The treatment of hemophilia A has progressed amazingly in recent years. Emicizumab, a bispecific-humanized monoclonal antibody, is able to improve coagulation by bridging activated factor IX and factor X. Emicizumab is administered subcutaneously and much less often compared to factor VIII products. It has low immunogenicity, does not require dose adjustment, and can be administered regardless of the presence of factor VIII inhibitors. Thrombin generation assays but not factor VIII activity are indicated to guide and monitor the treatment. Emicizumab has enabled the conversion of patients with severe forms into patients with milder forms of hemophilia A. It has reduced the number of bleeding episodes compared to both on-demand and prophylactic substitution therapy and has an excellent safety profile. Gene therapy can elevate factor VIII plasma levels for many years after a single treatment course, could offer long-term protection from bleeding episodes, and minimize or eliminate the need for substitutive treatment with factor VIII concentrates. Gene therapy can provoke an immune response, manifested by an increase in common liver enzymes, that require immunotherapy. Long term monitoring is necessary to identify possible adverse effects. Future objectives are: the development of an ideal viral vector, the possibility of its re-administration, the use of gene therapy in hemophiliac children, and determining whether it can be successfully used to induce immune tolerance to factor VIII ceteri paribus. The future will determine the place of each type of treatment and group of patients for which it is indicated.

Faculty of Medicine Lucian Blaga University of Sibiu Romania

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Cadé M, Muñoz-Garcia J, Babuty A, Fouassier M, Heymann MF, Monahan PE, Heymann D. FVIII at the crossroad of coagulation, bone and immune biology: Emerging evidence of biological activities beyond hemostasis. Drug Discov Today 2022;27(1):102-16. PubMed DOI

Gourzoulidis G, Stefanou G, Economou M, Vakalopoulou S, Filippidis G, Soultatis G, Kontos D, Tzima S, Ntemousis F, Fassa A, Kourlaba G. Application of Multicriteria Decision Analysis to Determine the Value of Prophylaxis Relative to On-Demand Treatment in Hemophilia A and Emicizumab versus Replacement Therapy in the Greek Healthcare Setting. Clin Drug Investig 2022;42(1):75-85. PubMed DOI

Gualtierotti R, Solimeno LP, Peyvandi F. Hemophilic arthropathy: Current knowledge and future perspectives. J Thromb Haemost 2021;19(9):2112-21. PubMed DOI

Rodriguez-Merchan EC. Hemophilic arthropathy: a teaching approach devoted to hemophilia treaters in under-development countries. Expert Rev Hematol 2021;14(10):887-96. PubMed DOI

Regling K, Callaghan MU, Sidonio R Jr. Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options. Pediatric Health Med Ther 2022;13:27-35. PubMed DOI

Ellsworth P, Ma A. Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates? Hematology Am Soc Hematol Educ Program 2021;2021(1):219-25. PubMed DOI

Dargaud Y, Janbain M. Clinical Utility of Subcutaneous Factor VIII Replacement Therapies in Hemophilia A: A Review of the Evidence. J Blood Med 2021;12:1031-6. PubMed DOI

Franchini M, Marano G, Pati I, Veropalumbo E, Vaglio S, Pupella S, Masiello F, Cruciani M, Mengoli C, Liumbruno GM. Investigational drugs to treat hemophilia. Expert Opin Investig Drugs 2020;29(3):295-301. PubMed DOI

Haeckel A, Appler F, Ariza de Schellenberger A, Schellenberger E. XTEN as Biological Alternative to PEGylation Allows Complete Expression of a Protease-Activatable Killin-Based Cytostatic. PLoS One 2016;11(6):e0157193. PubMed DOI

Okaygoun D, Oliveira DD, Soman S, Williams R. Advances in the management of haemophilia: emerging treatments and their mechanisms. J Biomed Sci 202128(1):64. PubMed DOI

Peyvandi F, Miri S, Garagiola I. Immune Responses to Plasma-Derived Versus Recombinant FVIII Products. Front Immunol 2021;11:591878. PubMed DOI

Dargaud Y, Escuriola-Ettingshausen C. Recombinant porcine factor VIII: Lessons from the past and place in the management of hemophilia A with inhibitors in 2021. Res Pract Thromb Haemost 2021;5(8):e12631. PubMed DOI

