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Semin Thromb Hemost 2022; 48(08): 904-910
DOI: 10.1055/s-0042-1756188
Review Article

The More Recent History of Hemophilia Treatment

Massimo Franchini
1   Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy
,
Pier Mannuccio Mannucci
2   Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico and University of Milan, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
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Abstract

The availability first in the 1970s of plasma-derived and then in the 1990s of recombinant clotting factor concentrates represented a milestone in hemophilia care, enabling not only treatment of episodic bleeding events but also implementation of prophylactic regimens. The treatment of hemophilia has recently reached new landmarks. The traditional clotting factor replacement therapy for hemophilia has been substituted over the last 10 years by novel treatments such as bioengineered factor VIII and IX molecules with extended half-life and non-factor treatments including the bispecific antibody emicizumab. This narrative review is dedicated to these newer therapies, which are contributing significantly to improving the long-term management of prophylaxis in hemophilia patients. Another section is focused on the current state of gene therapy, which is a promising definitive cure for severe hemophilia A and B.

Keywords

hemophilia - history - therapy


Publication History

Article published online:
15 September 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Mannucci PM, Tuddenham EGD. The hemophilias—from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
    CrossrefPubMedSearch in Google Scholar
  • 2 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371): 1801-1809
    Search in Google Scholar
  • 3 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
  • 4 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
    CrossrefPubMedSearch in Google Scholar
  • 5 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
    CrossrefPubMedSearch in Google Scholar
  • 6 Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost 2014; 40 (05) 571-576
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Schramm W. The history of haemophilia—a short review. Thromb Res 2014; 134 (Suppl. 01) S4-S9
    CrossrefPubMedSearch in Google Scholar
  • 8 Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK. Genotype analysis identifies the cause of the “royal disease”. Science 2009; 326 (5954): 817
    CrossrefPubMedSearch in Google Scholar
  • 9 Mannucci PM. Back to the future: a recent history of haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 10-18
    CrossrefPubMedSearch in Google Scholar
  • 10 Mannucci PM. Hemophilia: treatment options in the twenty-first century. J Thromb Haemost 2003; 1 (07) 1349-1355
    CrossrefPubMedSearch in Google Scholar
  • 11 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
  • 12 Nilsson IM. Experience with prophylaxis in Sweden. Semin Hematol 1993; 30 (03, Suppl 2): 16-19
    PubMedSearch in Google Scholar
  • 13 Moreno MM, Cuesta-Barriuso R. A history of prophylaxis in haemophilia. Blood Coagul Fibrinolysis 2019; 30 (02) 55-57
    CrossrefPubMedSearch in Google Scholar
  • 14 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years. Haemophilia 2000; 6 (Suppl. 01) 60-67
    CrossrefPubMedSearch in Google Scholar
  • 15 Evatt BL. The tragic history of AIDS in the hemophilia population, 1982-1984. J Thromb Haemost 2006; 4 (11) 2295-2301
    CrossrefPubMedSearch in Google Scholar
  • 16 Franchini M. The modern treatment of haemophilia: a narrative review. Blood Transfus 2013; 11 (02) 178-182
    PubMedSearch in Google Scholar
  • 17 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
  • 18 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
  • 19 Franchini M, Mannucci PM. The safety of pharmacologic options for the treatment of persons with hemophilia. Expert Opin Drug Saf 2016; 15 (10) 1391-1400
    CrossrefPubMedSearch in Google Scholar
  • 20 Mannucci PM. Hemophilia therapy: the future has begun. Haematologica 2020; 105 (03) 545-553
    CrossrefPubMedSearch in Google Scholar
  • 21 Schulte S. Innovative coagulation factors: albumin fusion technology and recombinant single-chain factor VIII. Thromb Res 2013; 131 (Suppl. 02) S2-S6
    CrossrefPubMedSearch in Google Scholar
  • 22 Ivens IA, Baumann A, McDonald TA, Humphries TJ, Michaels LA, Mathew P. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia 2013; 19 (01) 11-20
    CrossrefPubMedSearch in Google Scholar
  • 23 Swierczewska M, Lee KC, Lee S. What is the future of PEGylated therapies?. Expert Opin Emerg Drugs 2015; 20 (04) 531-536
    CrossrefPubMedSearch in Google Scholar
  • 24 Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus 2019; 17 (06) 479-486
    PubMedSearch in Google Scholar
  • 25 Hermans C, Mancuso ME, Nolan B, Pasi KJ. Recombinant factor VIII Fc for the treatment of haemophilia A. Eur J Haematol 2021; 106 (06) 745-761
