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BioDrugs

, Volume 32, Issue 6, pp 561–570 | Cite as

Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors

  • Johnny N. Mahlangu
Leading Article
  • 141 Downloads

Abstract

Current unmet needs in haemophilia A patients with inhibitors include the need for intravenous infusion of replacement therapy and the high burden of treatment associated with prophylaxis. Emicizumab is a humanised bispecific monoclonal antibody designed to address these unmet needs and has completed phase III clinical trials in adolescents/adults (HAVEN 1) and paediatric (HAVEN 2) inhibitor populations. In HAVEN 1, there was an 80% bleed reduction across all bleeds, 89% reduction in treated joint bleeds, 92% reduction in treated spontaneous bleeds, and 95% reduction in treated target joint bleeds on emicizumab compared with no prophylaxis. In HAVEN 2, there was a 63% reduction in all bleeds, 94.7% reduction in treated bleeds, 94.7% reduction in treated spontaneous bleeds, 100% reduction in treated joint bleeds, and 100% reduction in treated target joint bleeds on emicizumab prophylaxis when compared with no prophylaxis. For patients on bypassing agent prophylaxis, emicizumab resulted in a 68% reduction in bleeds in HAVEN 1 and a 100% reduction in bleed rates in HAVEN 2. In HAVEN 1, three patients developed thrombotic microangiopathy (TMA) and two developed thrombosis when emicizumab was used together with an activated prothrombin complex concentrate (aPCC) at high or frequent doses. When the combination was avoided in HAVEN 2, no patient developed TMA or thrombosis. In both studies, no anti-emicizumab antibodies developed and the pharmacokinetic profile of emicizumab was similar. Emicizumab use is currently being explored in haemophilia A patients without inhibitors as well as in combination with other haemophilia A replacement therapies. The role of emicizumab in combination with current factor VIII replacement therapies and evolving non-replacement therapies remains to be established.

Notes

Compliance with ethical standards

Funding

The preparation of this article required no external funding.

Conflict of interest

JN Mahlangu declares no relevant conflicts of interest.

