Challenges in prophylactic therapy with Emicizumab in patients with hemophilia A: Focus on monitoring tests

1 Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan; 19(1):e1-47. DOI: 10.1111/j.1365-2516.2012.02909.x Search in Google Scholar

2 Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost. 2012 Oct; 38(7):727-34. DOI: 10.1055/s-0032-1326786 Search in Google Scholar

3 Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug DOI: 10.1111/hae.14046 26. Suppl 6:1-158. doi: 10.1111/hae.14046. Epub 2020 Aug 3. Erratum in: Haemophilia. 2021 Jul;27(4):699. DOI: 10.1111/hae.14308 Search in Google Scholar

4 Khair K, Mazzucconi MG, Parra R, Santagostino E, Tsakiris DA, Hermans C, et al. Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study. Haemophilia. 2018 Jan; 24(1):85-96. DOI: 10.1111/hae.13361 Search in Google Scholar

5 Oldenburg J, Khair K, Mazzucconi MG. Real World prospective data on bleeding frequency in 1,000 patients with hemophilia A - is the goal of zero bleeds achievable? Paper presented at: 10th Annual Congress of the European Association for Haemophilia and Allied Disorders 2017(1-3), pp. February 2017. Paris: France; 2017. Search in Google Scholar

6 Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357:535-544. DOI: 10.1056/NEJMoa067659 Search in Google Scholar

7 Manco-Johnson MJ, Lundin B, Funk S, Peterfy C, Raunig D, Werk M, et al. Effect of late prophylaxis in hemophilia on joint status: a randomized trial. J Thromb Haemost. 2017; 15:2115-2124. DOI: 10.1111/jth.13811 Search in Google Scholar

8 Kim JY, You CW. The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A. Blood Res. 2019 Sep; 54(3):204-209. DOI: 10.5045/br.2019.54.3.204 Search in Google Scholar

9 Petrini P, Valentino LA, Gringeri A, Re WM, Ewenstein B. Individualizing prophylaxis in hemophilia: a review. Expert Rev Hematol. 2015 Apr; 8(2):237-46. DOI: 10.1586/17474086.2015.1002465 Search in Google Scholar

10 Giangrande PLF, Hermans C, O’Mahony B, de Kleijn P, Bedford M, Batorova A, et al. European principles of inhibitor management in patients with haemophilia. Orphanet J Rare Dis. 2018;13:66. DOI: 10.1186/s13023-018-0800-z Search in Google Scholar

11 Matino D, Makris M, Dwan K, D’Amico R, Iorio A. Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database Syst Rev. 2015 Dec 16; 2015(12):CD004449 DOI: 10.1002/14651858.CD004449.pub4 Search in Google Scholar

12 Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102(07):2358-63. DOI: 10.1182/blood-2003-03-0941 Search in Google Scholar

13 Scalone L, Mantovani LG, Mannucci PM, Gringeri A; COCIS Study Investigators. Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors. Haemophilia 2006; 12(02):154-62. DOI: 10.1111/j.1365-2516.2006.01204.x Search in Google Scholar

14 Morfini M, Haya S, Tagariello G, Pollmann H, Quintana M, Siegmund B, et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007;13:606-12. DOI: 10.1111/j.1365-2516.2007.01518.x Search in Google Scholar

15 Manco-Johnson MJ, Lundin B, Funk S, Peterfy C, Raunig D, Werk M, et al. Effect of late prophylaxis in hemophilia on joint status: a randomized trial. J Thromb Haemost. 2017; 15:2115-24. DOI: 10.1111/jth.13811 Search in Google Scholar

16 Petrini P, Valentino LA, Gringeri A, Re WM, Ewenstein B. Individualizing prophylaxis in hemophilia: a review. Expert Rev Hematol. 2015; 8:237-46. DOI: 10.1586/17474086.2015.1002465 Search in Google Scholar

17 Valentino LA, Kawji M, Grygotis M. Venous access in the management of hemophilia. Blood Rev. 2011;25:11-15. DOI: 10.1016/j.blre.2010.10.001 Search in Google Scholar

18 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. DOI: 10.1038/nm.2942 Search in Google Scholar

19 HEMLIBRA product characteristics: https://www.ema.europa.eu/en/documents/product-information/hemlibra-epar-product-information_ro.pdf Search in Google Scholar

20 Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018; 379(9):811-22. DOI: 10.1056/NEJMoa1803550 Search in Google Scholar

21 Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017; 377(9):809-18. DOI: 10.1056/NEJMoa1703068 Search in Google Scholar

22 Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al; Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021 Apr 22; 137(16):2231-42. DOI: 10.1182/blood.2020009217 Search in Google Scholar

23 Gelbenegger G, Schoergenhofer C, Knoebl P, Jilma B. Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A. Thromb Haemost. 2020 Oct; 120(10):1357-70. DOI: 10.1055/s-0040-1714279 Search in Google Scholar

24 Paz-Priel I, Chang T, Asikanius E, Chebon S, Emrich T, Fernandez E. Immunogenicity of Emicizumab in People with Hemophilia A (PwHA): Results from the HAVEN 1-4 Studies. Blood. 2018;1329S1):633. DOI: 10.1182/blood-2018-99-118492 Search in Google Scholar

25 Food and Drug Administration. HEMLIBRA® (emicizumab-kxwh) injection for subcutaneous use, prescribing information. Initial U.S. approval: 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf. Accessed January 9, 2019. Search in Google Scholar

26 Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS One. 2013;8(2):e57479. DOI: 10.1371/journal.pone.0057479 Search in Google Scholar

27 Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 2017; 130(23):2463-68. DOI: 10.1182/blood-2017-08-801662 Search in Google Scholar

28 Castaman G, Santoro C, Coppola A, Mancuso ME, Santoro RC, Bernardini S, et al. Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET. Blood Transfus. 2020 Mar; 18(2):143-51. DOI: 10.2450/2019.0186-19 Search in Google Scholar

29 Jonsson F, Mercier F, Prins NH, Schmitt C, Retout S. Exposure-Response Modeling of Emicizumab for the Prophylaxis of Bleeding in Hemophilia A Patients. 27th Meeting of the Population Approach Group in Europe (PAGE): Montreux, Switzerland; 2018. Search in Google Scholar

30 Müller J, Pekrul I, Pötzsch B, Berning B, Oldenburg J, Spannagl M. Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A. Thromb Haemost. 2019 Sep; 119(9):1384-93. DOI: 10.1055/s-0039-1692427 Search in Google Scholar

31 Adamkewicz JI, Chen DC, Paz-Priel I. Effects and Interferences of Emicizumab, a Humanised Bispecific Antibody Mimicking Activated Factor VIII Cofactor Function, on Coagulation Assays. Thromb Haemost. 2019 Jul; 119(7):1084-93. DOI: 10.1055/s-0039-1688687 Search in Google Scholar

32 Nardi MA. Emicizumab and the clinical laboratory. American Society for Clinical Laboratory Science. 2020:ascls.119.002204. DOI: 10.29074/ascls.119.002204 Search in Google Scholar

33 Jonsson F, Schmitt C, Petry C, Mercier F, Frey N, Retout S. Exposure-Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII. Clin Pharmacokinet. 2021 Jul;60(7):931-41. DOI: 10.1007/s40262-021-01006-0 Search in Google Scholar

34 Giangrande PL, Wilde JT, Madan B, Ludlam CA, Tuddenham EG, Goddard NJ, et al. Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors. Haemophilia. 2009 Mar;15(2):501-8. DOI: 10.1111/j.1365-2516.2008.01952.x Search in Google Scholar