    Search in Google Scholar
  • 26 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
  • 27 Shapiro AD, Ragni MV, Valentino LA. et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 2012; 119 (03) 666-672
    CrossrefPubMedSearch in Google Scholar
  • 28 Powell JS, Pasi KJ, Ragni MV. et al; B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369 (24) 2313-2323
    CrossrefPubMedSearch in Google Scholar
  • 29 Nolan B, Klukowska A, Shapiro A. et al. Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B. Blood Adv 2021; 5 (13) 2732-2739
    CrossrefPubMedSearch in Google Scholar
  • 30 Collins PW, Young G, Knobe K. et al; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014; 124 (26) 3880-3886
    CrossrefPubMedSearch in Google Scholar
  • 31 Chan AK, Alamelu J, Barnes C. et al. Nonacog beta pegol (N9-GP) in hemophilia B: first report on safety and efficacy in previously untreated and minimally treated patients. Res Pract Thromb Haemost 2020; 4 (07) 1101-1113
    CrossrefPubMedSearch in Google Scholar
  • 32 Santagostino E, Martinowitz U, Lissitchkov T. et al; PROLONG-9FP Investigators Study Group. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016; 127 (14) 1761-1769
    CrossrefPubMedSearch in Google Scholar
  • 33 Mahlangu J, Powell JS, Ragni MV. et al; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123 (03) 317-325
    CrossrefPubMedSearch in Google Scholar
  • 34 Konkle BA, Stasyshyn O, Chowdary P. et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015; 126 (09) 1078-1085
    CrossrefPubMedSearch in Google Scholar
  • 35 Giangrande P, Andreeva T, Chowdary P. et al; Pathfinder™2 Investigators. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost 2017; 117 (02) 252-261
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Mullins ES, Stasyshyn O, Alvarez-Román MT. et al. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia 2017; 23 (02) 238-246
    CrossrefPubMedSearch in Google Scholar
  • 37 Reding MT, Ng HJ, Poulsen LH. et al. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost 2017; 15 (03) 411-419
    CrossrefPubMedSearch in Google Scholar
  • 38 Nolan B, Mahlangu J, Pabinger I. et al. Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: final results from the ASPIRE extension study. Haemophilia 2020; 26 (03) 494-502
    CrossrefPubMedSearch in Google Scholar
  • 39 Chowdary P, Carcao M, Holme PA. et al. Fixed doses of N8-GP prophylaxis maintain moderate-to-mild factor VIII levels in the majority of patients with severe hemophilia A. Res Pract Thromb Haemost 2019; 3 (03) 542-554
    CrossrefPubMedSearch in Google Scholar
  • 40 Meunier S, Alamelu J, Ehrenforth S. et al. Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A. Thromb Haemost 2017; 117 (09) 1705-1713
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Santagostino E, Lalezari S, Reding MT. et al. Safety and efficacy of BAY 94-9027, an extended-half-life factor VIII, during surgery in patients with severe hemophilia A: results of the PROTECT VIII clinical trial. Thromb Res 2019; 183: 13-19
    CrossrefPubMedSearch in Google Scholar
  • 42 Königs C, Ozelo MC, Dunn A. et al. First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results. Blood 2022; 139 (26) 3699-3707
    CrossrefPubMedSearch in Google Scholar
  • 43 Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016; 128 (16) 2007-2016
    CrossrefPubMedSearch in Google Scholar
  • 44 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
  • 45 Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J Clin Med 2017; 6 (04) 39
    CrossrefPubMedSearch in Google Scholar
  • 46 Gruppo R, López-Fernández MF, Wynn TT, Engl W, Sharkhawy M, Tangada S. Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: final results of a multicentre, single-arm phase III trial. Haemophilia 2019; 25 (05) 773-781
    CrossrefPubMedSearch in Google Scholar
  • 47 Santagostino E, Negrier C, Klamroth R. et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood 2012; 120 (12) 2405-2411
    CrossrefPubMedSearch in Google Scholar
  • 48 Ozelo MC, Yamaguti-Hayakawa GG. Impact of novel hemophilia therapies around the world. Res Pract Thromb Haemost 2022; 6 (03) e12695
    CrossrefPubMedSearch in Google Scholar
  • 49 Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br J Clin Pharmacol 2011; 72 (04) 553-562
    CrossrefPubMedSearch in Google Scholar
  • 50 Astermark J, Santagostino E, Keith Hoots W. Clinical issues in inhibitors. Haemophilia 2010; 16 (Suppl. 05) 54-60
    CrossrefPubMedSearch in Google Scholar
  • 51 Male C, Andersson NG, Rafowicz A. et al. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica 2021; 106 (01) 123-129
    CrossrefPubMedSearch in Google Scholar
  • 52 Meeks SL, Batsuli G. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 657-662
    CrossrefPubMedSearch in Google Scholar
  • 53 Peyvandi F, Mannucci PM, Garagiola I. et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374 (21) 2054-2064
