Real-world clinical experience of extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) in comparison to conventional factor products in patients with severe hemophilia A
Abstract
Introduction: The recombinant factor FVIII Fc fusion protein (rFVIIIFc) is a first-in-class extended half-life FVIII product to treat patients with hemophilia A. The safety, efficacy and prolonged half-life of rFVIIIFc was demonstrated in the phase 3 studies A-LONG, Kids A-LONG and the extension study ASPIRE. Despite robust efficacy and safety data of rFVIIIFc therapy from clinical trials, evidence on the effectiveness of rFVIIIFc use in real-world remains scarce. Our analysis aimed at investigating the effectiveness of prophylactic rFVIIIFc treatment in routine clinical use in Germany.
Material and Methods: Twenty-seven patients with severe hemophilia A, who switched from prophylaxis with conventional recombinant factor VIII (rFVIII) products to rFVIIIFc, were included. Annualized bleeding rates, factor consumption, number of injections and adherence to prophylaxis were compared. The retrospective period prior switching to rFVIIIFc was three years, while the mean follow-up period after switching to rFVIIIFc was 24.9 months.
Results: Switching to rFVIIIFc led to a 33.7% reduction in mean annualized number of injections and a 18.3% reduction in mean annualized factor consumption while maintaining low bleeding rates. The mean annualized bleeding rate (ABR) was 2.5 and 1.7 for rFVIII and rFVIIIFc, respectively. The adherence improved from 87% to 94%. During the follow-up period eleven surgeries were performed; all with a hemostatic response rated as excellent. No FVIII inhibitor formation after switching to rFVIIIFc has been detected.
Conclusion: Real-world treatment with rFVIIIFc was associated with substantial reductions in consumption and injection frequenies while maintaining low bleeding rates supporting safety and efficacy data from clinical trials.
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References
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42. Klamroth, R., et al., Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study. Blood, 2020.
43. Peyvandi, F., et al., Kreuth V initiative: European consensus proposals for treatment of hemophilia using standard products, extended half-life coagulation factor concentrates and non-replacement therapies. Haematologica, 2020. 105(8): p. 2038-2043.
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2. Lobet, S., C. Hermans, and C. Lambert, Optimal management of hemophilic arthropathy and hematomas. J Blood Med, 2014. 5: p. 207-18.
3. Manco-Johnson, M.J., et al., Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med, 2007. 357(6): p. 535-44.
4. Manco-Johnson, M.J., et al., Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost, 2013. 11(6): p. 1119-27.
5. White, G.C., 2nd, et al., Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost, 2001. 85(3): p. 560.
6. Srivastava, A., et al., Guidelines for the management of hemophilia. Haemophilia, 2013. 19(1): p. e1-47.
7. Ingersoll, K.S. and J. Cohen, The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med, 2008. 31(3): p. 213-24.
8. Wiley, R.E., et al., From the voices of people with haemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies. Haemophilia, 2019. 25(3): p. 433-440.
9. Carcao, M., Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia, 2014. 20 Suppl 4: p. 99-105.
10. European Medicines Agency (EMA), Summary of Product Characteristics: Elocta. https://www.ema.europa.eu/en/documents/product-information/elocta-epar-product-information_en.pdf (accessed 19 Aug 2019).
11. Peters, R.T., et al., Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost, 2013. 11(1): p. 132-41.
12. Roopenian, D.C. and S. Akilesh, FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol, 2007. 7(9): p. 715-25.
13. Powell, J.S., et al., Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood, 2012. 119(13): p. 3031-7.
14. Mahlangu, J., et al., Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood, 2014. 123(3): p. 317-25.
15. Young, G., et al., Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost, 2015. 13(6): p. 967-77.
16. Nolan, B., et al., Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study. Haemophilia, 2020. 26(3): p. 494-502.
17. Nolan, B., et al., Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia, 2016. 22(1): p. 72-80.
18. Berntorp, E., et al., Dosing regimens, FVIII levels and estimated haemostatic protection with special focus on rFVIIIFc. Haemophilia, 2016. 22(3): p. 389-96.
