Skip to main content

Emicizumab: A Review in Haemophilia A

Drugs volume 79, pages 1697–1707 (2019)Cite this article

Abstract

Emicizumab (Hemlibra®), a recombinant, humanized, bispecific monoclonal antibody, restores the function of missing activated factor VIII (FVIII) by bridging FIXa and FX to facilitate effective haemostasis in patients with haemophilia A. Subcutaneous emicizumab is approved in several countries, including in the USA and Japan, for the routine prophylaxis of bleeding episodes in patients with haemophilia A with or without FVIII inhibitors. It is also approved in the EU for the routine prophylaxis of bleeding episodes in patients with haemophilia A with inhibitors or severe haemophilia A without inhibitors. In phase III clinical trials, emicizumab prophylaxis significantly reduced annualized bleeding rates compared with no prophylaxis in adolescents and adults with haemophilia A with or without inhibitors, and prevented or substantially reduced bleeding in children with haemophilia A with or without inhibitors. Emicizumab was also associated with beneficial effects on health-related quality of life and health status, and was generally well tolerated. In view of its convenient route of administration and versatile dosage regimens (maintenance dose of once every 1, 2 or 4 weeks), emicizumab provides an effective and generally well-tolerated alternative to conventional FVIII replacement products for the prophylaxis of bleeding episodes in patients with haemophilia A, regardless of the presence or absence of inhibitors.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–47.

    Article  CAS  PubMed  Google Scholar 

  2. Pelland-Marcotte MC, Carcao MD. Hemophilia in a changing treatment landscape. Hematol Oncol Clin North Am. 2019;33(3):409–23.

    Article  PubMed  Google Scholar 

  3. Ljung R, Auerswald G, Benson G, et al. Inhibitors in haemophilia A and B: management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol. 2019;102(2):111–22.

    Article  PubMed  Google Scholar 

  4. Genentech Inc. Hemlibra® (emicizumab-kxwh) injection, for subcutaneous use: US prescribing information. 2018. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2483adba-fab6-4d1b-96c5-c195577ed071. Accessed 9 Sept 2019.

  5. Chugai Pharmaceutical Co Ltd. Chugai’s Hemlibra® subcutaneous injection receives approval for hemophilia A without inhibitors and extension of dosing interval [media release]. 21 Dec 2018. http://www.chugai-pharm.co.jp/english/news/detail/20181221153002_580.html.

  6. Roche. Hemlibra solution for injection: summary of product characteristics. 2019. http://www.ema.europa.eu/en/documents/product-information/hemlibra-epar-product-information_en.pdf. Accessed 9 Sep 2019.

  7. Kitazawa T, Esaki K, Tachibana T, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kitazawa T, Igawa T, Sampei Z, 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.

    Article  CAS  PubMed  Google Scholar 

  9. Muto A, Yoshihashi K, Takeda M, 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.

    Article  CAS  PubMed  Google Scholar 

  10. Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124(20):3165–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sampei Z, Igawa T, Soeda 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ogiwara K, Horiuchi H, Nogami K, et al. Assessment of emicizumab-driven clot stability in hemophilia A model [abstract]. Blood. 2018;132(Suppl 1):2478.

    Article  Google Scholar 

  13. Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med. 2016;374(21):2044–53.

    Article  CAS  PubMed  Google Scholar 

  14. Shima M, Hanabusa H, Taki M, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv. 2017;1(22):1891–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Uchida N, Sambe T, Yoneyama K, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Adamkewicz J, Schmitt C, Calatzis A, et al. Pharmacodynamic data and coagulation biomarkers in persons with hemophilia A (PwHA) with inhibitors: results from the HAVEN 1 emicizumab (ACE910) phase 3 study [abstract no. OC 47.1]. Res Pract Thromb Haemost. 2017;1(Suppl 1):162.

    Google Scholar 

  17. Kiialainen A, Schmitt C, Oldenburg J, et al. Pharmacokinetics and biomarkers in persons with haemophilia a (PwHA) without FVIII inhibitors receiving emicizumab once weekly in the phase 3 HAVEN 3 study [abstract no. P022]. Haemophilia. 2019;25(Suppl 1):46–7.

    Google Scholar 

  18. Kiialainen A, Schmitt C, Adamkewicz JI, et al. Pharmacokinetics and biomarkers in persons with haemophilia a (PwHA) receiving emicizumab every 2 or 4 weeks [abstract no. P021]. Haemophilia. 2019;25(Suppl 1):45–6.