    CrossrefPubMedSearch in Google Scholar
  • 54 Astermark J, Donfield SM, DiMichele DM. et al; FENOC Study Group. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109 (02) 546-551
    CrossrefPubMedSearch in Google Scholar
  • 55 Knight C, Danø AM, Kennedy-Martin T. Systematic review of efficacy of rFVIIa and aPCC treatment for hemophilia patients with inhibitors. Adv Ther 2009; 26 (01) 68-88
    CrossrefPubMedSearch in Google Scholar
  • 56 Treur MJ, McCracken F, Heeg B. et al. Efficacy of recombinant activated factor VII vs. activated prothrombin complex concentrate for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta-regression. Haemophilia 2009; 15 (02) 420-436
    CrossrefPubMedSearch in Google Scholar
  • 57 Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39 (07) 772-778
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42 (05) 526-532
    Thieme ConnectPubMedSearch in Google Scholar
  • 59 Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Blood Transfus 2018; 16 (05) 457-461
    PubMedSearch in Google Scholar
  • 60 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) 1570-1574
    CrossrefPubMedSearch in Google Scholar
  • 61 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) 1633-1641
    CrossrefPubMedSearch in Google Scholar
  • 62 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) 2044-2053
    CrossrefPubMedSearch in Google Scholar
  • 63 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
    CrossrefPubMedSearch in Google Scholar
  • 64 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
  • 65 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 (09) 811-822
    CrossrefPubMedSearch in Google Scholar
  • 66 Pipe SW, 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 (06) e295-e305
    CrossrefPubMedSearch in Google Scholar
  • 67 Samuelson Bannow B, Recht M, Négrier C. et al. Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev 2019; 35: 43-50
    CrossrefPubMedSearch in Google Scholar
  • 68 Coppola A, Castaman G, Santoro RC. et al. ad hoc Working Group. Management of patients with severe haemophilia A without inhibitors on prophylaxis with emicizumab: AICE recommendations with focus on emergency in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET. Haemophilia 2020; 26: 937-945
    CrossrefPubMedSearch in Google Scholar
  • 69 Castaman G, Santoro C, Coppola A. et al; ad hoc Working Group. 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; 18 (02) 143-151
    PubMedSearch in Google Scholar
  • 70 Le Quellec S, Negrier C. Emicizumab should be prescribed independent of immune tolerance induction. Blood Adv 2018; 2 (20) 2783-2786
    CrossrefPubMedSearch in Google Scholar
  • 71 Santagostino E, Young G, Escuriola Ettingshausen C, Jimenez-Yuste V, Carcao M. Inhibitors: a need for eradication?. Acta Haematol 2019; 141 (03) 151-155
    CrossrefPubMedSearch in Google Scholar
  • 72 Jair Lara-Navarro I, Rebeca Jaloma-Cruz A. Current therapies in hemophilia: from plasma-derived factor modalities to CRISPR/Cas alternatives. Tohoku J Exp Med 2022; 256 (03) 197-207
    CrossrefPubMedSearch in Google Scholar
  • 73 Wang L, Takabe K, Bidlingmaier SM, Ill CR, Verma IM. Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. Proc Natl Acad Sci U S A 1999; 96 (07) 3906-3910
    CrossrefPubMedSearch in Google Scholar
  • 74 Chao H, Mao L, Bruce AT, Walsh CE. Sustained expression of human factor VIII in mice using a parvovirus-based vector. Blood 2000; 95 (05) 1594-1599
    CrossrefPubMedSearch in Google Scholar
  • 75 Ward NJ, Buckley SM, Waddington SN. et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 2011; 117 (03) 798-807
    CrossrefPubMedSearch in Google Scholar
  • 76 Samelson-Jones BJ, Finn JD, Raffini LJ. et al. Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants. Blood Adv 2021; 5 (05) 1324-1332
    CrossrefPubMedSearch in Google Scholar
  • 77 Nathwani AC, Reiss U, Tuddenham E. et al. Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing “empty viral particles” on safety and efficacy of gene transfer. Blood 2018; 132 (Suppl. 01) 491
    CrossrefPubMedSearch in Google Scholar
  • 78 Manno CS, Pierce GF, Arruda VR. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12 (03) 342-347
    CrossrefPubMedSearch in Google Scholar
  • 79 Pasi KJ, Rangarajan S, Mitchell N. et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med 2020; 382 (01) 29-40
    CrossrefPubMedSearch in Google Scholar
  • 80 George LA, Monahan PE, Eyster ME. et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med 2021; 385 (21) 1961-1973
    CrossrefPubMedSearch in Google Scholar
  • 81 Ozelo MC, Mahlangu J, Pasi KJ. et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med 2022; 386 (11) 1013-1025
    CrossrefPubMedSearch in Google Scholar
  • 82 Miesbach W, Baghaei F, Boban A. et al. Gene therapy of hemophilia: Hub centres should be haemophilia centres: a joint publication of EAHAD and EHC. Haemophilia 2022; 28 (03) e86-e88
    CrossrefPubMedSearch in Google Scholar