Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 StudyFunding This study was sponsored by F. Hoffmann-La Roche Ltd.
Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.
C.S., J.I.A., C.N., M.U.C., and G.G.L. contributed to the development of the HAVEN 1 study design. C.P. and O.C. contributed to the acquisition of data for these analyses. C.S., J.I.A., J.X., C.P., O.C., G.Y., C.N., M.U.C., and G.G.L. contributed to data analysis and interpretation. All authors critically reviewed this manuscript and approved the final version for submission.
Received: 23 April 2020
Accepted: 18 August 2020
21 October 2020 (online)
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
Stuttgart · New York
- 1 Makris M, Kasper C. The World Federation of Hemophilia guideline on management of haemophilia. Haemophilia 2013; 19 (01) 1
- 2 Valentino LA, Mamonov V, Hellmann A. et al. Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10 (03) 359-367
- 3 Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Blood 2014; 124 (23) 3365-3372
- 4 Maahs J, Donkin J, Recht M, Cooper DL. Mixing and administration times of bypassing agents: observations from the Dosing Observational Study in Hemophilia (DOSE). J Blood Med 2014; 5: 153-156
- 5 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
- 6 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
- 7 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 (02) e57479
- 8 Kotani N, Yoneyama K, Kawakami N, Shimuta T, Fukase H, Kawanishi T. Relative and absolute bioavailability study of emicizumab to bridge drug products and subcutaneous injection sites in healthy volunteers. Clin Pharmacol Drug Dev 2019; 8 (06) 702-712
- 9 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
- 10 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
- 11 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
- 12 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
- 13 Young G, Liesner R, Sidonio RF. et al. Emicizumab prophylaxis provides flexible and effective bleed control in children with hemophilia A with inhibitors: results from the HAVEN 2 study. 60th Annual Meeting of the American Society of Hematology (ASH); 2018 December 1–4; San Diego, CA: 2018
- 14 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
- 15 European Medicines Agency. HEMLIBRA® solution for injection: emicizumab piIEa. Initial EU approval; 2018
- 16 Genentech. HEMLIBRA® (emicizumab-kxwh) injection for subcutaneous use, prescribing information. Revised 10/2018; 2018
- 17 Lieuw K. Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?. J Blood Med 2017; 8: 67-73
- 18 Petrini P. Identifying and overcoming barriers to prophylaxis in the management of haemophilia. Haemophilia 2007; 13 (Suppl. 02) 16-22
- 19 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
- 20 Mahlangu J, Oldenburg J, Callaghan MU. et al. Bleeding events and safety outcomes in persons with haemophilia A with inhibitors: a prospective, multi-centre, non-interventional study. Haemophilia 2018; 24 (06) 921-929
- 21 Calatzis A, Kotani N, Levy GG, Adamkewicz JI. Effect of emicizumab (ACE910) – a humanized bispecific antibody mimicking FVIII cofactor function – on a variety of assay systems. 1st European Congress on Thrombosis and Haemostasis (ECTH); 2016 September 28–30; The Hague, The Netherlands: 2016
- 22 Waters EK, Hilden I, Sørensen BB, Ezban M, Holm PK. Thrombin generation assay using factor XIa to measure factors VIII and IX and their glycoPEGylated derivatives is robust and sensitive. J Thromb Haemost 2015; 13 (11) 2041-2052
- 23 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
- 24 Retout S, Schmitt C, Petry C, Mercier F, Frey N. Population pharmacokinetic analysis and exploratory exposure-bleeding rate relationship of emicizumab in adult and pediatric persons with hemophilia A. Clin Pharmacokinet 2020; DOI: 10.1007/s40262-020-00904-z.
- 25 Jonsson F, Schmitt C, Petry C, Mercier F, Frey N, Retout S. Exposure-response modeling of emicizumab for the prophylaxis of bleeding in haemophilia A patients with and without inhibitors against factor VIII. Res Pract Thromb Haemost 2019; 3 (S1): 1-891
- 26 Peerlinck K, Jacquemin MG, Arnout J. et al. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A. Blood 1999; 93 (07) 2267-2273
- 27 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17 (01) 41-44
- 28 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
- 29 Li H, Zhang W, Petry C. et al. Evaluation of the pharmacokinetics, pharmacodynamics, and safety of a single dose of emicizumab in healthy Chinese subjects. Clin Pharmacol Drug Dev 2020; DOI: 10.1002/cpdd.805.
- 30 Schmitt C, Pannier A, McIntyre C. et al. Crossover dose escalation study to assess safety, pharmacokinetics, and pharmacodynamics of single doses of R1663, an oral factor Xa inhibitor, in healthy male volunteers. J Clin Pharmacol 2012; 52 (04) 499-510
- 31 van Veen JJ, Gatt A, Bowyer AE, Cooper PC, Kitchen S, Makris M. Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A. Thromb Res 2009; 123 (06) 895-901
- 32 Aghighi S, Riddell A, Lee CA, Brown SA, Tuddenham E, Chowdary P. Global coagulation assays in hemophilia A: a comparison to conventional assays. Res Pract Thromb Haemost 2019; 4 (02) 298-308
- 33 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
- 34 Manco-Johnson M, Wang M, Boulden Warren B. et al. Emicizumab improves factor X activation and thrombin generation similar to mild hemophilia in persons with hemophilia A and inhibitors. Res Pract Thromb Haemost 2019; 3 (S1): 336
- 35 Adamkewicz JI, Schmitt C, Asikanius E. et al. Factor VIII Inhibitor Testing Using a Validated Chromogenic Bethesda Assay (CBA) in HAVEN 1 (bh29884), a Phase 3 Trial of Emicizumab in Persons with Hemophilia A (PwHA) with Inhibitors. Berlin, Germany: International Society on Thrombosis and Haemostasis; 2017
- 36 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
- 37 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 (07) 1348-1357
- 38 Food and Drug Administration. FEIBA® for intravenous use, prescribing information. Initial U.S. Approval: 1986; 2013