The More Recent History of Hemophilia Treatment

Massimo Franchini; Pier Mannuccio Mannucci

doi:10.1055/s-0042-1756188

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

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

Review Article

The More Recent History of Hemophilia Treatment

Autor*innen

Massimo Franchini

¹Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy
Pier Mannuccio Mannucci

²Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico and University of Milan, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy

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

Volltext

Referenzen

References
1 Mannucci PM, Tuddenham EGD. The hemophilias—from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
2 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371): 1801-1809
3 Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388 (10040): 187-197
4 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
5 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
6 Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost 2014; 40 (05) 571-576
7 Schramm W. The history of haemophilia—a short review. Thromb Res 2014; 134 (Suppl. 01) S4-S9
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
9 Mannucci PM. Back to the future: a recent history of haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 10-18
10 Mannucci PM. Hemophilia: treatment options in the twenty-first century. J Thromb Haemost 2003; 1 (07) 1349-1355
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
12 Nilsson IM. Experience with prophylaxis in Sweden. Semin Hematol 1993; 30 (03, Suppl 2): 16-19
13 Moreno MM, Cuesta-Barriuso R. A history of prophylaxis in haemophilia. Blood Coagul Fibrinolysis 2019; 30 (02) 55-57
14 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years. Haemophilia 2000; 6 (Suppl. 01) 60-67
15 Evatt BL. The tragic history of AIDS in the hemophilia population, 1982-1984. J Thromb Haemost 2006; 4 (11) 2295-2301
16 Franchini M. The modern treatment of haemophilia: a narrative review. Blood Transfus 2013; 11 (02) 178-182
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
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
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
20 Mannucci PM. Hemophilia therapy: the future has begun. Haematologica 2020; 105 (03) 545-553
21 Schulte S. Innovative coagulation factors: albumin fusion technology and recombinant single-chain factor VIII. Thromb Res 2013; 131 (Suppl. 02) S2-S6
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
23 Swierczewska M, Lee KC, Lee S. What is the future of PEGylated therapies?. Expert Opin Emerg Drugs 2015; 20 (04) 531-536
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
45 Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J Clin Med 2017; 6 (04) 39
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
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
48 Ozelo MC, Yamaguti-Hayakawa GG. Impact of novel hemophilia therapies around the world. Res Pract Thromb Haemost 2022; 6 (03) e12695
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
50 Astermark J, Santagostino E, Keith Hoots W. Clinical issues in inhibitors. Haemophilia 2010; 16 (Suppl. 05) 54-60
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
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
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
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
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
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
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
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
59 Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Blood Transfus 2018; 16 (05) 457-461
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
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
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
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
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
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
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
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
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
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
70 Le Quellec S, Negrier C. Emicizumab should be prescribed independent of immune tolerance induction. Blood Adv 2018; 2 (20) 2783-2786
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
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
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
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
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
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
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
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
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
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
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
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