References

  1. 1.
    Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia. 2012;19(1):e1–47.CrossRefPubMedGoogle Scholar
  2. 2.
    Iorio A, Krishnan S, Myrén K-J, Lethagen S, McCormick N, Yermakov S, et al. Continuous prophylaxis with recombinant factor IX Fc fusion protein and conventional recombinant factor IX products: comparisons of efficacy and weekly factor consumption. J Med Econ. 2017;20(4):337–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Ljung R, Fischer K, Carcao M, Santagostino E, Manco-Johnson MJ, Mathew P, et al. Practical considerations in choosing a factor VIII prophylaxis regimen: Role of clinical phenotype and trough levels. Thromb Haemost. 2016;115(5):913–20.CrossRefPubMedGoogle Scholar
  4. 4.
    Carcao M. Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia. 2014;20(Suppl 4):99–105.CrossRefPubMedGoogle Scholar
  5. 5.
    Makris M. Prophylaxis in haemophilia should be life-long. Blood Transfus. 2012;10(2):165–8.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice. Haemophilia. 2007;13(Suppl 2):4–9.PubMedGoogle Scholar
  7. 7.
    Ota S, McLimont M, Carcao MD, Blanchette VS, Graham N, Paradis E, et al. Definitions for haemophilia prophylaxis and its outcomes: the Canadian consensus study. Haemophilia. 2007;13(1):12–20.CrossRefPubMedGoogle Scholar
  8. 8.
    Wyrwich KW, Krishnan S, Auguste P, Maltzahn R, Yu R, Bozkaya D, et al. Health-related quality of life data changes from baseline using HAEM-A-QOL scores in the A-LONG clinical study of recombinant factor VIII Fc fusion protein. Haemophilia. 2014;20:169.Google Scholar
  9. 9.
    Angelini D, Konkle BA, Sood SL. Aging among persons with hemophilia: contemporary concerns. Semin Hematol. 2016;53(1):35–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Di Minno G, Cerbone AM, Coppola A, Cimino E, Di Capua M, Pamparana F, et al. Longer-acting factor VIII to overcome limitations in haemophilia management: the PEGylated liposomes formulation issue. Haemophilia. 2010;16(Suppl 1):2–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Plug I, Van Der Bom JG, Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost. 2006;4(3):510–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Oldenburg J, Kulkarni R, Srivastava A, Mahlangu JN, Blanchette VS, Tsao E, et al. Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein. Haemophilia. 2018;24(1):77–84.CrossRefPubMedGoogle Scholar
  13. 13.
    Carcao M, Hilliard P, Escobar MA, Solimeno L, Mahlangu J, Santagostino E. Optimising musculoskeletal care for patients with haemophilia. Eur J Haematol. 2015;95(Suppl 81):11–21.CrossRefPubMedGoogle Scholar
  14. 14.
    DeKoven M, Karkare S, Lee WC, Kelley LA, Cooper DL, Pham H, et al. Impact of haemophilia with inhibitors on caregiver burden in the United States. Haemophilia. 2014;20(6):822–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Weatherall J, Barnes N, Brown C, Preaud E. Future characteristics of bypassing agents to improve care of hemophilia inhibitor patients: an economic and health-related quality of life perspective. Expert Rev Pharmacoecon Outcomes Res. 2011;11(4):411–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Kavakli K, Yesilipek A, Antmen B, Aksu S, Balkan C, Yilmaz D, et al. The value of early treatment in patients with haemophilia and inhibitors. Haemophilia. 2010;16(3):487–94.PubMedGoogle Scholar
  17. 17.
    Hemophilia Goudemand J. Treatment of patients with inhibitors: cost issues. Haemophilia. 1999;5(6):397–401.CrossRefGoogle Scholar
  18. 18.
    Astermark J, Donfield SM, DiMichele DM, Gringeri A, Gilbert SA, Waters J, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood. 2007;109(2):546–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003;9(4):418–35.CrossRefPubMedGoogle Scholar
  20. 20.
    Collins PW, Chalmers E, Hart DP, Liesner R, Rangarajan S, Talks K, et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization. Br J Haematol. 2013;160(2):153–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Bardi E, Astermark J. Genetic risk factors for inhibitors in haemophilia A. Eur J Haematol. 2015;94(Suppl 77):7–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Lochan A, Macaulay S, Chen WC, Mahlangu JN, Krause A. Genetic factors influencing inhibitor development in a cohort of South African haemophilia A patients. Haemophilia. 2014;20(5):687–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Lacroix-Desmazes S, Scott DW, Goudemand J, Van Den Berg M, Makris M, Van Velzen AS, et al. Summary report of the First International Conference on inhibitors in haemophilia A. Blood Transfus. 2017;15(6):568–76.Google Scholar
  24. 24.
    van den Berg HM, Hashemi SM, Fischer K, Petrini P, Ljung R, Rafowicz A, et al. Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors. Thromb Haemost. 2016;115(4):729–37.CrossRefPubMedGoogle Scholar
  25. 25.
    Fischer K, van der Bom JG, Mauser-Bunschoten EP, Roosendaal G, Prejs R, Grobbee DE, et al. Changes in treatment strategies for severe haemophilia over the last 3 decades: effects on clotting factor consumption and arthropathy. Haemophilia. 2001;7(5):446–52.CrossRefPubMedGoogle Scholar
  26. 26.
    Gringeri A, Ewenstein B, Reininger A. The burden of bleeding in haemophilia: is one bleed too many? Haemophilia. 2014;20(4):459–63.CrossRefPubMedGoogle Scholar
  27. 27.
    Gater A, Thomson TA, Strandberg-Larsen M. Haemophilia B: impact on patients and economic burden of disease. Thromb Haemost. 2011;106(3):398–404.PubMedGoogle Scholar
