Download PDF
Semin Thromb Hemost 2025; 51(01): 010-017
DOI: 10.1055/s-0044-1796629
Review Article

The Evolution of Hemophilia Pharmacological Treatments and Therapeutic Targets at the Turn of the Third Millennium

Antonio Coppola
1   Regional Hub Center for Hemophilia and Congenital Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
Matteo Zani
2   Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua, Italy
,
Gabriele Quintavalle
1   Regional Hub Center for Hemophilia and Congenital Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
Daniele Focosi
3   North-Western Tuscany Blood Bank, Pisa University Hospital, Pisa, Italy
,
Massimo Franchini
2   Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua, Italy
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Historically, the aim of treatment for hemophilia, the congenital X-linked hemorrhagic disorder due to deficiencies of coagulation Factor (F) VIII (hemophilia A) or FIX (hemophilia B), has been the replacement through factor concentrates, whose regular administration (i.e., prophylaxis) has been shown to be highly effective in preventing bleeding complications and it is currently considered the gold standard of hemophilia treatment. However, continuous technological progress (i.e., plasma-derived factor concentrates, recombinant standard and extended half-life [EHL] products) has allowed clinicians operating at hemophilia treatment centers to individualize the management of persons with hemophilia, improving outcomes, adherence to therapy, and their quality of life. The achievement of normal hemostasis, the final goal that now seems possible with new-generation EHL products, non-replacement and gene therapies, will translate into normalization of life for persons with hemophilia, also addressing health equity (i.e., rendering them indistinguishable from their healthy peers). The evolution of hemophilia treatment and, in parallel, of therapeutic targets in the management of hemophilia patients over the last decades will be critically discussed in this narrative review.

Keywords

factor concentrates - health equity - hemophilia - management - non-replacement treatment - prophylaxis


