Tratamiento moderno de la hemofilia  y el desarrollo de terapias innovadoras.:

Arlette  Ruiz-Sáez

doi:10.22209/IC.v62n1a07

Arlette Ruiz-Sáez Banco Municipal de Sangre, Caracas, Venezuela

DOI: https://doi.org/10.22209/IC.v62n1a07

Palabras clave: hemofilia, tratamiento, innovaciones, terapia génica

Resumen

La hemofilia es una enfermedad hemorrágica resultante de mu-taciones en el gen del factor VIII (F8) de la coagulación en el caso de la hemo-filia A o en el gen del factor IX (F9) en el caso de la hemofilia B, siendo ambas formas indistinguibles clínicamente. El fenotipo clínico usualmente refleja la actividad del factor en plasma y la principal complicación del tratamiento es el desarrollo de aloanticuerpos neutralizantes. El tratamiento moderno de la hemofilia comienza a despuntarse en la década de 1970 con la disponibilidad de concentrados de factores de la coagulación de origen plasmático, el inicio de programas de profilaxis y el manejo multidisciplinario de la condición. Pos-teriormente, la producción de concentrados seguros, debidamente inactivados o de origen recombinante, facilitó la individualización de la terapia y el desa-rrollo de los agentes baipás mejoró el tratamiento de pacientes con inhibidores. Para todas esas opciones, la gran limitante ha sido la necesidad de frecuentes infusiones endovenosas por un tiempo indefinido. La biotecnología ha permi-tido el desarrollo de concentrados de factor VIII y IX de vida media plasmática extendida y a la producción de terapias novedosas, diferentes a la terapia de remplazo, que mejoran la coagulación o inhiben las vías anticoagulantes natu-rales. Por último, los progresos en la terapia génica como potencial cura de la condición generan grandes expectativas. Si bien estos avances ofrecen alterna-tivas terapéuticas para pacientes con o sin inhibidores, aún están por definirse aspectos relacionados a sus indicaciones, monitorización y seguridad a corto y largo plazo.

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Mannucci PM, Tuddenham EG. The hem--ophilias--from royal genes to gene therapy. N Engl J Med 2001;344(23):1773-9.

Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014;12(11):1935-1939.

Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug 3. doi: 10.1111/ hae.14046.

Iorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C, Germini F; Data and Demographics Committee of the World Federation of Hemophilia. Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries. Ann In- tern Med 2019;171(8):540-546.

Van den Berg HM, Fischer K, Carcao M, Chambost H, Kenet G, Kurnik K, Königs C, Male C, Santagostino E, Ljung R; Ped Net Study Group. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood 2019;134(3):317-320.

Ljung R, Auerswald G, Benson G, Dolan G, Duffy A, Hermans C, Jiménez-Yuste V, Lambert T, Morfini M, Zupančić-Šalek S, Santagostino E. Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol 2019;102(2):111-122.

Male C, Andersson NG, Rafowicz A, Liesner R, Kurnik K, Fischer K, Platokouki H, Santagostino E, Chambost H, Nolan B, Königs C, Kenet G, Ljung R, van den Berg M; PedNet study group. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica 2020 Jan 9:haematol.2019.239160. doi: 10.3324/ haematol.2019.239160.

Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, Chambost H, Kurnik K, Liesner R, Petrini P, Platokouki H, Altisent C, Oldenburg J, Nolan B, Garrido RP, Mancuso ME, Rafowicz A, Williams M, Clausen N, Middelburg RA, Ljung R, van der Bom JG; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013;121(20):4046-4055.

Peyvandi F, Mannucci PM, Garagiola I, El- Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, Manglani MV, Ross C, Young G, Seth T, Apte S, Nayak DM, Santagostino E, Mancuso ME, Sandoval Gonzalez AC, MahlanguJN, Bonanad Boix S, Cerqueira M, Ewing NP, Male C, Owaidah T, Soto Arellano V, Kobrinsky NL, Majumdar S, Perez Garrido R, Sachdeva A, Simpson M, Thomas M, Zanon E, Antmen B, Kavakli K, Manco-Johnson MJ, Martinez M, Marzouka E, Mazzucconi MG, Neme D, Palomo Bravo A, Paredes Aguilera R, Prezotti A, Schmitt K, Wicklund BM, Zulfikar B, Rosendaal FR. A randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. New Engl J Med 2016;374(21):2054-2064.

