Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations

References

• White GC II, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia: recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85(3):560. doi:10.1055/s-0037-161562111307831
   PubMed Web of Science ®Google Scholar
• Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg. 2004;12(4):234–245.15473675
   PubMed Web of Science ®Google Scholar
• Ferreira AA, Leite IC, Bustamante-Teixeira MT, et al. Health-related quality of life in hemophilia: results of the Hemophilia-Specific Quality of Life Index. (Haem-a-Qol) at a Brazilian blood center. Rev Bras Hematol Hemoter. 2013;35(5):314–318. doi:10.5581/1516-8484.2013010824255613
   PubMedGoogle Scholar
• Nilsson IM, Hedner U, Ahlberg A. Hemophilia prophylaxis in Sweden. Acta Paediatr Scand. 1976;65(2):129–135.1258628
   PubMed Web of Science ®Google Scholar
• 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(6):535–544. doi:10.1056/NEJMoa06765917687129
   PubMed Web of Science ®Google Scholar
• De Moerloose P, Urbancik W, Van Den Berg HM, et al. A survey of adherence to haemophilia therapy in six European countries: results and recommendations. Haemophilia. 2008;14(5):931–938. doi:10.1111/j.1365-2516.2008.01843.x18684125
   PubMed Web of Science ®Google Scholar
• van Os SB, Troop NA, Sullivan KR, Hart DP. Adherence to prophylaxis in adolescents and young adults with severe haemophilia: a quantitative study with patients. PLoS One. 2017;12(1):e0169880. doi:10.1371/journal.pone.016988028103266
   PubMed Web of Science ®Google Scholar
• KyngAÈ s HA, Kroll T, Duffy ME. Compliance in adolescents with chronic diseases: a review. J Adolesc Health. 2000;26(6):379–388.10822178
   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;123(3):317–325. doi:10.1182/blood-2013-10-52997424227821
   PubMed Web of Science ®Google Scholar
• Coyle TE, Reding MT, Lin JC, Michaels LA, Shah A, Powell J. 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(4):488–496.24843882
   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):S29–38.22961422
   PubMed Web of Science ®Google Scholar
• Stennicke HR, Kjalke M, Karpf DM, et al. A novel B-domain O-glyco PEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood. 2013;121(11):2108–2116. doi:10.1182/blood-2012-01-40749423335368
   PubMed Web of Science ®Google Scholar
• Coppola A, Franchini M, Castaman G, et al. Treatment regimens with bypassing agents in patients with hemophilia A and inhibitors: a survey from the Italian Association of Hemophilia Centers (AICE). Semin Thromb Hemost. 2018;44(6):551–560. doi:10.1055/s-0038-164823029723892
   PubMed Web of Science ®Google Scholar
• Walsh CE, Jiménez-Yuste V, Auerswald G, et al. The burden of inhibitors in haemophilia patients. Thromb Haemost. 2016;116(Suppl 1):S10–S17. doi:10.1160/TH16-01-004927528280
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1182/blood-2011-08-36913222101900
   PubMed Web of Science ®Google Scholar
• Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011;365(18):1684–1692. doi:10.1056/NEJMoa110443522047559
   PubMed Web of Science ®Google Scholar
• Rodriguez V, Mancuso ME, Warad D, et al. Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: lessons from the international immune tolerance study. Haemophilia. 2015;21(5):e369–e374. doi:10.1111/hae.1274026178581
   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;18(10):1570–1574. doi:10.1038/nm.294223023498
