2017 Clinical trials update: Innovations in hemophilia therapy

American Journal of Hematology

Volumn 91, Issue 12, 2016, Pages 1252-1260

  Hartmann, Jan ^a   Croteau, Stacy E ^b  

^a HAEMONETICS CORPORATION   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTITHROMBIN; BLOOD CLOTTING FACTOR 8; BLOOD CLOTTING FACTOR 8 CONCENTRATE; BLOOD CLOTTING FACTOR 9 CONCENTRATE; TISSUE FACTOR PATHWAY INHIBITOR; BLOOD CLOTTING FACTOR 9; HYBRID PROTEIN; RECOMBINANT FACTOR VIII SQ;

ADENO ASSOCIATED VIRUS; ARTICLE; CLINICAL TRIAL (TOPIC); DNA MODIFICATION; DRUG HALF LIFE; GENE THERAPY; HEMOPHILIA; HEMOPHILIA A; HEMOPHILIA B; HUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; BLOOD CLOTTING; DRUG EFFECTS; HALF LIFE TIME; PROCEDURES;

BLOOD COAGULATION; CLINICAL TRIALS AS TOPIC; FACTOR IX; FACTOR VIII; GENETIC THERAPY; HALF-LIFE; HEMOPHILIA A; HEMOPHILIA B; HUMANS; RECOMBINANT FUSION PROTEINS;

EID: 84994745295     PISSN: 03618609     EISSN: 10968652     Source Type: Journal    
DOI: 10.1002/ajh.24543     Document Type: Article

References (92)