Ruiz-Saez A, Boadas A, Echenagucia M, Castro-Mendez J. Risk factors associatedd with hightitre inhibitors development in previously untreated hemophilia A patients (PUPS-HA) born between 2000 and 2013: a single center experience. WFH 2016 Con- gress Abstracts, Orlando, Florida. Haemophilia 2016; 22 Suppl 4 P65

Liesner RJ, Abashidze M, Aleinikova O, Altisent C, Belletrutti MJ, Borel-Derlon A, Carcao M, Chambost H, Chan AKC, Dubey L, Ducore J, Fouzia NA, Gattens M, Gruel Y, Guillet B, Kavardakova N, El Khorassani M, Klukowska A, Lambert T, Lohade S, Sigaud M, Turea V, Wu JKM, Vdovin V, Pavlova A, Jansen M, Belyanskaya L, Walter O, Knaub S, Neufeld EJ. Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study. Haemophilia 2018;24(2):211-220.

Königs C, Ozelo MC, Dunn A, Kulkarni R, Nolan B, Brown SA. Final Results of PUPs A-LONG Study: Evaluating Safety and Efficacy of rFVIIIFc in Previously Untreated Patients with Haemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl1). https://abstracts.isth.org/abstract/final-results-of-pups-a-long-study-evaluating-safety-and-efficacy-of-rfviiifc-in-previously- untreated-patients-with-haemophilia-a/. Accessed September 4, 2020.

Lai J, Hough C, Tarrant J, Lillicrap D. Biological considerations of plasma-derived and recombinant factor VIII immunogenicity. Blood 2017 ;129(24):3147-3154.

WHO Hereditary Diseases Programme. Report of a Joint WHO/WFH Meeting on the Possibilities for the Prevention and Control of Haemophilia, Geneva, 26-28 March 1990. Geneva Switzerland: World Health Orhanization; 1990. https://apps.who.int/ iris/handle/10665/60986. Accessed 3 de septiembre de 2020

Colvin BT, Astermark J, Fischer K, Gringeri A, Lassila R, Schramm W, Thomas A, Ingerslev J; Inter Disciplinary Working Group. European principles of haemophilia care. Haemophilia 2008;14(2):361-374.

Boadas A, Ozelo MC, Solano M, Berges A, Ruiz-Saez A, Linares A, Lamas JL, Aparicio R, Aversa L, Baques A, Estrada A, Herrejon M, Mancia A, Nieves-Paulino R, Pinto I, Prezoti A, Soto V, Ugalde D. Haemophilia care in Latin America: assessment and perspectives. Haemophilia 2018;24(6):e395-e401.

Fischer K, Collins PW, Ozelo MC, Srivastava A, Young G, Blanchette VS. When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 2016;14(5):1105-1109.

Poonnoose P, Carneiro JDA, Cruickshank AL, El Ekiaby M, Perez Bianco RP, Ozelo MC, De Bosch N, Baghaipour M, Tien SL, Chuansumrit A, D’Amico EA, van Zyl A, Sabour A, Candela M, Ricciardi JBS, Ruiz- Sàez A, Ravanbod R, Lam JCL, Jaovisidha S, Kavitha ML, Gibikote S, Shyamkumar N, Srivastava A; MUSFIH Study group. Episodic replacement of clotting factor concentrates does not prevent bleeding or musculoskeletal damage - the MUSFIH study. Haemophilia 2017;23(4):538-546.

Swystun LL, Ogiwara K, Rawley O, Brown C, Georgescu I, Hopman W, Labarque V, Male C, Thom K, Blanchette VS, Carcao MD, Lillicrap D. Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients. Blood 2019;134(11):880- 891.

Collins PW, Fischer K, Morfini M, Blanchette VS, Björkman S; International Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of hae- mophilia. Haemophilia 2011;17(1):2-10.

Iorio A, Blanchette V, Blatny J, Collins P, Fischer K, Neufeld E. Estimating and interpreting the pharmacokinetic profiles of individual patients with hemophilia A or B using a population pharmaco- kinetic approach: communication from the SSC of the ISTH. J Thromb Haemost 2017;15(12):2461-2465.

