Safety evaluation of emicizumab prophylaxis in individuals with haemophilia A

References

• Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood. 2015;125(13):2038–2044.
   PubMed Web of Science ®Google Scholar
• Thornburg CD, Duncan NA. Treatment adherence in hemophilia. Patient Prefer Adherence. 2017;11:1677–1686.
   PubMed Web of Science ®Google Scholar
• Gringeri A. Factor VIII safety: plasma-derived versus recombinant products. Blood Transfus. 2011;9(4):366–370.
   PubMed Web of Science ®Google Scholar
• Franchini M. The modern treatment of haemophilia: a narrative review. Blood Transfusion. 2013;11(2):178.
   PubMed Web of Science ®Google Scholar
• Franchini M. Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: recombinant is better. Blood Transfus. 2010;8(4):292–296.
   PubMedGoogle Scholar
• Blanchette VS, Shapiro AD, Liesner RJ, et al. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost. 2008;6(8):1319–1326.
   PubMed Web of Science ®Google Scholar
• Négrier C, Shapiro A, Berntorp E, et al. Surgical evaluation of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of advate in previously treated patients. Thromb Haemost. 2008;100(2):217–223.
   PubMed Web of Science ®Google Scholar
• Chowdary P, Fosbury E, Riddell A, et al. Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate®) in hemophilia A. J Blood Med. 2016;7:187–198.
   PubMed Web of Science ®Google Scholar
• Ducore JM, Miguelino MG, Powell JS. Alprolix (recombinant Factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B. Expert Rev Hematol. 2014;7(5):559–571.
   PubMed Web of Science ®Google Scholar
• Suzuki T, Ishii-Watabe A, Tada M, et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010;184(4):1968–1976.
   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.
   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;369(24):2313–2323.
   PubMed Web of Science ®Google Scholar
• Meeks SL, Batsuli G. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches. Hematology Am Soc Hematol Educ Program. 2016;2016(1):657–662.
   PubMedGoogle Scholar
• Eckhardt CL, Van Velzen AS, Peters M, et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013;122(11):1954–1962.
   PubMed Web of Science ®Google Scholar
• Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia. 2002;8(3):280–287.
   PubMed Web of Science ®Google Scholar
• Rocha P, Carvalho M, Lopes M, et al. Costs and utilization of treatment in patients with hemophilia. BMC Health Serv Res. 2015;15(1):484.
   PubMedGoogle Scholar
• Valentino LA, Pipe SW, Tarantino MD, et al. Healthcare resource utilization among haemophilia A patients in the United States. Haemophilia. 2012;18(3):332–338.
   PubMed Web of Science ®Google Scholar
• Shapiro AD, Hedner U. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes. Ther Adv Drug Saf. 2011;2(5):213–225.
   PubMedGoogle Scholar
• Knight T, Callaghan MU. The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A. Ther Adv Hematol. 2018;9(10):319–334.
   PubMed Web of Science ®Google Scholar
• 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.
   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.
   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;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;379(9): 811–822.
   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;6(6): e295–e305.
   PubMed Web of Science ®Google Scholar
• Franchini M, Marano G, Pati I, et al. Emicizumab for the treatment of haemophilia A: a narrative review. Blood Transfus. 2019;17(3):223–228.
   PubMed Web of Science ®Google Scholar
• Yada K, Nogami K. Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations. J Blood Med. 2019;10:171–181.
   PubMed Web of Science ®Google Scholar
• Mahlangu J, Oldenburg J, Callaghan MU, et al. Health-related quality of life and health status in persons with haemophilia A with inhibitors: a prospective, multicentre, non-interventional study (NIS). Haemophilia. 2019;25(3):382–391.
   PubMed Web of Science ®Google Scholar
• Young G, Sidonio RF, Liesner R, et al. HAVEN 2 updated analysis: multicenter, open-label, phase 3 study to evaluate efficacy, safety and pharmacokinetics of subcutaneous administration of emicizumab prophylaxis in pediatric patients with hemophilia A with inhibitors. Blood. 2017;130(Supplement 1):85.
   Google Scholar
• Mancuso ME, Mahlangu J, Sidonio R, et al. Health-related quality of life and caregiver burden of emicizumab in children with haemophilia A and factor VIII inhibitors—results from the HAVEN 2 study. Haemophilia. 2020;26(6):1009–1018.
   Google Scholar
• Rodriguez-Merchan EC, Valentino LA. Emicizumab: review of the literature and critical appraisal. Haemophilia. 2019;25(1):11–20.
   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.
   PubMed Web of Science ®Google Scholar
• Levy GG, Asikanius E, Kuebler P, et al. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: experience from the HAVEN clinical program. J Thromb Haemost. 2019;17(9):1470–1477.
   PubMed Web of Science ®Google Scholar
• Hartmann R, Feenstra T, Valentino L, et al., In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost. 2018;16(8): 1580–1591.