  28. 28.
    Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110(3):815–25.CrossRefPubMedGoogle Scholar
  29. 29.
    Szeto CC, Kwan BC, Chow KM, Pang WF, Kwong VW, Leung CB, et al. Life expectancy of Chinese patients with chronic kidney disease without dialysis. Nephrology (Carlton). 2011;16(8):715–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Witmer CM. Low mortality from intracranial haemorrhage in paediatric patients with haemophilia. Haemophilia. 2015;21(5):e359–63.CrossRefPubMedGoogle Scholar
  31. 31.
    Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol. 2008;140(4):378–84.CrossRefPubMedGoogle Scholar
  32. 32.
    Traivaree C, Blanchette V, Armstrong D, Floros G, Stain AM, Carcao MD. Intracranial bleeding in haemophilia beyond the neonatal period–the role of CT imaging in suspected intracranial bleeding. Haemophilia. 2007;13(5):552–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Tarantino MD, Gupta SL, Brusky RM. The incidence and outcome of intracranial haemorrhage in newborns with haemophilia: analysis of the Nationwide Inpatient Sample database. Haemophilia. 2007;13(4):380–2.CrossRefPubMedGoogle Scholar
  34. 34.
    Zanon E, Milan M, Brandolin B, Barbar S, Spiezia L, Saggiorato G, et al. High dose of human plasma-derived FVIII-VWF as first-line therapy in patients affected by acquired haemophilia A and concomitant cardiovascular disease: four case reports and a literature review. Haemophilia. 2013;19(1):e50–3.CrossRefPubMedGoogle Scholar
  35. 35.
    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(5):606–12.CrossRefPubMedGoogle Scholar
  36. 36.
    McCarthy A, Moore A, Redhead L, McLaughlin P, Iorio A, Chowdary P. Development of haemophilic arthropathy of the ankle: results of a Delphi consensus survey on potential contributory factors. Haemophilia. 2015;21(1):116–23.CrossRefPubMedGoogle Scholar
  37. 37.
    Teitel JM, Carcao M, Lillicrap D, Mulder K, Rivard GE, St-Louis J, et al. Orthopaedic surgery in haemophilia patients with inhibitors: a practical guide to haemostatic, surgical and rehabilitative care. Haemophilia. 2009;15(1):227–39.CrossRefPubMedGoogle Scholar
  38. 38.
    Santagostino E, Mancuso ME, Novembrino C, Anzoletti Boscolo M, Clerici M, Pasta G, et al. Management of Joint Replacement in Hemophilia a with Inhibitors during Emicizumab Prophylaxis. Blood. 2017;130(Suppl 1):2360.Google Scholar
  39. 39.
    Iorio A, Barbara AM, Makris M, Fischer K, Castaman G, Catarino C, et al. Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia. 2017;23(2):255–63.CrossRefPubMedGoogle Scholar
  40. 40.
    Escobar M, Colberg T, Karim F, Caliskan U, Chowdary P, Giangrande P, et al. Perioperative hemostatic management of major surgery in hemophilia B with long-acting recombinant glycopegylated factor IX: results from the paradigm (TM) 3 clinical trial. J Thromb Haemost. 2015;13:229.Google Scholar
  41. 41.
    Guideline for the management of haemophilia in Australia. Australian Haemophilia Centre Directors’ Organisation, 2016.Google Scholar
  42. 42.
    von Mackensen S, Seifert W. Health-related quality of life in pediatric hemophilia B patients treated with rIX-FP. Res Pract Thromb Haemost. 2017;1(1 Supp 1):767.Google Scholar
  43. 43.
    Carcao M, Kearney S, Santagostino E, Oyesiku JOO, Young NL, Meunier J, et al. Insight into health-related quality of life of young children with haemophilia B treated with long-acting nonacog beta pegol recombinant factor IX. Haemophilia. 2017;23(3):e222–4.CrossRefPubMedGoogle Scholar
  44. 44.
    Young J, Grabell J, Rydz N, Hopman W, Good D, Mahlangu J, et al. Relationship between quality of life and coagulation factor level in hemophilia carriers: preliminary results. J Thromb Haemost. 2015;13:590.CrossRefGoogle Scholar
  45. 45.
    Witt CM, Ausserer O, Baier S, Heidegger H, Icke K, Mayr O, et al. Effectiveness of an additional individualized multi-component complementary medicine treatment on health-related quality of life in breast cancer patients: a pragmatic randomized trial. Breast Cancer Res Treat. 2015;149(2):449–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Mishra SI, Scherer RW, Snyder C, Geigle P, Gotay C. The effectiveness of exercise interventions for improving health-related quality of life from diagnosis through active cancer treatment. Oncol Nurs Forum. 2015;42(1):E33–53.CrossRefPubMedGoogle Scholar
  47. 47.
    Kobiela J, Kaska L, Pindel M, Szarmach A, Janiak M, Proczko-Markuszewska M, et al. Dynamics of quality of life improvement after floppy Nissen fundoplication for gastroesophageal reflux disease. Wideochir Inne Tech Maloinwazyjne. 2015;10(3):389–97.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Hajek A, Brettschneider C, Ernst A, Lange C, Wiese B, Prokein J, et al. Complex coevolution of depression and health-related quality of life in old age. Qual Life Res. 2015;24(11):2713–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Gray WN, Boyle SL, Graef DM, Janicke DM, Jolley CD, Denson LA, et al. Health-related quality of life in youth with Crohn disease: role of disease activity and parenting stress. J Pediatr Gastroenterol Nutr. 2015;60(6):749–53.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Granstrom T, Forsman H, Leksell J, Jani S, Raghib AM, Granstam E. Visual functioning and health-related quality of life in diabetic patients about to undergo anti-vascular endothelial growth factor treatment for sight-threatening macular edema. J Diabetes Complications. 2015;29(8):1183–90.CrossRefPubMedGoogle Scholar
