New directions to develop therapies for people with hemophilia

References

• Mannucci PM, Tuddenham EGD. The Hemophilias — From Royal Genes to Gene Therapy. N Engl J Med. 2001 Jun 7;344(23):1773–1779.
   PubMed Web of Science ®Google Scholar
• Accessed on 2022 Sep 4. https://www.hemophilia.org/bleeding-disorders-a-z/overview/history
   Google Scholar
• Schramm W. The history of haemophilia - a short review. Thromb Res. 2014 Nov;134(Suppl 1):S4–9.
   PubMedGoogle Scholar
• Mannucci PM. Hemophilia and related bleeding disorders: a story of dismay and success. In: Hematology Am Soc Hematol Educ Program. ASH. 2002. p. 1–9.
   Google Scholar
• Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418–435.
   PubMed Web of Science ®Google Scholar
• Volkers P, Hanschmann KM, Calvez T, et al. Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies. Haemophilia. 2019 May;25(3):398–407.
   PubMed Web of Science ®Google Scholar
• Male C, NG A, Rafowicz A, et al. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica. 2021 Jan 1;106(1): 123–9.
   PubMed Web of Science ®Google Scholar
• Valentino LA, Kempton CL, Kruse-Jarres R, et al. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia. 2015 Sep;21(5):559–567.
   PubMed Web of Science ®Google Scholar
• Di Minno G, Castaman G, de Cristofaro R, et al. Progress, and prospects in the therapeutic armamentarium of persons with congenital hemophilia. Defining the place for liver-directed gene therapy. Blood Rev. 2022 Aug;23:101011.
   Google Scholar
• Sherman A, Biswas M, Herzog RW. Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A. Front Immunol. 2017;8:1604.
   PubMed Web of Science ®Google Scholar
• Reipert BM, Gangadharan B, Hofbauer CJ, et al. The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development. Blood Adv. 2020 Nov 24;4(22):5785–5796.
   PubMed Web of Science ®Google Scholar
• AD S, IS M, Nasr S, et al. The future of bypassing agents for hemophilia with inhibitors in the era of novel agents. J Thromb Haemost. 2018 Dec;16(12): 2362–74.
   Web of Science ®Google Scholar
• Matino D, Makris M, Dwan K, et al. Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database Syst Rev. 2015 Dec 16;2015(12):CD004449.
   PubMedGoogle Scholar
• Langer AL, Etra A, Aledort L. Evaluating the safety of emicizumab in patients with hemophilia A. Expert Opin Drug Saf. 2018 Dec;17(12):1233–1237.
   PubMed Web of Science ®Google Scholar
• Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. N Engl J Med. 2017 Aug 31;377(9):819–828.
   PubMed Web of Science ®Google Scholar
• Mahlangu JN. Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management. Front Med (Lausanne). 2021;8:670526.
   PubMed Web of Science ®Google Scholar
• Shapiro AD, Angchaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973–1982.
   PubMed Web of Science ®Google Scholar
• https://hemophilianewstoday.com/2021/03/01/fitusiran-dosing-phase-3-trials-reduced-to-lower-risk-of-blood-clots (Accessed on 2022 Sep 4th).
   Google Scholar
• Aledort L, Mannucci PM, Schramm W, et al. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019 Nov;17(6):479–486.
   PubMed Web of Science ®Google Scholar
• 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 Apr 7;127(14):1761–1769.
   PubMed Web of Science ®Google Scholar
• Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):1–8.
   PubMedGoogle Scholar
• Margaritis P, Roy E, Aljamali MN, et al. Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood. 2009 Apr 16;113(16):3682–3689.
   PubMed Web of Science ®Google Scholar
• Trevisan B, Rodriguez M, Medder H, et al. Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels. Front Immunol. 2022;13:1070476.
   PubMed Web of Science ®Google Scholar
• Nilsson IM, Berntorp E, Löfqvist T, et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992 Jul;232(1):25–32.
   PubMed Web of Science ®Google Scholar
• Berntorp E, Astermark J, Björkman S, et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia. 2003 May;9(Suppl 1):1–4.
   PubMed Web of Science ®Google Scholar
• Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med. 1994 Oct;236(4):391–399.