   PubMed Web of Science ®Google Scholar
• 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(2):e57479. doi:10.1371/journal.pone.005747923468998
   PubMed Web of Science ®Google Scholar
• Kitazawa T, Esaki K, Tachibana T, et al. Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens. Thromb Haemost. 2017;117(7):1348–1357. doi:10.1160/TH17-01-003028451690
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1182/blood-2015-06-65022626626991
   PubMed Web of Science ®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;374(21):2044–2053. doi:10.1056/NEJMoa151176927223146
   PubMed Web of Science ®Google Scholar
• Shima M, Hanabusa H, Taki M, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv. 2017;1(22):1891–1899. doi:10.1182/bloodadvances.201700668429296836
   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;377(9):809–818. doi:10.1056/NEJMoa170306828691557
   PubMed Web of Science ®Google Scholar
• 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(5):743–754. doi:10.1111/jth.1286425641556
   PubMed Web of Science ®Google Scholar
• Eichler H, Angchaisuksiri P, Kavakli K, et al. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. J Thromb Haemost. 2018;16(11):2184–2195. doi:10.1111/jth.1427230137664
   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;377(9):819–828. doi:10.1056/NEJMoa161656928691885
   PubMed Web of Science ®Google Scholar
• Fay PJ. Regulation of factor VIIIa in the intrinsic factor Xase. Thromb Haemost. 1999;82(2):193–200.10605704
   PubMed Web of Science ®Google Scholar
• Minami H, Nogami K, Soeda T, Kitazawa T, Hattori K, Shima M. The factor VIII heavy chain improves emicizumab-tenase assembly to enhance the factor VIII-mimicking cofactor activity. Thromb Res. 2018;166:77–79. doi:10.1016/j.thromres.2018.04.01629684725
   PubMed Web of Science ®Google Scholar
• Yada K, Nogami K, Shinozawa K, et al. Emicizumab-mediated hemostatic function in patients with hemophilia A is down regulated by activated protein C through inactivation of activated factor V. Br J Haematol. 2018;183(2):257–266. doi:10.1111/bjh.1552530125997
   PubMed Web of Science ®Google Scholar
• Noguchi-Sasaki M, Soeda T, Ueyama A, et al. Emicizumab, a bispecific antibody to factors IX/IXa and X/Xa, does not interfere with antithrombin or TFPI activity in vitro. TH Open. 2018;2(1):e96–e103. doi:10.1055/s-0038-163653831249933
   PubMedGoogle Scholar
• Yoneyama K, Schmitt C, Kotani N, et al. A pharmacometric approach to substitute for a conventional dose-finding study in rare diseases: example of phase III dose selection for emicizumab in hemophilia A. Clin Pharmacokinet. 2018;57(9):1123–1134. doi:10.1007/s40262-017-0616-329214439
   PubMed Web of Science ®Google Scholar
• Young G, Liesner R, Sidonio RF, et al. Emicizumab prophylaxis provides flexible and effective bleed control in children with hemophilia α with inhibitors: results from the HAVEN 2 study. Blood. 2018;132:632.
   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;379(9):811–822. doi:10.1056/NEJMoa180355030157389
   PubMed Web of Science ®Google Scholar
• 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 [Epub ahead of print]. doi:10.1016/S2352-3026(19)30054-7
   Web of Science ®Google Scholar
• Shima M, Nogami K, Nagami S, et al. Every 2 weeks or every 4 weeks subcutaneous injection of emicizumab in pediatric patients with severe hemophilia a without inhibitors: a multi-center, open-label study in Japan (HOHOEMI study). Blood. 2018;132:1186.