   Web of Science ®Google Scholar
• Castaman G. The role of recombinant activated factor VII in the haematological management of elective orthopaedic surgery in haemophilia A patients with inhibitors. Blood Transfus. 2017;15(5):478–486.
   PubMed Web of Science ®Google Scholar
• Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol. 2008;3(1):249–277.
   PubMedGoogle Scholar
• Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ. 2017;189(4):E153–E159. E153-E159.
   PubMed Web of Science ®Google Scholar
• Khoo L, Matthews S, Kershaw G, et al. Case report of a fatal rectal haemorrhage in a person with severe haemophilia A receiving emicizumab and high-dose bypassing agents in the HAVEN 1 study. Haemophilia. 2020 July 22;26(6). Published online. DOI: 10.1111/hae.14110
   Web of Science ®Google Scholar
• Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: the story so far. J Thromb Haemost. 2019;17(8):1269–1272.
   PubMed Web of Science ®Google Scholar
• Adamkewicz J, Muto A, Soeda T, et al. In vitro thrombin generation testing and in vivo venous stasis model for assessing the pro-coagulant effects of FVIII, emicizumab, rFVIIa, and aPCC. Haemophilia. 2017;23(Suppl S2):OR37–OR37.
   Google Scholar
• Weyand AC, Dorfman AL, Shavit JA, et al. Emicizumab prophylaxis to facilitate anticoagulant therapy for management of intra‐atrial thrombosis in severe haemophilia with an inhibitor. Haemophilia. 2019;25(3):3.
   Web of Science ®Google Scholar
• George NB, Paschke A, Scott K. Central line-associated thrombus formation in an inhibitor negative severe hemophilia A patient on Emicizumab. Blood. 2019;134(Supplement_1):4938.
   Google Scholar
• Gundabolu K, Goldsweig A, Bhatt VR, et al. ST-Segment Elevation Myocardial Infarction (STEMI) and pulmonary embolism in a hemophilia A patient receiving Emicizumab and recombinant activated Factor VII. Haemophilia. 2020;26(1):e5–e8.
   PubMed Web of Science ®Google Scholar
• Lee L, Moreno K, Kuebler P, et al. Summary of thromboembolic (TE) or thrombotic microangiopathy (TMA) events in persons taking emicizumab. Haemophilia. 2020;26:131.
   Web of Science ®Google Scholar
• Wall C, Hall G, Collins P, et al. Adverse event reporting in haemophilia A patients with and without inhibitors treated with emicizumab: a report from the co-morbidity working party of the UK Haemophilia Centres Doctors’ Organisation (UKHCD). Res Pract Thromb Haemost. 2020;4(Suppl 1):0962.
   Google Scholar
• Krishna M, Nadler SG. Immunogenicity to biotherapeutics – the role of anti-drug immune complexes. Front Immunol. 2016;7:7.
   PubMed Web of Science ®Google Scholar
• Davda J, Declerck P, Hu-Lieskovan S, et al. Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer. 2019;7(1):105.
   PubMedGoogle Scholar
• Van Brummelen EMJ, Ros W, Wolbink G, et al. Antidrug antibody formation in oncology: clinical relevance and challenges. Oncologist. 2016;21(10):1260–1268.
   PubMed Web of Science ®Google Scholar
• Vultaggio A, Nencini F, Pratesi S, et al. Manifestations of antidrug antibodies response: hypersensitivity and infusion reactions. J Interferon Cytokine Res. 2014;34(12):946–952.
   PubMed Web of Science ®Google Scholar
• Gunn GR, Sealey DCF, Jamali F, et al. From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals. Clin Exp Immunol. 2016;184(2):137–146.
   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.
   PubMed Web of Science ®Google Scholar
• Paz-Priel I, Chang T, Asikanius E, et al., Immunogenicity of Emicizumab in people with hemophilia A (PwHA): results from the HAVEN 1-4 studies. Blood. 2018;132(Supplement1): 633.
   Google Scholar
• Jani M, Isaacs JD, Morgan AW, et al. Detection of anti-drug antibodies using a bridging ELISA compared with radioimmunoassay in adalimumab-treated rheumatoid arthritis patients with random drug levels. Rheumatology (Oxford). 2016;55(11):2050–2055.
   PubMed Web of Science ®Google Scholar
• Ubah OC, Porter AJ, Barelle CJ. In Vitro ELISA and Cell-based assays confirm the low immunogenicity of VNAR therapeutic constructs in a mouse model of human RA: an encouraging milestone to further clinical drug development. J Immunol Res. 2020;2020:2020.
   Web of Science ®Google Scholar
• Hock BD, Stamp LK, Hayman MW, et al. Development of an ELISA-based competitive binding assay for the analysis of drug concentration and antidrug antibody levels in patients receiving adalimumab or infliximab. Ther Drug Monit. 2016;38(1):32–41. .