Ozelo MC, Villaça PR, Pérez-Bianco R, Candela M, Garcia-Chavez J, Moreno- Rodriguez B, Rodrigues MB, Rodriguez- Grecco I, Solano MH, Chumpitaz G, Morales-Gana MM, Ruiz-Sáez A. Musculos- keletal evaluation in severe haemophilia A patients from Latin America. Haemophilia 2014;20(1):e63-70.

Gouider E, Jouini L, Achour M, Elmahmoudi H, Zahra K, Saied W, Meddeb B. Low dose prophylaxis in Tunisian children with haemophilia. Haemophilia 2017;23(1):77-81.

Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015;125(13):2038-2044.

Buckley B, Dreyfus J, Prasad M, Gayle J, Kendter J, Hall E 2nd. Burden of illness and costs among paediatric haemophilia patients with and without central venous access devices treated in US hospitals. Haemophilia 2018;24(3):e93-e102

Carcao M, Lambert T, Leissinger C, Escuriola-Ettingshausen C, Santagostino E, Aledort L; International Prophylaxis Study Group (IPSG). Prophylaxis revisited: The potential impact of novel factor and non-factor therapies on prophylaxis. Haemophilia 2018;24(6):845-848.

Peyvandi F, Garagiola I. Treatment of hemophilia in the near future. Semin Thromb Hemost 2015;41(8):838-848.

Powell JS. Lasting power of new clotting proteins. Hematology Am Soc Hematol Educ Program 2014(1):355-363.

Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, Hanabusa H, Gupta N, Kulkarni R, Fogarty P, Perry D, Shapiro A, Pasi KJ, Apte S, Nestorov I, Jiang H, Li S, Neelakantan S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Dodd N, Nugent K, Vigliani G, Luk A, Brennan A, Pierce GF; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014;123(3):317-325.

Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, Barnes C, Neelakantan S, Gambino G, Cristiano LM, Pierce GF, Allen G. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia J Thromb Haemost 2015(6):967-977.

Nolan B, Mahlangu J, Perry D, Young G, Liesner R, Konkle B, Rangarajan S, Brown S, Hanabusa H, Pasi KJ, Pabinger I, Jackson S, Cristiano LM, Li X, Pierce GF, Allen G. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIII- Fc) in subjects with haemophilia A. Haemophilia 2016;22(1):72-80.

Ruiz-Saez A, Boadas A, Echenagucia M. Use of extended half-life rFVIIIFc or rFIXFc in previously treated patients with haemophilia A or B. A single centre experience. Haemophilia 2019,25, S1 p50. 12th Annual Congress of the European Association for Haemophilia and Allied Disorders, 2019. Prague Czech Republic. https://www.clinicaltrials.gov/ct2/show/ NCT04303559

Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, Josephson NC, Perry D, Manco-Johnson MJ, Apte S, Baker RI, Chan GC, Novitzky N, Wong RS, Krassova S, Allen G, Jiang H, Innes A, Li S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Nugent K, Vigliani G, Brennan A, Luk A, Pierce GF; 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.

Fischer K, Kulkarni R, Nolan B, Mahlangu J, Rangarajan S, Gambino G, Diao L, Ramirez-Santiago A, Pierce GF, Allen G. Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B- LONG): results from a multicentre, non- randomised phase 3 study. The Lancet Haematol 2017.; 4(2), e75–e82.

Pasi KJ, Fischer K, Ragni M, Kulkarni R, Ozelo MC, Mahlangu J, Shapiro A, P’Ng S, Chambost H, Nolan B, Bennett C, Matsushita T, Winding B, Fruebis J, Yuan H, Rudin D, Oldenburg J. Long-term safety and sustained efficacy for up to 5 years of treatment with recombinant factor IX Fc fusion protein in subjects with haemophilia B: Results from the B-YOND extension study. Haemophilia 2020;June 4. doi: 10.1111/ hae.14036.

Nolan B, Klukowska A, Shapiro A, Rauch A, Recht M, Ragni M. Final Results of PUPs B-LONG Study: Evaluating Safety and Efficacy of rFIXFc in Previously Untreated Patients with Haemophilia B [abstract]. Res Pract Thromb Haemost 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/final- results-of-pups-b-long-study-evaluating- safety-and-efficacy-of-rfixfc-in-previously- untreated-patients-with-haemophilia-b/. Accessed September 3, 2020.