   PubMed Web of Science ®Google Scholar
• Mannucci PM. AIDS, hepatitis and hemophilia in the 1980s: memoirs from an insider. J Thromb Haemost. 2003 Oct;1(10):2065–2069.
   PubMed Web of Science ®Google Scholar
• Lambert T, Benson G, Dolan G, et al. Practical aspects of extended half-life products for the treatment of haemophilia. Ther Adv Hematol. 2018 9;Sep(9):295–308.
   Google Scholar
• Dumont JA, Liu T, Low SC, et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood. 2012 Mar 29;119(13):3024–3030.
   PubMed Web of Science ®Google Scholar
• Ivens IA, Baumann A, McDonald TA, et al. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia. 2013 Jan;19(1):11–20.
   PubMed Web of Science ®Google Scholar
• Gringeri A, Mantovani LG, Scalone L, et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003 Oct 1;102(7):2358–2363.
   PubMed Web of Science ®Google Scholar
• Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020 Mar;105(3):545–553.
   PubMed Web of Science ®Google Scholar
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761083s002s004lbl.pdf (Accessed on 2022 Oct 4).
   Google Scholar
• Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Adv. 2021 Jan 12;5(1):279.
   PubMed Web of Science ®Google Scholar
• Mannucci PM. The choice of plasma-derived clotting factor concentrates. Baillieres Clin Haematol. 1996 Jun;9(2):273–290.
   PubMedGoogle Scholar
• US Food and Drug Administration [internet]. https://www.fda.gov/vaccines-blood-biologics/approved-blood-products (cited 2022 Sep 15).
   Google Scholar
• Lusher JM. Recombinant clotting factor concentrates. Baillieres Clin Haematol. 1996 Jun;9(2):291–303.
   PubMedGoogle Scholar
• Fijnvandraat K, Berntorp E, ten Cate JW, et al. Recombinant, B-domain deleted factor VIII (r-VIII SQ): pharmacokinetics and initial safety aspects in hemophilia A patients. Thromb Haemost. 1997 Feb;77(2):298–302.
   PubMed Web of Science ®Google Scholar
• Schmidbauer S, Witzel R, Robbel L, et al. Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res. 2015 Aug;136(2):388–395.
   PubMed Web of Science ®Google Scholar
• Berntorp E. Second generation, B-domain deleted recombinant factor VIII. Thromb Haemost. 1997 Jul;78(1):256–260.
   PubMed Web of Science ®Google Scholar
• Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood. 1994 May 1;83(9):2428–2435.
   PubMed Web of Science ®Google Scholar
• Seremetis S, Lusher JM, Abildgaard CF, et al. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group. Haemophilia. 1999 Jan;5(1):9–16.
   PubMed Web of Science ®Google Scholar
• Saxena K, Lalezari S, Oldenburg J, et al. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016 Sep;22(5):706–712.
   PubMed Web of Science ®Google Scholar
• Stasyshyn O, Djambas Khayat C, Iosava G, et al. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial. J Thromb Haemost. 2017 Apr;15(4):636–644.
   PubMed Web of Science ®Google Scholar
• White G, Shapiro A, Ragni M, et al. Clinical evaluation of recombinant factor IX. Semin Hematol. 1998 Apr;35(2 Suppl 2):33–38.
   PubMed Web of Science ®Google Scholar
• Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood. 2001 Dec 15;98(13):3600–3606.
   PubMed Web of Science ®Google Scholar
• Shapiro AD, Di Paola J, Cohen A, et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood. 2005 Jan 15;105(2):518–525.
   PubMed Web of Science ®Google Scholar
• Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B. Haemophilia. 2014 Jan;20(1):15–24.
   PubMed Web of Science ®Google Scholar
• Schiavoni M, Napolitano M, Giuffrida G, et al. Status of Recombinant Factor VIII Concentrate Treatment for Hemophilia a in Italy: Characteristics and Clinical Benefits. Front Med (Lausanne). 2019;6:261.
   PubMed Web of Science ®Google Scholar
• Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy–International Kogenate-FS Study Group. Thromb Haemost. 2000 Jun;83(6):811–816.