    Google Scholar 

  19. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809–18.

    Article  CAS  PubMed  Google Scholar 

  20. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379(9):811–22.

    Article  CAS  PubMed  Google Scholar 

  21. Pipe S, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6(6):e295–305.

    Article  PubMed  Google Scholar 

  22. Jimenez-Yuste V, Klamroth R, Castaman G, et al. A single-arm, multicentre, open-label, phase III clinical trial to evaluate the safety and tolerability of prophylactic emicizumab in persons with haemophilia A (PwHA) with FVIII inhibitors (STASEY): interim analysis results [abstract no. OC 60.3]. Res Pract Thromb Haemost. 2019;3(Suppl 1):116–7.

    Google Scholar 

  23. Young G, Liesner R, Sidonio RF Jr, et al. Emicizumab prophylaxis provides flexible and effective bleed control in children with hemophilia A with inhibitors: results from the HAVEN 2 study [abstract]. Blood. 2018;132(Suppl 1):632.

    Article  Google Scholar 

  24. Shima M, Nogami K, Nagami S, et al. Every 2 weeks or every 4 weeks subcutaneous injection of emicizumab in pediatric patients with severe hemophilia a without inhibitors: a multi-center, open-label study in Japan (HOHOEMI study) [abstract]. Blood. 2018;132(Suppl 1):1186.

    Article  Google Scholar 

  25. Callaghan MU, Kuebler PJ, Gao L, et al. Characterization of the impact of prior ITI on patient outcomes in HAVEN1 [abstract]. Am J Hematol. 2018;93(9):e10–1.

    Google Scholar 

  26. Mancuso ME, Oldenburg J, Callaghan M, et al. Emicizumab prophylaxis in adolescent/adult patients with haemophilia A previously receiving episodic or prophylactic bypassing agent treatment: updated analyses from the HAVEN 1 study [abstract no. BSH18-PO-146]. Br J Haematol. 2018;181(Suppl 1):127.

    Google Scholar 

  27. Oldenburg J, Mahlangu JN, Bujan W, et al. The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 study. Haemophilia. 2019;25(1):33–44.

    Article  CAS  PubMed  Google Scholar 

  28. Skinner M, Negrier C, Paz-Priel I, et al. Emicizumab prophylaxis improves long-term physical health scores in persons with haemophilia A (PwHA) with and without inhibitors: update from the HAVEN 3 and HAVEN 4 studies [abstract no. PB0698]. Res Pract Thromb Haemost. 2019;3(Suppl 3):328–9.

    Google Scholar 

  29. Jimenez-Yuste V, Shima M, Paz-Priel I, et al. Preference for emicizumab over prior factor treatments: results from the HAVEN 3 and HAVEN 4 studies [abstract]. Blood. 2018;132(Suppl 1):1187.

    Article  Google Scholar 

  30. Mancuso ME, Mahlangu J, Sidonio RF, et al. Emicizumab prophylaxis in paediatric persons with haemophilia A (PWHA) with inhibitors: impact on health-related outcomes and caregiver burden in the HAVEN 2 study [abstract no. OR10]. Haemophilia. 2018;24(Suppl 1):28–9.

    Google Scholar 

  31. Santagostino E, Oldenburg J, Chang T, et al. Surgical experience from four phase III studies (HAVEN 1-4) of emicizumab in persons with haemophilia A (PwHA) with or without FVIII inhibitors [abstract no. OC 60.1]. Res Pract Thromb Haemost. 2019;3(Suppl 1):115.

    Google Scholar 

  32. Callaghan M, Negrier C, Paz-Priel I, et al. Emicizumab treatment is efficacious and well tolerated long term in persons with haemophilia A (PwHA) with or without FVIII inhibitors: pooled data from four HAVEN studies [abstract no. OC 60.2]. Res Pract Thromb Haemost. 2019;3(Suppl 1):116.

    Google Scholar 

  33. Levy GG, Asikanius E, Kuebler P, et al. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: experience from the HAVEN clinical program. J Thromb Haemost. 2019. https://doi.org/10.1111/jth.14491.

    Article  PubMed  Google Scholar 

  34. Paz-Priel I, Chang T, Asikanius E, et al. Immunogenicity of emicizumab in people with hemophilia A (PwHA): results from the HAVEN 1-4 studies [abstract]. Blood. 2018;132(Suppl 1):633.