Jiménez-Yuste V, Auerswald G, Benson G, Dolan G, Hermans C, Lambert T, Ljung R, Morfini M, Santagostino E, Zupančić Šalek S. Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors. Haemophilia 2021;27(3):340-50. PubMed DOI

Song J. Advances in laboratory assessment of thrombosis and hemostasis. Blood Res 2022;57(S1):93-100. PubMed DOI

Bowyer A, Gray E, Lowe A, Murphy P, Platton S, Riddell A, Chowdary P, Lester W, Jenkins PV. Laboratory coagulation tests and recombinant porcine factor VIII: A United Kingdom Haemophilia Centre Doctors' Organisation guideline. Haemophilia 2022;28(3):515-9. PubMed DOI

Nougier C, Jeanpierre E, Ternisien C, Proulle V, Hezard N, Pouplard C, Lasne D; With contributions from the Working Group on Biology of Haemorrhagic Disorders (BIMHO, Under the Aegis of GFHT). Emicizumab treatment: Impact on coagulation tests and biological monitoring of haemostasis according to clinical situations (BIMHO group proposals). Eur J Haematol 2020;105(6):675-81. PubMed DOI

Lowe A, Kitchen S, Jennings I, Kitchen DP, Woods TAL, Walker ID. Effects of Emicizumab on APTT, FVIII assays and FVIII Inhibitor assays using different reagents: Results of a UK NEQAS proficiency testing exercise. Haemophilia 2020;26(6):1087-91. PubMed DOI

Verhagen MJA, Valke LLFG, Schols SEM. Thrombin generation for monitoring hemostatic therapy in hemophilia A: A narrative review. J Thromb Haemost 2022;20(4):794-805. PubMed DOI

Barg AA, Avishai E, Budnik I, Levy-Mendelovich S, Barazani TB, Kenet G, Livnat T. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatr Blood Cancer 2019;66(11):e27886. PubMed DOI

Di Minno A, Spadarella G, Esposito S, Mathew P, Di Minno G, Mannucci PM. Perspective - The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021. Blood Rev 2021;50:100849. PubMed DOI

Wang CP, Young G, Thornburg CD. Safety evaluation of emicizumab prophylaxis in individuals with haemophilia A. Expert Opin Drug Saf 2021;20(4):387-96. PubMed DOI

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;120(10):1357-70. PubMed DOI

Li H, Zhang W, Petry C, Li L, Fernandez E, Kiialainen A, Feng S, Hsu W, Li L, Wei Y, Schmitt C. Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Emicizumab in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2021;10(1):30-8. PubMed DOI

Donners AAMT, Rademaker CMA, Bevers LAH, Huitema ADR, Schutgens REG, Egberts TCG, Fischer K. Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review. Clin Pharmacokinet 2021;60(11):1395-406. PubMed DOI

Schmitt C, Adamkewicz JI, Xu J, Petry C, Catalani O, Young G, Negrier C, Callaghan MU, Levy GG. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thromb Haemost 2021;121(3):351-60. PubMed DOI

Trinchero A, Sholzberg M, Matino D. The Evolution of Hemophilia Care: Clinical and Laboratory Advances, Opportunities, and Challenges. Hamostaseologie 2020;40(3):311-21. PubMed DOI

Yada K, Nogami K. Novel Insights and New Developments Regarding Coagulation Revealed by Studies of the Anti-Factor IXa (Activated Factor IX)/Factor X Bispecific Antibody, Emicizumab. Arterioscler Thromb Vasc Biol 2020;40(5):1148-54. PubMed DOI

Garcia J, Zia A. Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab. Pediatr Blood Cancer 2021;68(5):e28942. PubMed DOI

Villarreal-Martínez L, Sepúlveda-Orozco MDC, García-Viera DA, Robles-Sáenz DA, Bautista-Gómez AJ, Ortiz-Castillo M, González-Martínez G, Mares-Gil JE. Spinal epidural hematoma in a child with hemophilia A with high titer inhibitors and follow-up with prophylactic emicizumab: case report and literature review. Blood Coagul Fibrinolysis 2021;32(6):418-22. PubMed DOI

Jiménez-Yuste V, Rodríguez-Merchán EC, Matsushita T, Holme PA. Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery. Haemophilia 2021;27(4):519-30. PubMed DOI