1. Mannucci PM, Tuddenham EG. The hemophilias–From royal genes to gene therapy. New Engl J Med 2001;344:1773–1779.
2. James AH. Women and bleeding disorders. Haemophilia 2010;16 Suppl 5:160–167.
3. Sidonio RF, Mili FD, Li T, et al. Females with FVIII and FIX deficiency have reduced joint range of motion. Am J Hematol 2014;89:831–836.
4. Rallapalli PM, Kemball-Cook G, Tuddenham EG, et al. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013;11:1329–1340.
5. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013;19:e1–e47.
6. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New Engl J Med 2007;357:535–544.
7. Oladapo AO, Epstein JD, Williams E, et al. Health-related quality of life assessment in haemophilia patients on prophylaxis therapy: A systematic review of results from prospective clinical trials. Haemophilia 2015;21:e344–e358.
8. Tiede A, Oldenburg J, Lissitchkov T, et al. Prophylaxis vs. on-demand treatment with Nuwiq((R)) (Human-cl rhFVIII) in adults with severe haemophilia A. Haemophilia 2016;22:374–380.
9. DiMichele DM, Hoots WK, Pipe SW, et al. International workshop on immune tolerance induction: Consensus recommendations. Haemophilia 2007;13:1–22.
10. Astermark J. Why do inhibitors develop? Principles of and factors influencing the risk for inhibitor development in haemophilia. Haemophilia 2006;12:52–60.
11. Astermark J. FVIII inhibitors: Pathogenesis and avoidance. Blood 2015;125:2045–2051.
12. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: A systematic review. Haemophilia 2003;9:418–435.
13. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New Engl J Med 2016;374:2054–2064.
14. Collins PW, Chalmers E, Hart DP, et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization. Br J Haematol 2013;160:153–170.
15. Coppola A, Di Minno MN, Santagostino E. Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence-based approaches. Br J Haematol 2010;150:515–528.
16. Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007;109:546–551.
17. Leissinger CA, Singleton T, Kruse-Jarres R. How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors. Blood 2015;126:153–159.
18. Croteau SE, Nakar C, Neufeld EJ, et al. Safety and efficacy of recombinant factor VIIa by pediatric age cohort: Reassessment of compassionate use and trial data supporting US label. Pediatr Blood Cancer 2016;63:1822–1828.
19. Darby SC, Keeling DM, Spooner RJ, et al. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977–1999. J Thromb Haemost 2004;2:1047–1054.
20. Di Minno MN, Di Minno G, Di Capua M, et al. Cost of care of haemophilia with inhibitors. Haemophilia 2010;16:e190–e201.
21. Mannucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 2012;119:4108–4114.
22. Barnes C. Importance of pharmacokinetics in the management of hemophilia. Pediatr Blood Cancer 2013;60:S27–S29.
23. Collins PW, Fischer K, Morfini M, et al. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia 2011;17:2–10.
24. Gruppo RA, Brown D, Wilkes MM, et al. Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis—A meta-analysis. Haemophilia 2003;9:251–260.
25. Fischer K, Steen Carlsson K, Petrini P, et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013;122:1129–1136.
26. Stonebraker JS, Brooker M, Amand RE, et al. A study of reported factor VIII use around the world. Haemophilia 2010;16:33–46.
27. Ezban M, Vad K, Kjalke M. Turoctocog alfa (NovoEight(R))—From design to clinical proof of concept. Eur J Haematol 2014;93:369–376.
28. Lissitchkov T, Hampton K, von Depka M, et al. Novel, human cell line-derived recombinant factor VIII (human-cl rhFVIII; Nuwiq(R)) in adults with severe haemophilia A: Efficacy and safety. Haemophilia 2016;22:225–231.
29. Kavakli K, Yang R, Rusen L, et al. Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: Results from a randomized trial (LEOPOLD II). J Thromb Haemost 2015;13:360–369.
30. Schmidbauer S, Witzel R, Robbel L, et al. Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res 2015;136:388–395.
31. Saenko EL, Pipe SW. Strategies towards a longer acting factor VIII. Haemophilia 2006;12:42–51.
32. Mancuso ME, Mannucci PM. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias. Drug Des Dev Ther 2014;8:365–371.
33. Tiede A, Brand B, Fischer R, et al. Enhancing the pharmacokinetic properties of recombinant factor VIII: First-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 2013;11:670–678.
34. Pisal DS, Balu-Iyer SV. Phospholipid binding improves plasma survival of factor VIII. Thrombosis and Haemostasis 2010;104:1073–1075.
35. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014;123:317–325.
36. Tang L, Leong L, Sim D, et al. von Willebrand factor contributes to longer half-life of PEGylated factor VIII in vivo. Haemophilia 2013;19:539–545.
37. Croteau SE, Neufeld EJ. Transition considerations for extended half-life factor products. Haemophilia 2015;21:285–288.
38. Peters RT, Toby G, Lu Q, et al. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost 2013;11:132–141.
39. Turecek PL, Bossard MJ, Graninger M, et al. BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation. Hamostaseologie 2012;32:S29–S38.
40. 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;126:1078–1085.
41. Bjornsdottir I, Sternebring O, Kappers WA, et al. Pharmacokinetics, tissue distribution and excretion of 40 kDa PEG and PEGylated rFVIII (N8-GP) in rats. Eur J Pharm Sci: Off J Eur Feder Pharm Sci 2016;87:58–68.
42. Ivens IA, Baumann A, McDonald TA, et al. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia 2013;19:11–20.
43. Coyle TE, Reding MT, Lin JC, et al. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost 2014;12:488–496.
44. Stidl R, Fuchs S, Bossard M, et al. Safety of PEGylated recombinant human full-length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates. Haemophilia 2016;22:54–64.