    Article  Google Scholar 

  35. Rocino A, Franchini M, Coppola A. Treatment and prevention of bleeds in haemophilia patients with inhibitors to factor VIII/IX. J Clin Med. 2017;6(4):46.

    Article  CAS  PubMed Central  Google Scholar 

  36. National Hemophilia Foundation. Recommendation on the use and management of emicizumab-kxwh (Hemlibra®) for hemophilia A with and without inhibitors. 2018. http://www.hemophilia.org. Accessed 9 Sept 2019.

  37. Collins PW, Liesner R, Makris M, 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.

    Article  CAS  PubMed  Google Scholar 

  38. Scott LJ, Kim ES. Emicizumab-kxwh: first global approval. Drugs. 2018;78(2):269–74.

    Article  CAS  PubMed  Google Scholar 

  39. Cassis FR, Querol F, Forsyth A, et al. Psychosocial aspects of haemophilia: a systematic review of methodologies and findings. Haemophilia. 2012;18(3):e101–14.

    Article  CAS  PubMed  Google Scholar 

  40. Coppola A, Cerbone AM, Mancuso G, et al. Confronting the psychological burden of haemophilia. Haemophilia. 2011;17(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  41. Nogami K, Soeda T, Matsumoto T, et al. Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost. 2018;16(7):1383–90.

    Article  CAS  PubMed  Google Scholar 

  42. Nogami K, Matsumoto T, Tabuchi Y, et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost. 2018;16(6):1078–88.

    Article  CAS  PubMed  Google Scholar 

  43. Adamkewicz J, Kim B, Steinbuesch D, et al. Measurement of FVIII inhibitor titer using a chromogenic Bethesda assay (CBA) in the presence of emicizumab (ACE910), a humanized bispecific antibody mimicking FVIIIa cofactor function [abstract]. Haemophilia. 2017;23(Suppl 3):3–4.

    Google Scholar 

  44. Adamkewicz J, 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;119:1084–93.

    Article  PubMed  Google Scholar 

  45. US National Institutes of Health (2019) http://www.clinicaltrials.gov. Accessed 9 Sept 2019

  46. Cafuir L, Kruse-Jarres R, Mancuso ME, et al. Emicizumab for hemophilia A without inhibitors. Expert Rev Hematol. 2019;12(7):515–24.

    Article  CAS  PubMed  Google Scholar 

  47. Escuriola-Ettingshausen C, Sidonio RF Jr, Oldenburg J, et al. Modern treatment of inhibitor-positive patients with haemophilia A (MOTIVATE)—an international observational study [abstract no. PB1406]. Res Pract Thromb Haemost. 2019;3(Suppl 1):423.

    Google Scholar 

  48. Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on patient management. Am J Manag Care. 2016;22(Suppl 5):s126–33.

    PubMed  Google Scholar 

  49. Institute for Clinical and Economic Review. Emicizumab for hemophilia A with inhibitors: effectiveness and value. 2018. http://icer-review.org/wp-content/uploads/2017/08/ICER_Hemophilia_Final_Evidence_Report_041618.pdf. Accessed 9 Sept 2019.

  50. Mahajerin A, Zhou ZY, Raimundo K, et al. Model of short and long-term outcomes of emicizumab prophylaxis treatment for persons with hemophilia A [abstract]. Blood. 2018;132(Suppl 1):3511.

    Article  Google Scholar 

  51. Sidonio RF, Patel A, Corman S, et al. Model of the impact of delayed inhibitor development on cumulative breakthrough bleeds and costs in persons with hemophilia a receiving emicizumab prophylaxis [abstract]. Blood. 2018;132(Suppl 1):4710.

    Article  Google Scholar 

Download references

Acknowledgements

During the review process, the manufacturer of emicizumab was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    Hannah A. Blair

Authors
  1. Hannah A. Blair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hannah A. Blair.

Ethics declarations

Conflict of interest

Hannah Blair is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

Funding

The preparation of this review was not supported by any external funding.

Additional information

Enhanced material for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.9784490.

The manuscript was reviewed by:J. N. Mahlangu, Haemophilia Comprehensive Care Centre, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, South Africa; M. E. Mancuso, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy; J. Oldenburg, University Clinic Bonn, Institute for Experimental Haematology and Transfusion Medicine, Bonn, Germany.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Blair, H.A. Emicizumab: A Review in Haemophilia A. Drugs 79, 1697–1707 (2019). https://doi.org/10.1007/s40265-019-01200-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01200-2