   PubMed Web of Science ®Google Scholar
• Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013 Jan 17;368(3):231–239.
   PubMed Web of Science ®Google Scholar
• 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 May 26;374(21):2054–2064.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration [internet] ELOCTATE prescribing information. 2017. [Accessed on 2022 Feb 09]. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM400192.pdf.
   Google Scholar
• Powell JS, Josephson NC, Quon D, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012 Mar 29;119(13):3031–3037.
   PubMed Web of Science ®Google Scholar
• Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16;123(3):317–325.
   PubMed Web of Science ®Google Scholar
• Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015 Jun;13(6):967–977.
   PubMed Web of Science ®Google Scholar
• Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia. 2016 Jan;22(1):72–80.
   PubMed Web of Science ®Google Scholar
• Mahlangu JN, Ragni M, Gupta N, et al. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) for perioperative haemostatic management in severe haemophilia A. Thromb Haemost. 2016 Jul 4;116(1):1–8.
   PubMed Web of Science ®Google Scholar
• Carcao M, Shapiro A, Staber JM, et al. Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis. Haemophilia. 2018 Mar;24(2):245–252.
   PubMed Web of Science ®Google Scholar
• 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(Suppl 1):S29–38.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration [internet]. ADYNOVATE prescribing information; 2016. Accessed on 2022 Feb 07. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM472594.pdf
   Google Scholar
• Gruppo R, López-Fernández MF, Wynn TT, et al. 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 Sep;25(5):773–781.
   PubMed Web of Science ®Google Scholar
• 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 Aug 27;126(9):1078–1085.
   PubMed Web of Science ®Google Scholar
• TE C, MT R, JC L, 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 Apr;12(4):488–496.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration [internet]. JIVI Antihemophilic Factor (Recombinant) PEGylated-aucl prescribing information; 2018. Accessed on 2022 Jan 11. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/UCM618979.pdf
   Google Scholar
• Shah A, Coyle T, Lalezari S, et al. BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies. Haemophilia. 2018 Sep;24(5):733–740.
   PubMed Web of Science ®Google Scholar
• 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 Nov;183:13–19.
   PubMed Web of Science ®Google Scholar
• 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 Mar;15(3):411–419.
   PubMed Web of Science ®Google Scholar
• Baumann A, Piel I, Hucke F, et al. Pharmacokinetics, excretion, distribution, and metabolism of 60-kDa polyethylene glycol used in BAY 94-9027 in rats and its value for human prediction. Eur J Pharm Sci. 2019 Mar 15;130:11–20.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration [internet]. February 19, 2019 Approval Letter - ESPEROCT. BL 125671/0. Accessed on 2022 Oct 10. Available at: https://www.fda.gov/media/120350/download
   Google Scholar
• 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 Apr;11(4):670–678.
   PubMed Web of Science ®Google Scholar
• 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 Aug 30;117(9):1705–1713.
   PubMed Web of Science ®Google Scholar
• Peters RT, Low SC, Kamphaus GD, et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood. 2010 Mar 11;115(10):2057–2064.
   PubMed Web of Science ®Google Scholar
• Shapiro AD, Ragni MV, LA V, 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 Jan 19;119(3):666–672.
   PubMed Web of Science ®Google Scholar
• Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B. N Engl J Med. 2013 Dec 12;369(24):2313–2323.
   PubMed Web of Science ®Google Scholar
• Fischer K, Kulkarni R, Nolan B, et al. Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study. Lancet Haematol. 2017 Feb;4(2):e75–82.
   PubMed Web of Science ®Google Scholar
• Cooley B, Funkhouser W, Monroe D, et al. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice. Blood. 2016 Jul 14;128(2):286–292.
   PubMed Web of Science ®Google Scholar
• https://www.fda.gov/media/96526/download. cited 2022 Sep 15.
   Google Scholar
• Martinowitz U, Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with hemophilia B. Thromb Res. 2013 Mar;131(Suppl 2):S11–4.
   PubMed Web of Science ®Google Scholar
• Østergaard H, Bjelke JR, Hansen L, et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood. 2011 Aug 25;118(8):2333–2341.
   PubMed Web of Science ®Google Scholar
• Negrier C, Knobe K, Tiede A, et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011 Sep 8;118(10):2695–2701.