  51. 51.
    Eisele M, Kaduszkiewicz H, Konig HH, Lange C, Wiese B, Prokein J, et al. Determinants of health-related quality of life in older primary care patients: results of the longitudinal observational AgeCoDe Study. Br J Gen Pract. 2015;65(640):e716–23.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–47.CrossRefPubMedGoogle Scholar
  53. 53.
    Shulman R, McKenzie CA, Landa J, Bourne RS, Jones A, Borthwick M, et al. Pharmacist’s review and outcomes: Treatment-enhancing contributions tallied, evaluated, and documented (PROTECTED-UK). J Crit Care. 2015;30(4):808–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Santagostino E, Escobar M, Ozelo M, Solimeno L, Arkhammar P, Lee HY, et al. Recombinant activated factor VII in the treatment of bleeds and for the prevention of surgery-related bleeding in congenital haemophilia with inhibitors. Blood Rev. 2015;29(Suppl 1):S9–18.CrossRefPubMedGoogle Scholar
  55. 55.
    Blanchette VS, O’Mahony B, McJames L, Mahlangu JN. Assessment of outcomes. Haemophilia. 2014;20(Suppl 4):114–20.CrossRefPubMedGoogle Scholar
  56. 56.
    Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Hematology Am Soc Hematol Educ Program. 2014;2014(1):364–71.CrossRefPubMedGoogle Scholar
  57. 57.
    Jimenez-Yuste V, Oldenburg J, Rangarajan S, Peiro-Jordan R, Santagostino E. Long-term outcome of haemophilia A patients after successful immune tolerance induction therapy using a single plasma-derived FVIII/VWF product: the long-term ITI study. Haemophilia. 2016;22(6):859–65.CrossRefPubMedGoogle Scholar
  58. 58.
    Jimenez-Yuste V, Oldenburg J, Rangarajan S, Kurth MH, Bozzo J, Santagostino E. Clinical overview of Fanhdi/Alphanate (plasma-derived, VWF-containing FVIII concentrate) in immune tolerance induction in haemophilia A patients with inhibitors. Haemophilia. 2016;22(1):e71–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Barnes C, Brown SA, Curtin J, Dunkley S. When is enough…enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors. Haemophilia. 2014;20(4):e275–9.Google Scholar
  60. 60.
    Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database Syst Rev. 2014;4:CD010561.Google Scholar
  61. 61.
    Walsh CE, Jimenez-Yuste V, Auerswald G, Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost. 2016;31(116 Suppl 1):S10–7.CrossRefGoogle Scholar
  62. 62.
    Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016;127(13):1633–41.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Nogami K. Bispecific antibody mimicking factor VIII. Thromb Res. 2016;141(Suppl 2):S34–5.CrossRefPubMedGoogle Scholar
  64. 64.
    Shima M, Hermans C, de Moerloose P. Novel products for haemostasis. Haemophilia. 2014;20(Suppl 4):29–35.CrossRefPubMedGoogle Scholar
  65. 65.
    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.CrossRefPubMedGoogle Scholar
  66. 66.
    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):2463–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Kitazawa T, Esaki K, Tachibana T, Ishii S, Soeda T, Muto A, et al. Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens. Thromb Haemost. 2017;117(7):1348–57.CrossRefPubMedGoogle Scholar
  68. 68.
    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):e574–79.CrossRefGoogle Scholar
  69. 69.
    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.CrossRefPubMedGoogle Scholar
  70. 70.
    Young G, Sidonio RF, Liesner R, Oldenburg J, Chang T, Uguen M, et al. HAVEN 2 updated analysis: multicenter, open-label, phase 3 study to evaluate efficacy, safety and pharmacokinetics of subcutaneous administration of emicizumab prophylaxis in pediatric patients with hemophilia A with inhibitors. Blood. 2017;130(Suppl 1):85.Google Scholar
  71. 71.
    Pipe SJ, Shapiro A, et al. . Emicizumab subcutaneous dosing every 4 weeks is safe and efficacious in the control of bleeding in persons with haemophilia A with and without inhibitors- results from the phase 3 HAVEN 4 study. In: Kessler M, editor. 2018 world congress of the World Federation Hemophilia. Glasgow, United Kingdom; 2018.Google Scholar
  72. 72.
    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.CrossRefPubMedGoogle Scholar
  73. 73.
    Hartmann R, Feenstra T, Valentino L, Dockal M, Scheiflinger F. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost. 2018.  https://doi.org/10.1111/jth.14203.CrossRefPubMedGoogle Scholar
  74. 74.
    Rebecca Kruse-Jarres MUC, Stacy E. Croteau, Victor Jimenez-Yuste, Liane Khoo, Ri Liesner, Tadashi Matsushita, Michael Recht, Guy Young, Tiffany Chang, Christophe Dhalluin, Yunming Mu, Jin Xu, Jenny Devenport, Richard H. Ko, Paul Solari and Johannes Oldenburg. Surgical Experience in Two Multicenter, Open-Label Phase 3 Studies of Emicizumab in Persons with Hemophilia A with Inhibitors (HAVEN 1 and HAVEN 2). Blood. 2017;130:89.Google Scholar
  75. 75.
    Collins PW, Liesner R, Makris M, Talks K, Chowdary P, Chalmers E, et al. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee. Haemophilia. 2018;24(3):344–7.Google Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Hemophilia Comprehensive Care Centre, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health SciencesUniversity of the Witwatersrand and NHLSParktownSouth Africa

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