Publication History

Article published online:
29 November 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371) 1801-1809
    CrossrefPubMedSearch in Google Scholar
  • 2 Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388 (10040): 187-197
    CrossrefPubMedSearch in Google Scholar
  • 3 Srivastava A, Santagostino E, Dougall A. et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020; 26 (Suppl. 06) 1-158
    CrossrefPubMedSearch in Google Scholar
  • 4 Franchini M, Mannucci PM. The more recent history of hemophilia treatment. Semin Thromb Hemost 2022; 48 (08) 904-910
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Coppola A, Santoro C, Franchini M. et al. Emerging issues on comprehensive hemophilia care: preventing, identifying, and monitoring age-related comorbidities. Semin Thromb Hemost 2013; 39 (07) 794-802
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Boban A, Baghaei F, Karin F. et al; EAHAD Accreditation and Audit of Haemophilia Centres Working Group. Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy. Haemophilia 2023; 29 (06) 1442-1449
    CrossrefPubMedSearch in Google Scholar
  • 7 Pool JG, Shannon AE. Production of high-potency concentrates of antihemophilic globulin in a closed-bag system. N Engl J Med 1965; 273 (27) 1443-1447
    CrossrefPubMedSearch in Google Scholar
  • 8 Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost 2014; 40 (05) 571-576
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Franchini M. The modern treatment of haemophilia: a narrative review. Blood Transfus 2013; 11 (02) 178-182
    PubMedSearch in Google Scholar
  • 10 Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99 (05) 840-850
    PubMedSearch in Google Scholar
  • 11 Franchini M, Lippi G. Recombinant activated factor VII: mechanisms of action and current indications. Semin Thromb Hemost 2010; 36 (05) 485-492
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Mannucci PM. Hemophilia and related bleeding disorders: a story of dismay and success. Hematology (Am Soc Hematol Educ Program) 2002; 1-9
    PubMedSearch in Google Scholar
  • 13 Kumar R, Dunn A, Carcao M. Changing paradigm of hemophilia management: extended half-life factor concentrates and gene therapy. Semin Thromb Hemost 2016; 42 (01) 18-29
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Mannucci PM. Hemophilia therapy: the future has begun. Haematologica 2020; 105 (03) 545-553
    CrossrefPubMedSearch in Google Scholar
  • 15 Hermans C, Reding MT, Astermark J, Klamroth R, Mancuso ME. Clinical studies of extended-half-life recombinant FVIII products for prophylaxis in adults and children: a critical review from the physician's perspective. Crit Rev Oncol Hematol 2022; 174: 103678
    CrossrefPubMedSearch in Google Scholar
  • 16 Franchini M, Zaffanello M, Focosi D. Current factor IX replacement options for hemophilia B and the challenges ahead. Expert Opin Pharmacother 2023; 24 (06) 729-736
    CrossrefPubMedSearch in Google Scholar
  • 17 Abdelgawad HAH, Foster R, Otto M. Nothing short of a revolution: Novel extended half-life factor VIII replacement products and non-replacement agents reshape the treatment landscape in hemophilia A. Blood Rev 2024; 64: 101164
    CrossrefPubMedSearch in Google Scholar
  • 18 Dargaud Y, Leuci A, Ruiz AR, Lacroix-Desmazes S. Efanesoctocog alfa: the renaissance of Factor VIII replacement therapy. Haematologica 2024; 109 (08) 2436-2444
    PubMedSearch in Google Scholar
  • 19 Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Blood Transfus 2018; 16 (05) 457-461
    PubMedSearch in Google Scholar
  • 20 Nogami K, Shima M. Current and future therapies for haemophilia-Beyond factor replacement therapies. Br J Haematol 2023; 200 (01) 23-34
    CrossrefPubMedSearch in Google Scholar
  • 21 Alcedo Andrade PE, Mannucci PM, Kessler CM. Emicizumab: the hemophilia A game-changer. Haematologica 2024; 109 (05) 1334-1347
    PubMedSearch in Google Scholar
  • 22 Nathwani AC. Gene therapy for hemophilia. Hematology (Am Soc Hematol Educ Program) 2022; 2022 (01) 569-578
    CrossrefPubMedSearch in Google Scholar
  • 23 Samelson-Jones BJ, Small JC, George LA. Roctavian gene therapy for hemophilia A. Blood Adv 2024; 8 (19) 5179-5189
    CrossrefPubMedSearch in Google Scholar
  • 24 Pipe SW, Leebeek FWG, Recht M. et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med 2023; 388 (08) 706-718
    CrossrefPubMedSearch in Google Scholar
  • 25 Nilsson IM, Hedner U, Ahlberg A. Haemophilia prophylaxis in Sweden. Acta Paediatr Scand 1976; 65 (02) 129-135
    CrossrefPubMedSearch in Google Scholar
  • 26 Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232 (01) 25-32
    CrossrefPubMedSearch in Google Scholar
  • 27 Ljung R. Prophylactic treatment of children with hemophilia in Sweden. Semin Thromb Hemost 2024; 50 (05) 714-719
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38 (01) 79-94
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (06) 535-544
    CrossrefPubMedSearch in Google Scholar
  • 30 Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM. ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9 (04) 700-710
    CrossrefPubMedSearch in Google Scholar