   PubMed Web of Science ®Google Scholar
• 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 Dec 18;124(26):3880–3886.
   PubMed Web of Science ®Google Scholar
• 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 Oct;18(10):1570–1574.
   PubMed Web of Science ®Google Scholar
• https://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf (Accessed on Nov 29, 2022).
   Google Scholar
• Shima M, Hanabusa H, Taki M, et al. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med. 2016 May 26;374(21):2044–2053.
   PubMed Web of Science ®Google Scholar
• Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809–818.
   PubMed Web of Science ®Google Scholar
• Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 Dec 12;134(24):2127–2138.
   PubMed Web of Science ®Google Scholar
• Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018 Aug 30;379(9):811–822.
   PubMed Web of Science ®Google Scholar
• Klamroth R, Wojciechowski P, Aballéa S, et al. Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials. J Blood Med. 2021;12:115–122.
   PubMed Web of Science ®Google Scholar
• Aledort LM. Deaths Associated with Emicizumab in Patients with Hemophilia A. N Engl J Med. 2019 Nov 7;381(19):1878–1879.
   PubMed Web of Science ®Google Scholar
• Linari S, Castaman G. Concomitant Use of rFVIIa and Emicizumab in People with Hemophilia A with Inhibitors: Current Perspectives and Emerging Clinical Evidence. Ther Clin Risk Manag. 2020;16:461–469.
   PubMed Web of Science ®Google Scholar
• 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 May;35:43–50.
   PubMed Web of Science ®Google Scholar
• Pipe SW, Montgomery RR, Pratt KP, et al. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood. 2016 Oct 20;128(16):2007–2016.
   PubMed Web of Science ®Google Scholar
• Croteau SE, Wang M, Wheeler AP. 2021 clinical trials update: Innovations in hemophilia therapy. Am J Hematol. 2021 Jan;96(1):128–144.
   PubMed Web of Science ®Google Scholar
• Østergaard H, Lund J, Greisen PJ, et al. A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021 Oct 7;138(14):1258–1268.
   PubMed Web of Science ®Google Scholar
• Vianello F, Belvini D, Dal Bello F, et al. Mild bleeding diathesis in a boy with combined severe haemophilia B (C(10400)–>T) and heterozygous factor V Leiden. Haemophilia. 2001 Sep;7(5):511–514.
   PubMed Web of Science ®Google Scholar
• Rodríguez-Merchán EC, de Pablo-Moreno JA, Liras A, et al. Gene Therapy in Hemophilia: Recent Advances. In: Int J Mol Sci. 2021;22:14.
   Google Scholar
• George LA, Monahan PE, Eyster ME, et al. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. N Engl J Med. 2021 Nov 18;385(21):1961–1973.
   PubMed Web of Science ®Google Scholar
• Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022 Mar 17;386(11):1013–1025.
   PubMed Web of Science ®Google Scholar
• Chowdary P, Shapiro S, Makris M, et al. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21;387(3):237–247.
   PubMed Web of Science ®Google Scholar
• Monahan PE, Négrier C, Tarantino M, et al. Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia. J Clin Med. 2021 Jun 2;10(11):2471.
   PubMed Web of Science ®Google Scholar
• Anti-AAV WT. Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions. Front Immunol. 2021;17:12.
   Google Scholar
• Schmidt M, Foster G R, Coppens M, et al. Liver Safety Case Report from the Phase 3 HOPE-B Gene Therapy Trial in Adults with Hemophilia B [abstract]. Res Pract Thromb Haemost. 2021;5(Suppl 2). Accessed 2023 Jan 6 https://abstracts.isth.org/abstract/liver-safety-case-report-from-the-phase-3-hope-b-gene-therapy-trial-in-adults-with-hemophilia-b/.
   PubMedGoogle Scholar
• Rogers GL, Herzog RW. Gene therapy for hemophilia. Front Biosci (Landmark Ed). 2015 Jan 1;20(3):556–603.
   PubMedGoogle Scholar
• Schellenberger V, Wang CW, Geething NC, et al. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat Biotechnol. 2009 Dec;27(12):1186–1190.