Hermans C, Apte S, Santagostino E. Invasive procedures in patients with haemophilia: Review of low-dose protocols and experience with extended half-life FVIII and FIX concentrates and non-replacement therapies. Haemophilia 2021;27 Suppl 3:46-52. PubMed DOI

Escuriola-Ettingshausen C, Auerswald G, Königs C, Kurnik K, Scholz U, Klamroth R, Oldenburg J. Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: Recommendations from a German expert panel. Haemophilia 2021;27(3):e305-13. PubMed DOI

Holstein K, Albisetti M, Bidlingmaier C, Halimeh S, Heine S, Klamroth R, Königs C, Kurnik K, Male C, Oldenburg J, Streif W, Wermes C, Escuriola-Ettingshausen C; 'Ständige Kommission Hämophilie' (Haemophilia board) of the German, Swiss Austrian Society for Thrombosis Haemostasis Research (GTH). Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A. Hamostaseologie 2020;40(5):561-71. PubMed DOI

Spadarella G, Di Minno A, Milan G, Franco N, Polimeno M, Castaldo F, Di Minno G. Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine. Blood Rev 2020;39:100618. PubMed DOI

Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus 2019;17(6):479-86. PubMed

Lillicrap D, Fijnvandraat K, Young G, Mancuso ME. Patients with hemophilia A and inhibitors: prevention and evolving treatment paradigms. Expert Rev Hematol 2020;13(4):313-21. PubMed DOI

Shima M, Sidonio RF Jr. Substitution therapy. Haemophilia 2021;27 Suppl 3:53-9. PubMed DOI

von Mackensen S, Catalani O, Asikanius E, Paz-Priel I, Lehle M, Trask P. Determining meaningful health-related quality-of-life improvement in persons with haemophilia A using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL). Haemophilia 2020;26(6):1019-30. PubMed DOI

Pharmacoeconomic Report: Emicizumab (Hemlibra): Hoffman-La Roche Ltd: Indication: Bleeding prevention, Hemophilia A [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021. [cited 2022 Aug 16]. Available from: https://pubmed.ncbi.nlm.nih.gov/34009766/

Peyvandi F, Garagiola I, Mannucci PM. Post-authorization pharmacovigilance for hemophilia in Europe and the USA: Independence and transparency are keys. Blood Rev 2021;49:100828. PubMed DOI

Bowyer AE, Lowe AE, Tiefenbacher S. Laboratory issues in gene therapy and emicizumab. Haemophilia 2021;27 Suppl 3:142-7. PubMed DOI

Thomas VM, Abou-Ismail MY, Lim MY. Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature. Haemophilia 2022;28(1):4-17. PubMed DOI

Streif W, Knöfler R. Perinatal Management of Haemophilia. Hamostaseologie 2020;40(2):226-32. PubMed DOI

Shima M, Nagao A, Taki M, Matsushita T, Oshida K, Amano K, Nagami S, Okada N, Maisawa S, Nogami K. Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A. Haemophilia 2021;27(1):81-9. PubMed DOI

Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, Mahlangu J, Young G, Kruse-Jarres R, Mancuso ME, Niggli M, Howard M, Bienz NS, Shima M, Jiménez-Yuste V, Schmitt C, Asikanius E, Levy GG, Pipe SW, Oldenburg J. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137(16):2231-42. PubMed DOI

Shima M. Bispecific Antibodies and Advances in Non-Gene Therapy Options in Hemophilia. Res Pract Thromb Haemost 2020;4(4):446-54. PubMed DOI

Rodriguez-Merchan EC, Valentino LA. Emicizumab: Review of the literature and critical appraisal. Haemophilia 2019;25(1):11-20. PubMed DOI

Reyes A, Révil C, Niggli M, Chebon S, Schlagmüller S, Flacke JP, Zortel M, Paz-Priel I, Asikanius E, Hampton R, Mahajan A, Schmidt E, Edwards SC. Efficacy of emicizumab prophylaxis versus factor VIII prophylaxis for treatment of hemophilia A without inhibitors: network meta-analysis and sub-group analyses of the intra-patient comparison of the HAVEN 3 trial. Curr Med Res Opin 2019;35(12):2079-87. PubMed DOI

Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jiménez-Yuste V. 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-e305. PubMed DOI

Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134(24):2127-38. PubMed DOI

Swan D, Paran S, Nolan B. Port removal in patients receiving emicizumab prophylaxis: A single centre experience and review of the literature. Haemophilia 2022;28(1):42-5. PubMed DOI

