Page 39 - Haematologica March 2020

Future of hemophilia therapy
netics and pharmacodynamics of concizum- ab in people with hemophilia A. J Thromb Haemost. 2018;16(11):2184-2195.
58. Gu JM, Zhao XY, Schwarz T, et al. Mechanistic modeling of the pharmacody- namic and pharmacokinetic relationship of tissue factor pathway inhibitor-neutralizing antibody (BAY 1093884) in cynomolgus monkeys. AAPS J. 2017;19(4):1186-1195.
59. Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med. 2017;377(9):819-828.
60. Ragni MV, Georgiev P, Mant T, et al. Fitusiran, an investigational RNAi therapeu- tic targeting antithrombin for the treatment of hemophilia: updated results from a phase 1 and phase 1/2 extension study in patients without inhibitors [abstract]. Blood. 2016;128(22):2572.
61. ClinicalTrials.gov. A Study study of fitusiran (ALN-AT3SC) in severe hemophilia A and B patients with inhibitors (ATLAS-INH). Identifier: NCT03417102. 2018. https://clin- icaltrials.gov/ct2/show/NCT03417102. Accessed February, 2019.
62. Clinicaltrials.gov. A study of fitusiran (ALN- AT3SC) in severe hemophilia A and B patients without inhibitors. Identifier: NCT03417245. 2018. https://clinicaltrials.gov/ct2/show/NCT034 17245. Accessed June, 2019.
63. Alnylam. Alnylam provides pipeline update on fitusiran and givosiran investigational RNAi therapeutic programs. 2017. http://investors.alnylam.com/news-releas- es/news-release-details/alnylam-provides- pipeline-update-fitusiran-and-givosiran. Accessed February, 2019.
64. Mannucci PM. Miracle of haemophilia drugs: Personal views about a few main players. Haemophilia. 2018;24:557-562.
65. von Mackensen S, Kalnins W, Krucker J, et al. Haemophilia patients' unmet needs and their expectations of the new extended half- life factor concentrates. Haemophilia. 2017;23:566-574.
66. Wang L, Takabe K, Bidlingmaier SM, Ill CR,
Verma IM. Sustained correction of bleeding disorder in hemophilia B mice by gene ther- apy. Proc Natl Acad Sci U S A. 1999;96: 3906 3910.
67. Chao H, Mao L, Bruce AT, Walsh CE. Sustained expression of human factor VIII in mice using a parvovirus based vector. Blood. 2000;95:1594 1599.
68. Mount JD, Herzog RW, Tillson DM, et al. Sustained phenotypic correction of hemo- philia B dogs with a factor IX null mutation by liver directed gene therapy. Blood. 2002;99:2670 2676.
69. Sarkar R, Mucci M, Addya S, et al. Long term efficacy of adeno associated virus serotypes 8 and 9 in hemophilia A dogs and mice. Hum Gene Ther. 2006;17:427 439.
70. Snyder RO, Miao C, Meuse L, et al. Correction of hemophilia B in canine and murine models using recombinant adeno associated viral vectors. Nat Med. 1999;5:64 70.
71. Nathwani AC, Tuddenham E, Rangarajan S, et al. Adenovirus associated virus vector mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357 2365.
72. Nathwani AC, Reiss UM, Tuddenham E, et al. Long term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994 2004.
73. Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia. 2019;25(5):738-746.
74. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene ther apy with a high specific activity factor IX variant. N Engl J Med. 2017;377:2215 2227.
75. http://ir.sparktx.com/news releases/news- release details/spark therapeutics and pfiz- er announce data 15 participants.
Thromb Haemost. 2017;1(Suppl. 1):144.
77. Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adenoassociated virus vector 5 human factor IX in adults with
hemophilia B. Blood. 2018;131:1022 1031. 78. Leebeek F, Meijer K, Coppens M, et al Reduction in annualized bleeding and factor IX consumption up to 2.5 years in adults with severe or moderate severe hemophilia B treated with AMT 060 (AAV5 hFIX) gene
therapy. Blood. 2018;132 (Suppl. 1): 3476. 79. Ward NJ, Buckley S, Waddington SN, et al. Codon optimization of human factor VIII cDNAs leads to high level expression.
Blood. 2011;117:798 807.
80. Siner JI, Iacobelli NP, Sabatino DE, et al.
Minimal modification in the factor VIII B domain sequence ameliorates the murine hemophilia A phenotype. Blood. 2013;121: 4396 4403.
81. Rangarajan S, Walsh L, Lester W, et al. AAV5 Factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377: 2519 2530.
82. 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;382:29-40 .
83. Donsante A, Miller DG, Li Y, et al. AAV vec- tor integration sites in mouse hepatocellular carcinoma. Science. 2007;317(5837):477.
84. Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutage- nesis in human hepatocellular carcinomas. Nat Genet. 2015;47:1187-1193.
85. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophil- ia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342-347.
86. Kaeppel C, Beattie SG, Fronza R, et al. A largely random AAV integration profile after LPLD gene therapy. Nat Med. 2013;19:889-
76. Chapin J, Rottensteiner H, Scheiflinger F,
Monahan PE. An analysis of bleeding rates
and factor IX consumption in the phase I/II 891.
BAX 335 gene therapy trial in subjects with hemophilia B. Abstracts of the XXVI Congress of the International Society on Thrombosis and Haemostasis. Res Pract
87. D'Avola D, López-Franco E, Sangro B, et al. Phase I open label liver-directed gene thera- py clinical trial for acute intermittent por- phyria. J Hepatol. 2016;65(4):776-783.
haematologica | 2020; 105(3)
553