   PubMed Web of Science ®Google Scholar
• Seth Chhabra E, Liu T, Kulman J, et al. BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood. 2020 Apr 23;135(17):1484–1496.
   PubMed Web of Science ®Google Scholar
• FDA grants priority review to efanesoctocog alfa for people with hemophilia A. pdf (Accessed 2022 Nov 3).
   Google Scholar
• Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020 Sep 10;383(11):1018–1027.
   PubMed Web of Science ®Google Scholar
• Spira J, Widlund L, Österberg T, et al. Pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration of factor VIII of factor IX. International patent application: US patent US5925739A, European patent EP0772452. 1995 March 30. https://patentimages.storage.googleapis.com/ec/59/6c/cfe13d59588396/US5925739.pdf
   Google Scholar
• Shi Q, Kuether EL, Schroeder JA, et al. Intravascular recovery of VWF and FVIII following intraperitoneal injection and differences from intravenous and subcutaneous injection in mice. Haemophilia. 2012 Jul;18(4):639–646.
   PubMed Web of Science ®Google Scholar
• Sadler JE. New concepts in von Willebrand disease. Annu Rev Med. 2005;56:173–191.
   PubMed Web of Science ®Google Scholar
• Fatouros A, Lidén Y, Recombinant Factor SB. VIII SQ—Stability of VIII: C in Homogenates from Porcine, Monkey and Human Subcutaneous Tissue. J Pharm Pharmacol. 2010 Feb 18;52(7):797–805.
   Google Scholar
• Vollack-Hesse N, Oleshko O, Werwitzke S, et al. Recombinant VWF fragments improve bioavailability of subcutaneous factor VIII in hemophilia A mice. Blood. 2021 Feb 25;137(8):1072–1081.
   PubMed Web of Science ®Google Scholar
• Klamroth R, Feistritzer C, Friedrich U, et al. Pharmacokinetics, immunogenicity, safety, and preliminary efficacy of subcutaneous turoctocog alfa pegol in previously treated patients with severe hemophilia A (alleviate 1). J Thromb Haemost. 2020 Feb;18(2):341–351.
   PubMed Web of Science ®Google Scholar
• Solecka-Wituska BA, Wuschko S, Kannicht C. Pharmacokinetics of subcutaneously administered simoctocog alfa with von Willebrand factor fragment candidates in a minipig model [abstract]. In: Disorders of coagulation or fibrinolysis. Blood. 2017;130(9):1073.
   PubMedGoogle Scholar
• Liu Z, van der Flier A, Ismail A, et al. Evaluation of Recombinant FIXFc-XTEN Bleeding Efficacy in Hemophilia-B Mouse Models [abstract]. Blood. 2016;128(22):Abstract 3757.
   Web of Science ®Google Scholar
• Csh WY, Levy H, Lee M, et al. Phase 1/2 trial of subcutaneously administered Factor IX variant CB2679d/ISU304: pharmacokinetic and activity [abstract]. Blood. 2017;130(suppl1):Abstract 87.
   Google Scholar
• Catalyst Biosciences provides update on CB 2679d/ISU304 factor IX clinical program in Hemophilia B. http://ir.catalystbiosciences.com/phoenix.zhtml. cited 2022 Oct 19
   Google Scholar
• Mahlangu J, Levy H, Lee M, et al. Efficacy and safety of subcutaneous prophylaxis with dalcinonacog alfa in adults with haemophilia B. Haemophilia. 2021 Jul;27(4):574–580.
   PubMed Web of Science ®Google Scholar
• Mahlangu J, Levy H, Kosinova MV, et al. Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety. Res Pract Thromb Haemost. 2021 Aug 17;5(6):e12576.
   PubMed Web of Science ®Google Scholar
• Mancuso ME, Mahlangu JN, Pipe SW. The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet. 2021 Feb 13;397(10274):630–640.
   PubMed Web of Science ®Google Scholar
• Hashim MA, Yamaguchi A, Vo AT, et al. Orally delivered factor VIII restores hemostasis in a hemophilia A dog. ISTH 2021 Congress. Abstract number: OC 48.4.
   Google Scholar
• Su J, Zhu L, Sherman A, et al. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B. Biomaterials. 2015 Nov;70:84–93.