Meeks SL, Lacroix-Desmazes S. Emerging benefits of Fc fusion technology in the context of recombinant factor VIII replacement therapy. Haemophilia 2020; Sep 3. doi: 10.1111/hae.14123.

Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger I, von Depka Prondzinski M, Altisent C, Castaman G, Yamamoto K, Álvarez-Roman MT, Voigt C, Blackman N, Jacobs I; PRO- LONG-9FP Investigators Study Group. Long-acting recombinant coagulation fac- tor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127(14):1761-1769.

Kenet G, Chambost H, Male C, Lambert T, Halimeh S, Chernova T, Mancuso ME, Curtin J, Voigt C, Li Y, Jacobs I, Santagostino E; PROLONG-9FP Investigator Study Group. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Results of a phase 3 trial. Thromb Haemost 2016;116(4):659-668.

Kenet G, Chambost H, Male C, Halimeh S, Lambert T, Li Y, Seifert W, Santagostino E. Long-term safety and efficacy of recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in previously treated pediatric patients with Hemophilia B: results from a Phase 3b Extension Study. Thromb Haemost 2020;120(4):599-606.

Konkle BA, Stasyshyn O, Chowdary P, Bevan DH, Mant T, Shima M, Engl W, Dyck-Jones J, Fuerlinger M, Patrone L, Ewenstein B, Abbuehl B. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015;126(9):1078-1085.

Mullins ES, Stasyshyn O, Alvarez-Román MT, Osman D, Liesner R, Engl W, Sharkhawy M, Abbuehl BE. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia 2017;23(2):238-246.

Reding MT, Ng HJ, Poulsen LH, Eyster ME, Pabinger I, Shin HJ, Walsch R, Lederman M, Wang M, Hardtke M, Michaels LA. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost 2017;15(3):411-419.

Lalezari S, Reding MT, Pabinger I, Holme PA, Negrier C, Chalasani P, Shin HJ, Wang M, Tseneklidou-Stoeter D, Maas Enriquez M. BAY 94-9027 prophylaxis is efficacious and well tolerated for up to>5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia 2019;25(6):1011-1019.

Giangrande P, Andreeva T, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FW, Lentz SR, Nemes L, Poulsen LH, Santagostino E, You CW, Clausen WH, Jönsson PG, Oldenburg J; Pathfinder™2 Investigators. Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A. Thromb Haemost 2017; 117(2):252-261.

Curry N, Albayrak C, Escobar M, Andre Holme P, Kearney S, Klamroth R, Misgav M, Négrier C, Wheeler A, Santagostino E, Shima M, Landorph A, Tønder SM, Lentz SR. Once-weekly prophylaxis with glycoPE- Gylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial). Haemophilia 2019;25(3):373-381.

Meunier S, Alamelu J, Ehrenforth S, Hanabusa H, Abdul Karim F, Kavakli K, Khodaie M, Staber J, Stasyshyn O, Yee DL, Rageliene L. Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A. Thromb Haemost 2017;117(9):1705-1713.

Negrier C, Knobe K, Tiede A, Giangran- de P, Møss J. Enhanced pharmacokinetic properties of a glycoPEGylated re-combinant factor IX: a first human dose trial in patients with hemophilia B. Blood 2011;118(10):2695-2701.

Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, Gürsel T, Mahlangu J, Matsushita T, Mauser-Bunschoten EP, Oldenburg J, Walsh CE, Negrier C; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124(26):3880-3886.

Carcao M, Zak M, Abdul Karim F, Hanabusa H, Kearney S, Lu MY, Persson P, Rangarajan S, Santagostino E. Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial. J Thromb Haemost 2016;14(8):1521-1529.

Santagostino E, Kenet G, Fischer K, Biss T, Ahuja S, Steele M. PROTECT VIII Kids: BAY 94-9027 (PEGylated Recombinant Factor VIII) safety and efficacy in previously treated children with severe haemophilia Haemophilia 2020;26(3):e55-e65. doi: 10.1111/hae.13963. Epub 2020 Mar 25.