   Web of Science ®Google Scholar
• Morfini M, Haya S, Tagariello G, et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia. 2007;13(5):606–612. doi:10.1111/j.1365-2516.2007.01518.x17880451
   PubMed Web of Science ®Google Scholar
• Monahan PE, Baker JR, Riske B, Soucie JM. Physical functioning in boys with hemophilia in the U.S. Am J Prev Med. 2011;41(6 suppl 4):S360–368. doi:10.1016/j.amepre.2011.09.01722099359
   PubMed Web of Science ®Google Scholar
• Walsh CE, Soucie JM, Miller CH; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol. 2015;90(5):400–405. doi:10.1002/ajh.2395725616111
   PubMed Web of Science ®Google Scholar
• Biss TT, Chan AK, Blanchette VS, Iwenofu LN, McLimont M, Carcao MD; Association of Hemophilia ClinicDirectors of Canada (AHCDC) Canadian Association of Nurses in Hemophilia Care (CANHC). Theuse of prophylaxis in 2663 children and adults with haemophilia: results of the 2006 Canadian national haemophilia prophylaxis survey. Haemophilia. 2008;14(5):923–930. doi:10.1111/j.1365-2516.2008.01810.x18637844
   PubMed Web of Science ®Google Scholar
• Ljung R, Lindgren AC, Petrini P, Tengborn L. Normal vaginal delivery is to be recommended for haemophilia carrier gravidae. Acta Paediatr. 1994;83(6):609–611.7919757
   PubMed Web of Science ®Google Scholar
• Klinge J, Auberger K, Auerswald G, Brackmann HH, Mauz-Körholz C, Kreuz W. Prevalence and outcome of intracranial haemorrhage in haemophiliacs – a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr. 1999;158(Suppl 3):S162–S165.10650860
   PubMed Web of Science ®Google Scholar
• Revel-Vilk S, Golomb MR, Achonu C, et al. Effect of intracranial bleeds on the health and quality of life of boys with hemophilia. J Pediatr. 2004;144(4):490–495. doi:10.1016/j.jpeds.2003.12.01615069398
   PubMed Web of Science ®Google Scholar
• Garagiola I, Palla R, Peyvandi F. Risk factors for inhibitor development in severe hemophilia A. Thromb Res. 2018;168:20–27. doi:10.1016/j.thromres.2018.05.02729879570
   PubMed Web of Science ®Google Scholar
• Di Minno MN, Ambrosino P, Franchini M, Coppola A, Di Minno G. Arthropathy inpatients with moderate hemophilia a: a systematic review of the literature. Semin Thromb Hemost. 2013;39(7):723–731. doi:10.1055/s-0033-135442224022804
   PubMed Web of Science ®Google Scholar
• Tiede A. Thromboembolic risks of non-factor replacement therapies in hemophilia. Hamostaseologie. 2017;37(4):307–310. doi:10.5482/2017000429582931
   PubMed Web of Science ®Google Scholar
• Nogami K, Matsumoto T, Tabuchi Y, et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost. 2018;16(6):1078–1088.29645406
   PubMed Web of Science ®Google Scholar
• Dargaud Y, Lienhart A, Janbain M, et al. Use of thrombin generation assay to personalize treatment of breakthrough bleeds in a patient with hemophilia and inhibitors receiving prophylaxis with emicizumab. Haematologica. 2018;103(4):e181–e183. doi:10.3324/haematol.2017.18533029472355
   PubMed Web of Science ®Google Scholar
• Yada K, Nogami K, Kitazawa T, et al. Mode of enhancement in the global hemostatic potentials with concomitant use of bypassing agents and emicizumab in hemophilia A patients with inhibitor evaluated by ROTEM. Res Pract Thromb Haemost. 2017;1(Suppl 1):163–164.
   Google Scholar
• Nogami K, Soeda T, Matsumoto T, Kawabe Y, Kitazawa T, Shima M. Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost. 2018;16(7):1383–1390. doi:10.1111/jth.1413529734520
   PubMed Web of Science ®Google Scholar
• Kruse-Jarres R, Callaghan MU, Croteau SE, et al. Surgical experience in two multicenter, open-label phase 3 studies of emicizumab in persons with hemophilia A with inhibitors (HAVEN 1 and HAVEN 2). Blood. 2017;130(Suppl):89.
   Google Scholar
• Young G. Implementing emicizumab in hemophilia inhibitor management: emicizumab should be prescribed after tolerance. Blood Adv. 2018;2(20):2780–2782. doi:10.1182/bloodadvances.201801584230352951
   PubMed Web of Science ®Google Scholar
• Le Quellec S, Negrier C. Emicizumab should be prescribed independent of immune tolerance induction. Blood Adv. 2018;2(20):2783–2786. doi:10.1182/bloodadvances.201801585930352952
   PubMed Web of Science ®Google Scholar
• Santagostino E, Young G, Escuriola Ettingshausen C, Jimenez-Yuste V, Carcao M. Inhibitors: a need for eradication? Acta Haematol. 2019;141(3):151–155. doi:10.1159/00049545430783066
   PubMed Web of Science ®Google Scholar