   PubMed Web of Science ®Google Scholar
• Herzog RW, Nichols TC, Su J, et al. Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce. Mol Ther. 2017 Feb 1;25(2):512–522.
   PubMed Web of Science ®Google Scholar
• Lauritzen B, Bjelke M, Björkdahl O, et al. A novel next‐generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys. J Thromb Haemost. 2022 Jun 6;20(6):1312–1324.
   PubMed Web of Science ®Google Scholar
• Wheeler AP, Benson G, Eichler H, et al. Surgeries and diagnostic procedures in hemophilia patients on concizumab prophylaxis: results from the phase 2 Explorer4 and Explorer5 trials [abstract]. In: Disorders of coagulation or fibrinolysis: Clinical and Epidemiological. Blood. 2021;138(Suppl 1):345.
   Google Scholar
• Mahlangu J, Lamas JL, Morales JC, et al. Long-term Safety and Efficacy of the Anti-TFPI Monoclonal Antibody Marstacimab in Patients with Severe Haemophilia A or B: Results from a Phase 2 Long-term Treatment Study [abstract]. 2021. https://abstracts.isth.org/abstract/long-term-safety-and-efficacy-of-the-anti-tfpi-monoclonal-antibody-marstacimab-in-patients-with-severe-haemophilia-a-or-b-results-from-a-phase-2-long-term-treatment-study/
   Google Scholar
• Kwak H, Lee S, Jo S, et al. MG1113, a specific anti–tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia. Res Pract Thromb Haemost. 2020 Nov 22;4(8):1301–1312.
   PubMed Web of Science ®Google Scholar
• Kwak E, Kim MJ, Park JH, et al. Target‐mediated drug disposition modeling of an anti‐TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics. J Thromb Haemost. 2021 Jun 17;19(6):1425–1435.
   PubMed Web of Science ®Google Scholar
• http://investors.alnylam.com/releasedetail.cfm?ReleaseID=1039464 (Accessed on 2022 Sep 07
   Google Scholar
• https://hemophilianewstoday.com/2021/03/01/fitusiran-dosing-phase-3-trials-reduced-to-lower-risk-of-blood-clots (Accessed on 2022 Nov 18
   Google Scholar
• Pasi KJ, Lissitchkov T, Mamonov V, et al. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort. J Thromb Haemost. 2021 Jun;19(6):1436–1446.
   PubMed Web of Science ®Google Scholar
• Srivastava A, Rangarajan S, Kavakli K, et al. Fitusiran, an investigational siRNA therapeutic targeting antithrombin for the treatment of hemophilia: first results from a phase 3 study to evaluate efficacy and safety in people with hemophilia A or B without inhibitors (ATLAS-A/B). ASH abstract. Blood. 2021;138(Suppl2):LBA–3.
   Google Scholar
• Bhagunde P, Ge S, Iqbal S, et al. Fitusiran population pharmacokinetic and pharmacodynamic (PopPK/PD) modeling to support revised dose, dosing regimens & dose mitigation scheme. ISTH abstract. Res Pract Thromb Haemost. 2021;5(Suppl):2.
   Google Scholar
• Rezaie AR. Vitronectin functions as a cofactor for rapid inhibition of activated protein C by plasminogen activator inhibitor-1. Implications for the mechanism of profibrinolytic action of activated protein C. J Biol Chem. 2001 May 11;276(19):15567–15570.
   PubMed Web of Science ®Google Scholar
• Suzuki K, Nishioka J, Kusumoto H, et al. Mechanism of inhibition of activated protein C by protein C inhibitor. J Biochem. 1984 Jan;95(1):187–195.
   PubMed Web of Science ®Google Scholar
• Polderdijk SGI, Adams TE, Ivanciu L, et al. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2017 Jan 5;129(1):105–113.
   PubMed Web of Science ®Google Scholar
• Zhao XY, Wilmen A, Wang D, et al. Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia. Nat Commun. 2020 Jun 12;11(1):2992.
   PubMed Web of Science ®Google Scholar
• Prince R, Bologna L, Manetti M, et al. Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood. 2018 Mar 22;131(12):1360–1371.
