Main directions for the development and modification of preparations for the treatment of hemophilia

The basic method of the treatment of haemophilia A and B is the replacement therapy by preparations obtained from plasma of donors, or by recombinant DNA technology. Among the major shortcomings of unmodified drugs VIII and IX factors should be allocated between the low time circulation of the drug in the body of the patient and the delivery of antibodies (inhibitors) to a protein preparation that significantly reduces their effectiveness. The improvement of the efficiency and safety of recombinant preparations is achieved by removing B-domain of factor VIII molecule, pegylation or development of preparations of fusion proteins (fusion molecules of the preparation to the albumin or Fc-fragment of IgG). These modifications, especially, enhance the stability of the molecule of the active substance to increase half-life and reduce immunogenicity of recombinant products. Replacement therapy with traditional preparations in hemophilia patients delivering antibodies (inhibitors) to the preparation is ineffective. Taking this into account, in recent years, new preparations have been developed for alternative approaches treatment of hemophilia. There were developed the preparation based on bispecific monoclonal antibody mimicking the function of factor VIII; monoclonal antibodies and aptamer blocking the activity of tissue factor pathway inhibitor, and the preparation based on antisense oligonucleotide blocking mRNA responsible for the synthesis of antithrombin III. The main advantage of these new formulations is that they do not cause the production of antibodies to coagulation factors and so can be used for the treatment of patients with inhibitors in blood.

1. Mannucci P.M. AIDS, hepatitis and hemophilia in the 1980s: memoirs from an insider. J. Thromb. Haemost. 2003; 1(10): 2065–9.

2. Wight J., Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003; 9(4): 418–35.

3. Ettingshausen C.E., Kreuz W. Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development. Haemophilia. 2006; 12(6): 102–6.

4. Chalmers E.A., Brown S.A , Keeling D.. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia. 2007; 13(2): 149–55.

5. Agostini D., Rosset C., Botton M.R., Kappel D.B., Vieira I.A., Gorziza R.P., et al. Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia A severe patients. Haemophilia. 2012; 18(6): e416–28. doi: 10.1111/hae.12015.

6. Srivastava A., Brewer A.K., Mauser-Bunschoten E.P., Key N.S., Kitchen S., Llinas A., et al. Guidelines for the management of hemophilia. Haemophilia. 2013; 19(1): e1–47.

7. Ljung R., Auerswald G., Benson G., Jetter A., Jiménez-Yuste V., et al. Novel coagulation factor concentrates: Issues relating to their clinical implementation and pharmacokinetic assessment for optimal prophylaxis in haemophilia patients. Haemophilia. 2013; 19(4): 481–6.

8. Collins P.W. Personalized prophylaxis. Haemophilia. 2012; 18(4): 131–5.

9. Ezban M., Vad K., Kjalke M. Turoctocog alfa (NovoEight ® ) – from design to clinical proof of concept. Eur. J. Haematol. 2014; 93 (Issue 5): 369–76.

10. Zollner S.B., Raquet E., Müller-Cohrs J., Metzner H.J., Weimer T., Pragst I., et al. Preclinical efficacy and safety of rVIII-Single Chain (CSL627), a novel recombinant single-chain factor VIII. Thromb. Res. 2013; 132(2): 280–7.

11. Tiede A., Klamroth R., Oldenburg J. Turoctocog alfa (recombinant factor VIII) Manufacturing, characteristics and clinical trial results. Hämostaseologie. 2015; 35(14): 1–9.

12. Casademunt E., Martinelle K., Jernberg M., Winge S., Tiemeyer M., Biesert L., et al. The first recombinant human coagulation factor VIII of human origin: human cell line and manufacturing characteristics. Eur. J. Haematol. 2012; 89(2): 165–76.

13. Kessler C., Oldenburg J., Escuriola Ettingshausen C., Tiede A., Khair K., Negrier C., Klamroth R. Spotlight on the human factor: building a foundation for the future of haemophilia A management: report from a symposium on human recombinant FVIII at the World Federation of Hemophilia World Congress, Melbourne, Australia on 12 May 2014. Haemophilia. 2015; 21(Suppl. 1): 1–12. doi: 10.1111/hat.12582.

14. Coyle T.E., Reding M.T., Lin J.C., Michaels L.A., Shah A., Powell J. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J. Thromb. Haemost. 2014; 12(4): 488–96.

15. Lillicrap D. Extending half-life in coagulation factors: where do we stand? Thromb Res. 2008; 122 (Suppl. 4): 2–8. doi: 10.1016/S0049-3848(08)70027-6.

16. George L.A., Camire R.M. Profile of efraloctocog alfa and its potential in the treatment of hemophilia A. J. Blood Med. 2015; 6: 131–41. doi: 10.2147/JBM.S54632.

17. 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. 2011; 118(10): 2695–701.