  • 31 Manco-Johnson MJ, Kempton CL, Reding MT. et al. Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in Adults With Severe Hemophilia A (SPINART). J Thromb Haemost 2013; 11: 1119-1127
    CrossrefPubMedSearch in Google Scholar
  • 32 Tagliaferri A, Feola G, Molinari AC. et al; POTTER Study Group. Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study. Thromb Haemost 2015; 114 (01) 35-45
    PubMedSearch in Google Scholar
  • 33 Mancuso ME, McLaughlin P, Forsyth AL, Valentino LA. Joint health and pain in the changing hemophilia treatment landscape. Expert Rev Hematol 2024; 17 (08) 431-444
    CrossrefPubMedSearch in Google Scholar
  • 34 Collins PW, Blanchette VS, Fischer K. et al; rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 2009; 7 (03) 413-420
    CrossrefPubMedSearch in Google Scholar
  • 35 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17 (01) 41-44
    CrossrefPubMedSearch in Google Scholar
  • 36 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
    CrossrefPubMedSearch in Google Scholar
  • 37 Iorio A, Iserman E, Blanchette V. et al. Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement. Haemophilia 2017; 23 (03) e170-e179
    CrossrefPubMedSearch in Google Scholar
  • 38 Coppola A, Franchini M, Pappagallo G. et al. Current choices and management of treatment in persons with severe hemophilia A without inhibitors: a mini-delphi consensus. J Clin Med 2022; 11 (03) 801
    CrossrefPubMedSearch in Google Scholar
  • 39 Peyvandi F, Berger K, Seitz R. 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 (08) 2038-2043
    CrossrefPubMedSearch in Google Scholar
  • 40 Konkle BA, Shapiro AD, Quon DV. et al. BIVV001 fusion protein as Factor VIII replacement therapy for hemophilia A. N Engl J Med 2020; 383 (11) 1018-1027
    CrossrefPubMedSearch in Google Scholar
  • 41 von Drygalski A, Chowdary P, Kulkarni R. et al; XTEND-1 Trial Group. Efanesoctocog alfa prophylaxis for patients with severe hemophilia A. N Engl J Med 2023; 388 (04) 310-318
    CrossrefPubMedSearch in Google Scholar
  • 42 Malec L, Peyvandi F, Chan AKC. et al; XTEND-Kids Trial Group. Efanesoctocog alfa prophylaxis for children with severe hemophilia A. N Engl J Med 2024; 391 (03) 235-246
    CrossrefPubMedSearch in Google Scholar
  • 43 Mannucci PM, Kessler CM, Germini F. et al. Bleeding events in people with congenital haemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: a systematic literature review. Haemophilia 2023; 29 (04) 954-962
    CrossrefPubMedSearch in Google Scholar
  • 44 Funding E, Lowe G, Poulsen LH. et al. Real-world effectiveness of rFIXFc prophylaxis in patients with haemophilia b switched from standard half-life therapy in three European countries. Adv Ther 2023; 40 (09) 3770-3783
    CrossrefPubMedSearch in Google Scholar
  • 45 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 (04) 46
    CrossrefPubMedSearch in Google Scholar
  • 46 Mazurkiewicz Ł, Czernikiewicz K, Rupa-Matysek J, Gil L. Emicizumab: a novel drug in hemophilia A prophylaxis - a narrative review. Expert Rev Hematol 2022; 15 (10) 933-942
    CrossrefPubMedSearch in Google Scholar
  • 47 Callaghan MU, Negrier C, Paz-Priel I. et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021; 137 (16) 2231-2242
    CrossrefPubMedSearch in Google Scholar
  • 48 Mannucci PM. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Haemost 2023; 21 (03) 403-412
    CrossrefPubMedSearch in Google Scholar
  • 49 Négrier C, Mahlangu J, Lehle M. et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. Lancet Haematol 2023; 10 (03) e168-e177
    CrossrefPubMedSearch in Google Scholar
  • 50 Meeks SL, Zimowski KL. Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?. Haemophilia 2024; 30 (Suppl. 03) 95-102
    CrossrefPubMedSearch in Google Scholar
  • 51 Miesbach W, von Drygalski A, Smith C. et al. The current challenges faced by people with hemophilia B. Eur J Haematol 2024; 112 (03) 339-349
    CrossrefPubMedSearch in Google Scholar
  • 52 Ay C, Frenzel L, Pinachyan K, Le Quellec S. Gene therapy for haemophilia A and B, from basic principles to clinical implementation: an illustrated review. Haemophilia 2024; 30 (01) 5-15
    CrossrefPubMedSearch in Google Scholar
  • 53 Batty P, Lillicrap D. Hemophilia gene therapy: approaching the first licensed product. HemaSphere 2021; 5 (03) e540
    CrossrefPubMedSearch in Google Scholar
  • 54 Cuker A, Kavakli K, Frenzel L. et al; BENEGENE-2 Trial Investigators. Gene therapy with Fidanacogene Elaparvovec in adults with hemophilia B. N Engl J Med 2024; 391 (12) 1108-1118
    CrossrefPubMedSearch in Google Scholar
  • 55 Hermans C, Pierce GF. Towards achieving a haemophilia-free mind. Haemophilia 2023; 29 (04) 951-953
    CrossrefPubMedSearch in Google Scholar
  • 56 Skinner MW, Nugent D, Wilton P. et al. Achieving the unimaginable: health equity in haemophilia. Haemophilia 2020; 26 (01) 17-24
    CrossrefPubMedSearch in Google Scholar
  • 57 Holme PA, Blatný J, Chowdary P. et al. Moving towards normalization of haemostasis and health equity: evolving treatment goals for haemophilia A. Haemophilia 2024; 30 (05) 1109-1114
    CrossrefPubMedSearch in Google Scholar