Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A

Abstract

Background Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab.

Materials and Methods Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors.

Results TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement.

Conclusion Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Keywords

emicizumab pharmacodynamics - global coagulation assays - non-factor replacement - thrombin generation - fibrin clot formation - fibrin clot structure

Authors' Contribution

D.B.C. and R.M.C. contributed to study design, performed research, collected laboratory data and analyzed results, wrote and critically revised the manuscript; M.G.Z. and A.A. critically revised the manuscript; A.P.B.M.S. coordinated sample and patient data collections and revised critically the manuscript; F.J.G. performed routine laboratory analyses including emicizumab measurements; A.C. contributed to study design, supervised fibrin clot structure and fibrinolytic assays, and critically revised the manuscript; L.A. designed the study, supervised patient treatment, laboratory assays, data analysis, and manuscript writing and revision.

^* D.B.C and R.M.C. share first authorship.

^** A.C. and L.A. share senior authorship.

Publication History

Received: 20 October 2022

Accepted: 01 May 2023

Article published online:
19 June 2023

• References

• 1 Santagostino E, Young G, Carcao M, Mannucci PM, Halimeh S, Austin S. A contemporary look at FVIII inhibitor development: still a great influence on the evolution of hemophilia therapies. Expert Rev Hematol 2018; 11 (02) 87-97
• 2 European Medicines Agency. Assessment report Hemlibra. 2018. EMA/88475/2018. Accessed May 18, 2023 at: https://www.ema.europa.eu/en/documents/assessment-report/hemlibra-epar-public-assessment-report_en.pdf
• 3 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
• 4 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
• 5 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
• 6 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 (09) 811-822
• 7 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 (06) e295-e305
• 8 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
• 9 Levy-Mendelovich S, Brutman-Barazani T, Budnik I. et al. Real-world data on bleeding patterns of hemophilia A patients treated with emicizumab. J Clin Med 2021; 10 (19) 4303
• 10 Lehtinen AE, Lassila R. Do we need all that emicizumab?. Haemophilia 2022; 28 (02) e53-e55
• 11 Adamkewicz JI, Chen DC, Paz-Priel I. Effects and interferences of emicizumab, a humanised bispecific antibody mimicking activated factor VIII cofactor function, on coagulation assays. Thromb Haemost 2019; 119 (07) 1084-1093
• 12 Lenting PJ. Laboratory monitoring of hemophilia A treatments: new challenges. Blood Adv 2020; 4 (09) 2111-2118
• 13 Yada K, Nogami K, Ogiwara K. et al. Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol 2019; 110 (04) 419-430
• 14 Valke LLFG, Beckers EAM, Blijlevens NMA, van Heerde WL, Schols SEM. Effect of emicizumab on thrombin generation: a case report of breakthrough bleeding during emicizumab treatment. Haemophilia 2020; 26 (06) e327-e330
• 15 Kizilocak H, Yukhtman CL, Marquez-Casas E, Lee J, Donkin J, Young G. Management of perioperative hemostasis in a severe hemophilia A patient with inhibitors on emicizumab using global hemostasis assays. Ther Adv Hematol 2019; 10: 2040620719860025
• 16 Kizilocak H, Marquez-Casas E, Phei Wee C, Malvar J, Carmona R, Young G. Comparison of bypassing agents in patients on emicizumab using global hemostasis assays. Haemophilia 2021; 27 (01) 164-172
• 17 Furukawa S, Nogami K, Shimonishi N, Nakajima Y, Matsumoto T, Shima M. Prediction of the haemostatic effects of bypassing therapy using comprehensive coagulation assays in emicizumab prophylaxis-treated haemophilia A patients with inhibitors. Br J Haematol 2020; 190 (05) 727-735
• 18 Dargaud Y, Lienhart A, Janbain M, Le Quellec S, Enjolras N, Negrier C. 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 (04) e181-e183
• 19 Brophy DF, Martin EJ, Kuhn J. Use of global assays to monitor emicizumab prophylactic therapy in patients with haemophilia A with inhibitors. Haemophilia 2019; 25 (02) e121-e123
