126(9):1078–1085, 2015.
[PubMed: 26157075]
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Mahlangu  J, Powell  JS, Ragni  MV, Chowdary  P, Josephson  NC, Pabinger  I,  et al: Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A.. Blood 123(3):317–325, 2014.
[PubMed: 24227821]
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Negrier  C, Knobe  K, Tiede  A, Giangrande  P, Moss  J: Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: A first human dose trial in patients with hemophilia B.. Blood 118(10):2695–2701, 2011.
[PubMed: 21555744]
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Peyvandi  F, Garagiola  I, Biguzzi  E: Advances in the treatment of bleeding disorders. J Thromb Haemost 14(11):2095–2106, 2016.
[PubMed: 27590165]
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Powell  JS, Pasi  KJ, Ragni  MV, Ozelo  MC, Valentino  LA, Mahlangu  JN,  et al: Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 369(24):2313–2323, 2013.
[PubMed: 24304002]