19. Oldenburg, J., et al., Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein. Haemophilia, 2018. 24(1): p. 77-84.
20. Srivastava, A., et al., WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia, 2020. 26 Suppl 6: p. 1-158.
21. Oldenburg, J., Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood, 2015. 125(13): p. 2038-44.
22. Collins, P.W., et al., Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost, 2009. 7(3): p. 413-20.
23. Collins, P.W., et al., Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia, 2011. 17(1): p. 2-10.
24. Ahnstrom, J., et al., A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia. Haemophilia, 2004. 10(6): p. 689-97.
25. McCue, J., et al., Manufacturing process used to produce long-acting recombinant factor VIII Fc fusion protein. Biologicals, 2015. 43(4): p. 213-9.
26. Coyle, T.E., et al., 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): p. 488-96.
27. Giangrande, P., et al., Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A. Thromb Haemost, 2017. 117(2): p. 252-261.
28. Konkle, B.A., et al., Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood, 2015. 126(9): p. 1078-85.
29. Mullins, E.S., et al., Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia, 2017. 23(2): p. 238-246.
30. Tiede, A., et al., Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost, 2013. 11(4): p. 670-8.
31. Collins, P.W., et al., Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood, 2014. 124(26): p. 3880-6.
32. Aledort, L., et al., A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States. J Manag Care Spec Pharm, 2020. 26(4): p. 492-503.
33. Dunn, A.L., S.P. Ahuja, and E.S. Mullins, Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A. Haemophilia, 2018. 24(3): p. e84-e92.
34. Peyvandi, F., et al., Real-life experience in switching to new extended half-life products at European haemophilia centres. Haemophilia, 2019. 25(6): p. 946-952.
35. Pouplard, C., et al., Multicentre pharmacokinetic evaluation of rFVIII-Fc (efmoroctocog alfa) in a real life and comparison with non-extended half-life FVIII concentrates. Haemophilia, 2020. 26(2): p. 282-289.
36. Simpson, M.L., et al., Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products. J Manag Care Spec Pharm, 2020. 26(4): p. 504-512.
37. Tagliaferri, A., et al., Optimising prophylaxis outcomes and costs in haemophilia patients switching to recombinant FVIII-Fc: a single-centre real-world experience. Blood Transfus, 2020. 18(5): p. 374-385.
38. Holmström, M., et al. Real-World Usage of rFVIIIFc in Sweden: A Report from the Swedish National Registry for Bleeding Disorders. Presented at the 13th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD); 5-7 February 2020, The Hague, Netherlands. 2020.
39. Oldenburg, J., et al. No Relapse in Patients with Previous Inhibitors Switched to rFVIIIFc in Ongoing Observational Phase 4 Studies. Presented at the International Society on Thrombosis and Haemostasis (ISTH) 2020 Virtual Congress; 12-14 July 2020. 2020.
40. Keepanasseril, A., et al., Switching to extended half-life products in Canada - preliminary data. Haemophilia, 2017. 23(4): p. e365-e367.
41. Iorio, A., et al., Indirect comparisons of efficacy and weekly factor consumption during continuous prophylaxis with recombinant factor VIII Fc fusion protein and conventional recombinant factor VIII products. Haemophilia, 2017. 23(3): p. 408-416.
42. Klamroth, R., et al., Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study. Blood, 2020.
43. Peyvandi, F., et al., Kreuth V initiative: European consensus proposals for treatment of hemophilia using standard products, extended half-life coagulation factor concentrates and non-replacement therapies. Haematologica, 2020. 105(8): p. 2038-2043.
44. Habermann, B., et al. S2k-Leitlinie Synovitis bei Hämophilie. 2018.
45. Federal Medical Association. Cross-Sectional Guidelines for Therapy with Blood Products and Plasma Derivates. 5th revised and updated edition 2020. Pages 118-146
46. Ar, M.C., et al., Methods for individualising factor VIII dosing in prophylaxis. Eur J Haematol Suppl, 2014. 76: p. 16-20.
Authors
Oldenburg, J. ., Goldmann, G. ., Marquardt, N., Horneff, S., Klein, C. ., Albert, T., & Perera, R. (2021). Real-world clinical experience of extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) in comparison to conventional factor products in patients with severe hemophilia A . Journal of Current Medical Research and Opinion, 4(05), 950–960. https://doi.org/10.15520/jcmro.v4i05.422
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