18. Krippendorff B.F., Kuester K., Kloft C., Huisinga W. Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. J. Pharmacokinet. Pharmacodyn. 2009; 36(3): 239–60.

19. Xu X., Vugmeyster Y. Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics. AAPS J. 2012; 14(4): 781–91. doi: 10.1208/s12248-012-9388-8.

20. Deng R., Loyet K.M., Lien S., Iyer S.,De ForgeL.E.,TheilF.P., et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-(alpha) antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab. Dispos. 2010; 38(4): 600–5.

21. Dall’Acqua W.F., Kiener P.A., Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 2006; 281(33): 23514–24.

22. Sarav M., Wang Y., Hack B.K., Chang A., Jensen M., Bao L., Quigg R.J. Renal FcRn reclaims albumin but facilitates elimination of IgG. J. Am. Soc. Nephrol. 2009; 20(9): 1941–52.

23. Lei T.C., Scott D.W. Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood. 2005; 105(12): 4865–70.

24. De Groot A.S., Moise L., McMurry J.A, Wambre E., Van Overvelt L., Moingeon P., et al. Activation of natural regulatory T cells by IgG Fcderived peptide “Tregitopes”. Blood. 2008; 112(8): 3303–11.

25. Young G., Mahlangu J.N., Kulkarni R., Nolan B., Liesner R., Pasi J., et al. Safety, efficacy, and pharmacokinetics of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously-treated children with severe hemophilia a (Kids-ALONG). Presented at: 56th Annual Meeting and Exposition, December 17, 2014, San Francisco, CA. Available: https://ash.confex.com/ash/2014/webprogram/Paper70146.html. Accessed February 10, 2015.

26. Hoots W.K. Urgent inhibitor issues: targets for expanded research. Haemophilia. 2006; 12(6): 107–13.

27. Metzner H.J., Pipe S.W., Weimer T., Schulte S. Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin. Thromb. Haemost. 2013; 110(5): 931–9.

28. Golor G., Bensen-KennedY D., Haffner S., Easton R., Jung K., Moises T., et al. Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers. J. Thromb. Haemost. 2013; 11(11): 1977–85. doi: 10.1111/jth.12409.

29. Mathias M., Khair K., Hann I., Liesner R. Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia. Br. J. Haematol. 2004; 125(3): 366–8.

30. Kitazawa T., Igawa T., Sampei Z., Muto A., Kojima T., Soeda T., et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat. Med. 2012; 18(10): 1570–4.

31. Muto A., Yoshihashi K., Takeda M., Kitazawa T., Soeda T., Igawa T., et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J. Thromb. Haemost. 2014; 12(2): 206–13.

32. Chowdary P., Lethagen S., Friedrich U., Brand B., Hay C., Abdul Karim A., et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J. Thromb. Haemost. 2015; 13(5): 743–54. doi: 10.1111/jth.12864.

33. Hilden I., Lauritzen B., Sorensen B.B., Clausen J.T., Jespersgaard C., Krogh B.O., et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood. 2012; 119(24): 5871–8.

34. Waters E.K., Genga R.M., Thomson H.A., Kurz J.C., Schaub R.G., Scheiflinger F., Mcginness K.E. Aptamer BAX 499 mediates inhibition of tissue factor pathway inhibitor via interaction with multiple domains of the protein. J. Thromb. Haemost. 2013; 11(6): 1137–45.

35. Gorczyca M.E., Nair S.C., Jilma B., Priya S., Male C., Reitter S., et al. Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma. Thromb. Haemost. 2012; 10(1): 1581–90.

36. Sorensen B., Mant T., Akinc A. Aln-AT3 Investigators. A subcutane ously administered RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim Phase 1 study results in healthy volunteers and patients with hemophilia A or B. Presented at: 56th Annual Meeting and Exposition, December 17, 2014, San Francisco, CA. Available: https://ash.confex.com/ash/2014/webprogram/Paper75077.html. Accessed: Feb. 19, 2015.

37. Jansen M., Schmaldienst S., Banyai S. Quehenberger P., Pabinger I., Derfler K., et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br. J. Haematol. 2001; 112(1): 91–7.

38. Zeitler H., Ulrich-Merzenich G., Hess L., Konsek E., Unkrig C., Walger P., et al. Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept. Blood. 2005; 105(6): 2287–93.

39. Berntorp E. Options for treating acute bleeds in addition to bypassing agents: extracorporeal immunoadsorption, FVIII/FIX, desmopressin and antifibrinolytics. Haemophilia. 2006; 12(6): 62–6.

40. Nathwani A.C., Tuddenham E.G., Rangarajan S., Rosales C., McIntosh J., Linch D.C., et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 2011; 365(25): 2357–65. doi: 10.1056/NEJMoa1108046.

41. Nathwani A.C., Reiss U.M., Tuddenham E.G.D., Rosales C., Chowdary P., McIntosh J., et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 2014; 371(21): 1994–2004.