   PubMed Web of Science ®Google Scholar
• Harkins Druzgal C, Kizilocak H, Brown J, et al. Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: new case with detailed laboratory evaluation. J Thromb Haemost. 2020 June 16;18(9):2205–2208. Published online.
   PubMed Web of Science ®Google Scholar
• Chehade H, Cachat F, Beck-Popovic M, et al. Emicizumab-induced seronegative full-house lupus nephritis in a child. Pediatrics. 2020;146(5):e20200123.
   PubMed Web of Science ®Google Scholar
• Emicizumab Info. Genentech. South San Francisco, CA: Genentech USA; 2020. [Last accessed 2020 Sept 30. Available at https://www.emicizumabinfo.global/us/en/homepage.html
   Google Scholar
• De Ford C, Kuebler P, Shang A, et al. An analysis of fatalities in persons with congenital hemophilia A reported in the FDA Adverse Event Reporting System (FAERS) database. Presented at the National Hemophilia Foundation Virtual Conference; August 1–8, 2020. NHF Poster #25.
   Google Scholar
• Adverse Events FDA. Reporting System (FAERS) Public Dashboard - FDA Adverse Events Reporting System (FAERS) Public Dashboard | sheets - Qlik Sense. In: US Food and Drug Administration. Silver Spring, MD: US FDA; 2020. [Last accessed 2020 Sept 30. Available at: https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis
   Google Scholar
• Recommendation on the Use and Management of Emicizumab-kxwh (Hemlibra®) for Hemophilia A with and without Inhibitors. National hemophilia foundation. New York, NY: National Hemophilia Foundation; 2020. [[Last accessed 2020 Oct 19]. Available at: https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/Recommendation-on-the-Use-and-Management-of-Emicizumab-kxwh-Hemlibra-for-Hemophilia-A-with-and-without-Inhibitors.
   Google Scholar
• Collins PW, Liesner R, Makris M, et al. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO inhibitor working party and executive committee. Haemophilia. 2018;24(3):344–347.
   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.
   PubMed Web of Science ®Google Scholar
• Hemlibra Highlights of Prescribing Information. US food and drug administration. Silver Spring, MD: US FDA; 2017. [Last accessed 2020 Oct 19. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf
   Google Scholar
• Shapiro AD, Neufeld EJ, Blanchette V, et al. Safety of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors: overall rFVIIa exposure and intervals following high (>240 μg kg−1) rFVIIa doses across clinical trials and registries. Haemophilia. 2014;20(1):e23–31.
   PubMed Web of Science ®Google Scholar
• Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost. 2004;2(6):899–909.
   PubMed Web of Science ®Google Scholar
• Abshire T, Kenet G. Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitors. Haemophilia. 2008;14(5):898–902.
   PubMed Web of Science ®Google Scholar
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program | FDA. US food and drug administration. Silver Spring, MD: US FDA; 2020. [Last accessed 2020 Oct 19. Available at https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program
   Google Scholar
• ATHN 7: Hemophilia Natural History Study - Full Text View - ClinicalTrials.gov. National Library of Medicine. Bethesda, MD: U.S. National Library of Medicine; 2020. [Last accessed 2020 Oct 19. Available at https://clinicaltrials.gov/ct2/show/NCT03619863
   Google Scholar
• Roche H-L. A randomized, multicenter, open-label, phase III clinical trial to evaluate the efficacy, safety, and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in hemophilia A patients. In: National Library of Medicine. Bethesda, MD: U.S. National Library of Medicine; 2020. [Last accessed 2020 Sept 27. Available at: https://clinicaltrials.gov/ct2/show/NCT03315455
   Google Scholar
• Roche H-L. A multicenter, open-label study to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in patients with mild or moderate hemophilia A without FVIII inhibitors. In: National Library of Medicine. Bethesda, MD: U.S. National Library of Medicine; 2020. [Last accessed 2020 Sept 27. Available at: https://clinicaltrials.gov/ct2/show/NCT04158648
   Google Scholar
• Roche H-L. A phase IIIb, multicenter, open-label, single-arm study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of subcutaneous emicizumab in patients from birth to 12 months of age with hemophilia A without inhibitors. In: National Library of Medicine. Bethesda, MD: U.S. National Library of Medicine; 2020. [Last accessed 2020 Sept 27. Available at: https://clinicaltrials.gov/ct2/show/NCT04431726
   Google Scholar
• Skinner MW, Nugent D, Wilton P, et al., Achieving the unimaginable: health equity in haemophilia. Haemophilia. 2020;26(1): 17–24.
   PubMed Web of Science ®Google Scholar
• Nossair F, Thornburg CD. The role of patient and healthcare professionals in the era of new hemophilia treatments in developed and developing countries. Ther Adv Hematol. 2018;9(8):239–249.
   PubMed Web of Science ®Google Scholar