Morfini M. Simoctocog alfa for the treatment of hemophilia A. Expert Opin Biol Ther 2017;17(12):1573-1580.

Tiede A, Oldenburg J, Lissitchkov T, Knaub S, Bichler J, Manco-Johnson MJ. Prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII) in adults with severe haemophilia A. Haemophilia 2016;22(3):374-380.

Klukowska A, Szczepański T, Vdovin V, Knaub S, Bichler J, Jansen M, Dzhunova I, Liesner RJ. Long-term tolerability, immunogenicity and efficacy of Nuwiq® (human- cl rhFVIII) in children with severe haemophilia A. Haemophilia 2018;24(4):595-603.

Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, Skotnicki A, Boggio LN, Klamroth R, Oldenburg J, Hellmann A, Santagostino E, Baker RI, Fischer K, Gill JC, P’Ng S, Chowdary P, Escobar MA, Khayat CD, Rusen L, Bensen-Kennedy D, Blackman N, Limsakun T, Veldman A, St Ledger K, Pabinger I; AFFINITY Investigators. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood 2016;128(5):630-637.

Stasyshyn O, Djambas Khayat C, Iosava G, Ong J, Abdul Karim F, Fischer K, Veldman A, Blackman N, St Ledger K, Pabinger I. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial. J Thromb Haemost 2017;15(4):636-644.

Seth Chhabra E, Liu T, Kulman J, Patarroyo-White S, Yang B, Lu Q, Drager D, Moore N, Liu J, Holthaus AM, Sommer JM, Ismail A, Rabinovich D, Liu Z, van der Flier A, Goodman A, Furcht C, Tie M, Carlage T, Mauldin R, Dobrowsky TM, Liu Z, Mercury O, Zhu L, Mei B, Schellenberger V, Jiang H, Pierce GF, Salas J, Peters R. BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood 2020;135(17):1484-1496.

Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Po- loskey S, Rice K, Katragadda S, Fruebis J, Benson CC. BIVV001 fusion protein as fac- tor VIII replacement therapy for Hemophilia A. N Engl J Med 2020;383(11):1018-1027.

Kitazawa T, Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity. Int J Hematol 2020;111(1):20- 30.

Shima M, Sidonio RF Jr. Substitution therapy. Haemophilia. 2020; Jun 19. doi: 10.1111/hae.14072. Epub ahead of print. Ferrière S, Peyron I, Christophe OD, Kawecki C, Casari C, Muczynski V, Nathwani A, Kauskot A, Lenting PJ, Denis CV. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood 2020 ;136(6):740-748.

Shima M. Bispecific antibodies and advances in non-gene therapy options in hemophilia. Res Pract Thromb Haemost 2020; 28(4):446-454. doi: 10.1002/rth2.12337.

Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab prophylaxis in Hemophilia A with inhibitors. N Engl J Med 2017;377(9):809-818.

Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134(24):2127-2138.

Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, Schmitt C, Jiménez-Yuste V, Kempton C, Dhalluin C, Callaghan MU, Bujan W, Shima M, Adamkewicz JI, Asikanius E, Levy GG, Kruse-Jarres R. Emicizumab prophylaxis in patients who have Hemophilia A without inhibitors. N Engl J Med 2018;379(9):811-822.

Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jiménez-Yuste V. Efficacy, safety, and pharmaco- kinetics 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(6):e295-e305.

Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, Suzuki T, Taki M. A multicentre, open-label study of emici- zumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25(6):979-987. doi: 10.1111/hae.13848. Epub 2019 Sep 12.

Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017; 130(23): 2463–2468.

Samuelson Bannow B, Recht M, Négrier C, Hermans C, Berntorp E, Eichler H, Mancuso ME, Klamroth R, O’Hara J, Santagostino E, Matsushita T, Kessler C. Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev 2019;35:43-50.

Shima M. Bispecific antibodies and advances in non-gene therapy options in Hemophilia. Res Pract Thromb Haemost 2020;4(4):446-454.