• 20 Barg AA, Budnik I, Avishai E. et al. Emicizumab prophylaxis: prospective longitudinal real-world follow-up and monitoring. Haemophilia 2021; 27 (03) 383-391
• 21 Barg AA, Livnat T, Budnik I. et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol 2020; 191 (02) 282-290
• 22 Grandoni J, Duretz V, Bonzo D, Evans S, Plantier JL. Exploratory in vitro evaluation of thrombin generation of eptacog beta (recombinant human fviia) and emicizumab in congenital haemophilia A plasma. Haemophilia 2021; 27 (02) 321-328
• 23 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 (06) 1078-1088
• 24 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
• 25 Zong Y, Antovic A, Soutari NMH, Antovic J, Pruner I. Synergistic effect of bypassing agents and sequence identical analogue of emicizumab and fibrin clot structure in the in vitro model of hemophilia A. TH Open 2020; 4 (02) e94-e103
• 26 Shimonishi N, Nogami K, Ogiwara K. et al. Emicizumab improves the stability and structure of fibrin clot derived from factor VIII-deficient plasma, similar to the addition of factor VIII. Haemophilia 2020; 26 (03) e97-e105
• 27 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
• 28 Spronk HM, Dielis AW, Panova-Noeva M. et al. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed?. Thromb Haemost 2009; 101 (06) 1156-1162
• 29 Sinauridze EI, Vuimo TA, Tarandovskiy ID. et al. Thrombodynamics, a new global coagulation test: measurement of heparin efficiency. Talanta 2018; 180: 282-291
• 30 Marchi R, Neerman-Arbez M, Gay V. et al. Comparison of different activators of coagulation by turbidity analysis of hereditary dysfibrinogenemia and controls. Blood Coagul Fibrinolysis 2021; 32 (02) 108-114
• 31 Longstaff C. subcommittee on fibrinolysis. Development of Shiny app tools to simplify and standardize the analysis of hemostasis assay data: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (05) 1044-1046
• 32 Pieters M, Undas A, Marchi R, De Maat MP, Weisel J, Ariëns RA. Factor XIII And Fibrinogen Subcommittee Of The Scientific Standardisation Committee Of The International Society For Thrombosis And Haemostasis. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. J Thromb Haemost 2012; 10 (10) 2179-2181
• 33 Hoffmann-La Roche F. European Commission approves Roche's Hemlibra for people with severe haemophilia A without factor VIII inhibitors. Accessed July 4, 2021 at: https://www.roche.com/media/releases/med-cor-2019-03-14.htm
• 34 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
• 35 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 (09) 1123-1134
• 36 Kizilocak H, Marquez-Casas E, Malvar J, Carmona R, Young G. Determining the approximate factor VIII level of patients with severe haemophilia A on emicizumab using in vivo global haemostasis assays. Haemophilia 2021; 27 (05) 730-735
• 37 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
• 38 Schmitt C, Adamkewicz JI, Xu J. et al. Pharmacokinetics and pharmacodynamics of emicizumab in persons with hemophilia A with factor VIII inhibitors: HAVEN 1 study. Thromb Haemost 2021; 121 (03) 351-360
• 39 Takeyama M, Furukawa S, Onishi T, Noguchi-Sasaki M, Shima M, Nogami K. Heterogeneous coagulant potential of emicizumab in neonatal factor VIII-deficient plasma. Pediatr Blood Cancer 2022; 69 (07) e29731
• 40 Mahlangu J, Iorio A, Kenet G. Emicizumab state-of-the-art update. Haemophilia 2022; 28 (Suppl 4): 103-110
• 41 Oldenburg J, Levy GG. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (22) 2194-2195
• 42 Leksa NC, Aleman MM, Goodman AG, Rabinovich D, Peters R, Salas J. Intrinsic differences between FVIIIa mimetic bispecific antibodies and FVIII prevent assignment of FVIII-equivalence. J Thromb Haemost 2019; 17 (07) 1044-1052
• 43 Santagostino E, Mancuso ME, Novembrino C, Solimeno LP, Tripodi A, Peyvandi F. Rescue factor VIII replacement to secure hemostasis in a patient with hemophilia A and inhibitors on emicizumab prophylaxis undergoing hip replacement. Haematologica 2019; 104 (08) e380-e382
• 44 Hartmann R, Feenstra T, Valentino L, Dockal M, Scheiflinger F. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost 2018; 16: 1580-1591