45. Webster R, Didier E, Harris P, et al. PEGylated proteins: Evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos: Biol Fate Chem 2007;35:9–16.
46. Knobe K, Berntorp E. New treatments in hemophilia: insights for the clinician. Ther Adv Hematol 2012;3:165–175.
47. Windyga J, Solano Trujillo MH, Hafeman AE. BAX326 (RIXUBIS): A novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B. Ther Adv Hematol 2014;5:168–180.
48. Monroe DM, Jenny RJ, Van Cott KE, et al. Characterization of IXINITY(R) (Trenonacog Alfa), a recombinant factor IX with primary sequence corresponding to the threonine-148 polymorph. Adv Hematol 2016;2016:7678901.
49. Lambert T, Recht M, Valentino LA, et al. Reformulated BeneFix: Efficacy and safety in previously treated patients with moderately severe to severe haemophilia B. Haemophilia 2007;13:233–243.
50. Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. New Engl J Med 2013;369:2313–2323.
51. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: Results of a phase 3 trial. Blood 2016;127:1761–1769.
52. Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124:3880–3886.
53. Walsh CE, Batt KM. Hemophilia clinical gene therapy: Brief review. Transl Res: J Lab Clin Med 2013;161:307–312.
54. Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 2003;101:2963–2972.
55. 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;12:342–347.
56. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New Engl J Med 2011;365:2357–2365.
57. Monahan PE. Gene therapy in an era of emerging treatment options for hemophilia B. J Thromb Haemost 2015;13:S151–160.
58. Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New Engl J Med 2014;371:1994–2004.
59. Guan Y, Ma Y, Li Q, et al. CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse. EMBO Mol Med 2016;8:477–488.
60. Calcedo R, Vandenberghe LH, Gao G, et al. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 2009;199:381–390.
61. Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum Gene Ther 2010;21:704–712.
62. Herzog RW. Hemophilia gene therapy: Caught between a cure and an immune response. Mol Ther: J Am Soc Gene Ther 2015;23:1411–1412.
63. High KA, Anguela XM. Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet 2016;25:R36–R41.
64. Ward NJ, Buckley SM, Waddington SN, et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 2011;117:798–807.
65. Arruda VR, Samelson-Jones BJ. Obstacles and future of gene therapy for hemophilia. Exp Opin Orphan Drugs 2015;3:997–1010.
66. George LA, Fogarty PF. Gene therapy for hemophilia: past, present and future. Semin Hematol 2016;53:46–54.
67. Brown BD, Cantore A, Annoni A, et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007;110:4144–4152.
68. Fomin ME, Togarrati PP, Muench MO. Progress and challenges in the development of a cell-based therapy for hemophilia A. J Thromb Haemost 2014;12:1954–1965.
69. Matrai J, Chuah MK, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol Ther: J Am Soc Gene Therapy 2010;18:477–490.
70. Shi Q, Wilcox DA, Fahs SA, et al. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Investig 2006;116:1974–1982.
71. Chen Y, Schroeder JA, Kuether EL, et al. Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice. Mol Ther: 2014;22:169–177.
72. Kuether EL, Schroeder JA, Fahs SA, et al. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-factor VIII immunity. J Thromb Haemost 2012;10:1570–1580.
73. Davidoff AM, Nathwani AC. Genetic targeting of the albumin locus to treat hemophilia. New Engl J Med 2016;374:1288–1290.
74. 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;18:1570–1574.
75. 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:e57479.
76. 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;127:1633–1641.
77. Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. New Engl J Med 2016;374:2044–2053.
78. Erhardtsen E, Ezban M, Madsen MT, et al. Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding time in rabbits with antibody induced haemophilia A. Blood Coagul Fibrinolysis Int J Haemost Thromb 1995;6:388–394.
79. Maroney SA, Mast AE. New insights into the biology of tissue factor pathway inhibitor. J Thromb Haemost 2015;13:S200–S207.
80. Petersen LC. Hemostatic properties of a TFPI antibody. Thromb Res 2012;129:S44–S45.
81. Lwaleed BA, Bass PS. Tissue factor pathway inhibitor: structure, biology and involvement in disease. J Pathol 2006;208:327–339.
82. Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: A randomized first human dose trial. J Thromb Haemost 2015;13:743–754.
83. Gissel M, Orfeo T, Foley JH, et al. Effect of BAX499 aptamer on tissue factor pathway inhibitor function and thrombin generation in models of hemophilia. Thromb Res 2012;130:948–955.
84. Waters EK, Genga RM, Thomson HA, et al. Aptamer BAX 499 mediates inhibition of tissue factor pathway inhibitor via interaction with multiple domains of the protein. J Thromb Haemost 2013;11:1137–1145.
85. Ragni MV. Targeting antithrombin to treat hemophilia. New Engl J Med 2015;373:389–391.
86. Franchini M, Lippi G. Factor V Leiden and hemophilia. Thromb Res 2010;125:119–123.
87. Shetty S, Vora S, Kulkarni B, et al. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients. Br J Haematol 2007;138:541–544.
88. Sehgal A, Barros S, Ivanciu L, et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 2015;21:492–497.
89. Mahdi AJ, Obaji SG, Collins PW. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia. Br J Haematol 2015;169:768–776.
90. Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014;20:607–615.
91. Peyvandi F, Oldenburg J, Friedman KD. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost 2016;14:248–261.
92. MASAC Recommendation on SIPPET (Survey of Inhibitors in Plasma Product Exposed Toddlers): Results and recommendations for treatment products for previously untreated patients with hemophilia A. MASAC Document #243; 2016.