Harkins Druzgal C, Kizilocak H, Brown J, Sennett M, Young G. Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: New case with detailed laboratory evaluation [published online ahead of print, 2020 Jun 16]. J Thromb Haemost. 2020;10.1111/ jth.14957. doi:10.1111/jth.14957

Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: The story so far. J Thromb Haemost 2019;17(8):1269-1272.

Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, Austin S, Hay CR, Hegemann I, Kazmi R, Chowdary P, Gercheva-Kyuchukova L, Mamonov V, Timofeeva M, Soh CH, Garg P, Vaishnaw A, Akinc A, Sørensen B, Ragni MV. Targeting of antithrombin in Hemophilia A or B with RNAi therapy. N Engl J Med 2017;377(9):819-828.

Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jiménez-Yuste V, Hyseni A, Friedrich U, Chowdary P. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. J Thromb Haemost. 2018;16(11):2184-2195.

Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, Eichler H, Jiménez-Yuste V, Kavakli K, Matsushita T, Poulsen LH, Wheeler AP, Young G, Zupancic-Salek S, Oldenburg J. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019;134(22):1973-1982.

Patel-Hett S, Martin EJ, Mohammed BM, Rakhe S, Sun P, Barrett JC, Nolte ME, Kuhn J, Pittman DD, Murphy JE, Brophy DF. Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. Haemophilia 2019;25(5):797-806.

Meeks SL & Leissinger CA. The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors. Haemophilia 2019; 25(6), 911–918.

Gruppo RA, Malan D, Kapocsi J, Nemes L, Hay CRM, Boggio L, Chowdary P, Tagariello G, von Drygalski A, Hua F, Scaramozza M, Arkin S. Marzeptacog alfa (activated) Study Group Investigators. Phase 1, single- dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost 2018;16(10):1984-1993.

Biron-Andreani C, Schved JF. Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors. Expert Rev Hematol 2019;12(1):21-28.

Ljung R, Auerswald G, Benson G, Dolan G, Duffy A, Hermans C, Jiménez-Yuste V, Lambert T, Morfini M, Zupančić-Šalek S, Santagostino E. Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult- to-treat patients. Eur J Haematol 2019; 102(2), 111–122.

Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012;119(6):1335-1344.

Collins P, Chalmers E, Alamelu J, Hay C, Liesner R, Makris M, Mathias M, Payne J, Rangarajan S, Richards M, Talks K, Tunstall O, Williams M, Hart DP. First-line im- mune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors’ Organisation Inhibitor and Paediatric Working Parties. Haemophilia 2017;23(5):654-659.

Carcao M, Escuriola-Ettingshausen C, Santagostino E, Oldenburg J, Liesner R, Nolan B, Bátorová A, Haya S, Young G; Future of Immunotolerance Treatment Group. The changing face of immune to- lerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019;25(4):676-684.

Pipe SW. Delivering on the promise of gene therapy for haemophilia. Haemophilia 2020 Jun 3. doi: 10.1111/hae.14027. Epub ahead of print. Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med 2020;382(1):29-40.

Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Ts- chakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371(21):1994- 2004.

George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA. Hemophilia B gene therapy with a high- specific-avtivity Factor IX variant. N Engl J Med 2017;377(23):2215-2227.

Von Drygalski A, Giermasz A, Castaman G, Key NS, Lattimore S, Leebeek FWG, Miesbach W, Recht M, Long A, Gut R, Sawyer EK, Pipe SW. Etranacogene deza- parvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv 2019;3(21):3241- 3247.

Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia 2019;25(5):738-746.

Pierce GF, Kaczmarek R, Noone D, O’Mahony B, Page D, Skinner MW. Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor? Haemophilia 2020 Sep 10. doi: 10.1111/ hae.14131. Epub ahead of print. http://fdaaa.trialstracker.net/trial/ NCT03370913/

Stonebraker JS, Bolton-Maggs PHB, Brooker M, Evatt B, Iorio A, Makris M, O’Mahony B, Skinner MW, Coffin D, Pierce GF, Tootoonchian E. The World Federation of Hemophilia Annual Global Survey 1999- 2018. Haemophilia 2020;26(4):591-600.

Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jiménez-Yuste V. Efficacy, safety, and pharmaco- kinetics 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(6):e295-e305.

Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, Suzuki T, Taki M. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25(6):979-987. doi: 10.1111/hae.13848. Epub 2019 Sep 12.