Matsushita T, Suzuki N, Nagao A, Nagae C, Yamaguchi-Suita H, Kyogoku Y, Ioka A, Nogami K. AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors. BMJ Open 2022;12(3):e057018. PubMed DOI

Ogiwara K, Taki M, Suzuki T, Takedani H, Matsushita T, Amano K, Matsumoto M, Nishio K, Shima M, Kasahara M, Nogami K. Assessment of global coagulation function under treatment with emicizumab concomitantly with bypassing agents in haemophilia A with inhibitor (UNEBI Study): multicentre open-label non-randomised clinical trial. BMJ Open 2022;12(2):e056922. PubMed DOI

Bao LW, Zhou YY, Zeng FY. [Advances in gene therapy for β-thalassemia and hemophilia based on the CRISPR/Cas9 technology]. Yi Chuan 2020;42(10):949-64.

Spadarella G, Di Minno A, Brunetti-Pierri N, Mahlangu J, Di Minno G. The evolving landscape of gene therapy for congenital haemophilia: An unprecedented, problematic but promising opportunity for worldwide clinical studies. Blood Rev 2021;46:100737. PubMed DOI

Valentino LA, Khair K. Prophylaxis for hemophilia A without inhibitors: treatment options and considerations. Expert Rev Hematol 2020;13(7):731-43. PubMed DOI

Reiss UM, Mahlangu J, Ohmori T, Ozelo MC, Srivastava A, Zhang L. Haemophilia gene therapy-Update on new country initiatives. Haemophilia 2022;28 Suppl 4:61-67. PubMed DOI

Pipe SW, Reddy KR, Chowdary P. Gene therapy: Practical aspects of implementation. Haemophilia 2022;28 Suppl 4:44-52. PubMed DOI

Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, Goodspeed K, Gray SJ, Kay CN, Boye SL, Boye SE, George LA, Salabarria S, Corti M, Byrne BJ, Tremblay JP. Current Clinical Applications of In Vivo Gene Therapy with AAVs. Mol Ther 2021;29(2):464-88. PubMed DOI

Cantore A, Naldini L. WFH State-of-the-art paper 2020: In vivo lentiviral vector gene therapy for haemophilia. Haemophilia 2021;27 Suppl 3(Suppl 3):122-5.

Ohmori T. Advances in gene therapy for hemophilia: basis, current status, and future perspectives. Int J Hematol 2020;111(1):31-41. PubMed DOI

Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia 2019;25(5):738-46. PubMed DOI

Rodríguez-Merchán EC, De Pablo-Moreno JA, Liras A. Gene Therapy in Hemophilia: Recent Advances. Int J Mol Sci 2021;22(14):7647. PubMed DOI

Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program 2019;2019(1):1-8. PubMed DOI

Lisowski L, Staber JM, Wright JF, Valentino LA. The intersection of vector biology, gene therapy, and hemophilia. Res Pract Thromb Haemost 2021;5(6):e12586. PubMed DOI

Samelson-Jones BJ, Arruda VR. Translational Potential of Immune Tolerance Induction by AAV Liver-Directed Factor VIII Gene Therapy for Hemophilia A. Front Immunol 2020;11:618. PubMed DOI

Monahan PE, Négrier C, Tarantino M, Valentino LA, Mingozzi F. Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia. J Clin Med 2021;10(11):2471. PubMed DOI

Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood 2019;133(5):407-14. PubMed DOI

Miesbach W, O'Mahony B, Key NS, Makris M. How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia 2019;25(4):545-57. PubMed DOI

Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B; GENEr8-1 Trial Group. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med 2022;386(11):1013-25. PubMed DOI

George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. N Engl J Med 2021;385(21):1961-73. PubMed DOI

Leebeek FWG, Miesbach W. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood 2021;138(11):923-31. PubMed DOI

Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med 2020;382(1):29-40. PubMed DOI

Yamaguti-Hayakawa GG, Ozelo MC. Gene Therapy: Paving New Roads in the Treatment of Hemophilia. Semin Thromb Hemost 2019;45(7):743-50. PubMed DOI

Gollomp KL, Doshi BS, Arruda VR. Gene therapy for hemophilia: Progress to date and challenges moving forward. Transfus Apher Sci 2019;58(5):602-12. PubMed DOI