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Author Notes:

Christophe Schmitt, Department of Clinical Pharmacology, F. Hoffmann‐La Roche Ltd, Grenzacherstrasse 124, Basel 4070, Switzerland. Email: chrisophe.schmitt@roche.com

Christophe Schmitt wrote the manuscript; Christophe Schmitt, Tiffany Chang, Koichiro Yoneyama and Michaela Lehle contributed to/designed the research; Christophe Schmitt, Maria Elisa Mancuso, Tiffany Chang, Maria Podolak‐Dawidziak, Claire Petry, Robert Sidonio Jr, Koichiro Yoneyama, Nigel S. Key, Markus Niggli, Michaela Lehle, Flora Peyvandi and Johannes Oldenburg performed the research; Christophe Schmitt, Claire Petry and Markus Niggli analysed the data. All authors reviewed and approved the final version submitted.

The authors thank all investigators, study participants and all members of the clinical study teams. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Katie Smith, PhD, of Ashfield MedComms, an Inizio company, and funded by F. Hoffmann‐La Roche Ltd. This research was sponsored by F. Hoffmann‐La Roche Ltd. and Chugai Pharmaceutical Co., Ltd.

CS is an employee and stockholder in F. Hoffmann‐La Roche Ltd., and is co‐inventor of a patent related to an anti‐FIXa/FX bispecific antibody. MEM has provided consultancy for Bayer, CSL Behring, Novo Nordisk, F. Hoffmann‐La Roche Ltd., Octapharma, Pfizer, Sanofi, Sobi, Kedrion, Grifols, BioMarin, Catalyst, UniQure and LFB; and has been on a speakers bureau for Bayer, CSL Behring, Novo Nordisk, F. Hoffmann‐La Roche Ltd., Octapharma, Pfizer, Sobi, Kedrion, Grifols, BioMarin and Spark Therapeutics. TC is an employee of Spark Therapeutics, which is part of the Roche group and holds stock in F. Hoffmann‐La Roche Ltd. MPD has received a research grant from Takeda; has participated as a speaker and/or on advisory boards for Amgen, Novartis, Novo Nordisk, F. Hoffmann‐La Roche Ltd., Sanofi and Takeda; and has received reimbursement for attending congresses from CSL Behring, F. Hoffmann‐La Roche Ltd., Sobi and Takeda. CP is an employee of F. Hoffmann‐La Roche Ltd. and holds stock in F. Hoffmann‐La Roche Ltd. RSJ has received research funding from Genentech, Inc.; consultancy fees from Genentech, Inc./F. Hoffmann‐La Roche Ltd.; honoraria from Genentech, Inc./F. Hoffmann‐La Roche Ltd.; and expenses from Genentech, Inc./F. Hoffmann‐La Roche Ltd. KY is an employee of Chugai Pharmaceutical Co., Ltd. and an inventor/co‐inventor of patents related to anti‐FIXa/FX bispecific antibodies.

NSK has acted as a paid consultant for Takeda, Novo Nordisk and UniQure/CSL Behring. MN is an employee of F. Hoffmann‐La Roche Ltd. and holds stock in F. Hoffmann‐La Roche Ltd. ML is an employee of F. Hoffmann‐La Roche Ltd. and holds stock in F. Hoffmann‐La Roche Ltd. FP has received speaker fees for participating in advisory boards from Sanofi, Sobi, Takeda, F. Hoffmann‐La Roche Ltd., BioMarin and educational meetings from Grifols and F. Hoffmann‐La Roche Ltd. JO has received research funding from Bayer, Biotest, Chugai Pharmaceutical Co., Ltd., CSL Behring, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann‐La Roche Ltd., Swedish Orphan Biovitrum and Takeda; consultancy, speakers bureau, honoraria, scientific advisory board and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical Co., Ltd., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann‐La Roche Ltd., Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum and Takeda.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • bleeding control
  • clinical study
  • dosage up-titration
  • emicizumab
  • haemophilia A
  • monoclonal antibodies
  • FACTOR-VIII
  • BISPECIFIC ANTIBODY
  • PROPHYLAXIS
  • DEFINITIONS

Emicizumab dose up-titration in case of suboptimal bleeding control in people with haemophilia A

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Journal Title:

HAEMOPHILIA

Volume:

Volume 29, Number 1

Publisher:

, Pages 90-99

Type of Work:

Article | Final Publisher PDF

Abstract:

Introduction: Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors. Aim: To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control. Methods: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration. Results: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0–32.0) weeks. The model-based annualised bleed rate for ‘treated bleeds’ and ‘all bleeds’ decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4–123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration. Conclusion: The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials.

Copyright information:

© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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