   PubMed Web of Science ®Google Scholar
• Favaro P, Finn JD, Siner JI, et al. Safety of liver gene transfer following peripheral intravascular delivery of adeno-associated virus (AAV)-5 and AAV-6 in a large animal model. Hum Gene Ther. 2011 Jul;22(7):843–852.
   PubMed Web of Science ®Google Scholar
• Laffan MA, Rangarajan S, Lester W, et al. Hemostatic results for up to 6 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A. Presentation OC 21.2. ISTH Congress, 9-13 Jul, 2022.
   Google Scholar
• Fong S, Yates B, Sihn CR, et al. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med. 2022 Apr;28(4):789–797.
   PubMed Web of Science ®Google Scholar
• Chapin JC, Ayash-Rashkovsky M, Kenniston J, et al. A translational analysis of immune components in peripheral blood from severe hemophilia A patients treated with TAK-754, an AAV8 vector with a codon-optimized B-domain deleted factor VIII transgene. Presentation PB0211. ISTH Congress, 9-13 Jul, 2022.
   Google Scholar
• https://investors.biomarin.com/2022-08-24-First-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC (Accessed on 2022 Oct 19
   Google Scholar
• https://www.fda.gov/media/163466/download. cited 2023 Jan 30.
   Google Scholar
• Itzler R, Miller J, Robson R, et al. Improvements in health-related quality of life in adults with severe or moderately severe hemophilia B after receiving etranacogene dezaparvovec gene therapy. Presentation OC 01.02. ISTH Congress, 9-13 July, 2022.
   Google Scholar
• Pipe Steven W, W.G Leebek Frank, Recht Michael, et al. 2141 Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up. [abstract]. ASH. 2022; 801;1. https://ash.confex.com/ash/2022/webprogram/Paper166135.html cited 2023 Jan 27.
   Google Scholar
• 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 Jan 2;382(1):29–40.
   PubMed Web of Science ®Google Scholar
• https://hemophilianewstoday.com/2020/12/11/high-dose-gene-therapy-sb-525-fviii-levels-prevents-bleeds-alta-trial-data/ (Accessed on 2022 Nov 17
   Google Scholar
• Young G, Chowdary P, Barton S, et al. Results from B-LIEVE, a phase 1/2 dose confirmation study of FLT180a AAV gene therapy in patients with hemophilia B. Presentation PB0213. ISTH Congress, 9-13 Jul, 2022.
   Google Scholar
• Lawton S, Manson M, Fan M, et al. Liver sinusoidal endothelial cells targeted with ultrasound mediated gene delivery shows long-term FVIII expression in hemophilia A mice. Presentation OC 12.5. ISTH Congress, 9-13 Jul, 2022.
   Google Scholar
• Wang X, Shin SC, Chiang AFJ, et al. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A. Mol Ther. 2015 Apr;23(4):617–626.
   PubMed Web of Science ®Google Scholar
• Chen C, Cai X, Miao C, et al. Rescue of the endogenous FVIII expression in hemophilia A mice using CRISPR/ Cas9 mRNA LNPs. Presentation OC 12.3. ISTH Congress, 9-13 Jul, 2022.
   Google Scholar
• Zintner SM, Small JC, Pavani G, et al. Gene-based FVIIa prophylaxis modulates the spontaneous bleeding phenotype of hemophilia A rats. Blood Adv. 2019 Feb 12;3(3):301–311.
   PubMed Web of Science ®Google Scholar
• Barbon E, Ayme G, Mohamadi A, et al. Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors. EMBO Mol Med. 2020 Apr 7;12(4):e11298.
   PubMed Web of Science ®Google Scholar
• Shi Q, Wilcox DA, Fahs SA, et al. Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A. J Thromb Haemost. 2007 Feb;5(2):352–361.
   PubMed Web of Science ®Google Scholar
• Du LM, Nurden P, Nurden AT, et al. Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun. 2013;4:2773.
   PubMed Web of Science ®Google Scholar
• Accessed on 2022 Sept 25. https://www.hemophilia.org/news/sigilon-announces-a-priority-shift-in-light-of-clinical-trial-setbacks
   Google Scholar