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Clinical and epidemiological research
Extended report
Low immunogenicity of tocilizumab in patients with rheumatoid arthritis
  1. Gerd R Burmester1,
  2. Ernest Choy2,
  3. Alan Kivitz3,
  4. Atsushi Ogata4,5,
  5. Min Bao6,
  6. Akira Nomura7,
  7. Stuart Lacey8,
  8. Jinglan Pei6,
  9. William Reiss6,
  10. Attila Pethoe-Schramm9,
  11. Navita L Mallalieu10,
  12. Thomas Wallace6,
  13. Margaret Michalska6,
  14. Herbert Birnboeck11,
  15. Kay Stubenrauch12,
  16. Mark C Genovese13
  1. 1Department of Rheumatology and Clinical Immunology, Charité—University Medicine Berlin, Free University and Humboldt University of Berlin, Berlin, Germany
  2. 2Cardiff University, Cardiff, UK
  3. 3Altoona Center for Clinical Research, Duncansville, Pennsylvania, USA
  4. 4Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan
  5. 5Division of Allergy, Rheumatology and Connective Tissue Diseases, Department of Internal Medicine, NTT West Osaka Hospital, Osaka, Japan
  6. 6Genentech, Inc., South San Francisco, California, USA
  7. 7Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
  8. 8Roche Products Limited, Welwyn Garden City, UK
  9. 9F. Hoffmann-La Roche Ltd, Basel, Switzerland
  10. 10Roche Innovation Center, New York, New York, USA
  11. 11Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
  12. 12Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
  13. 13Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA
  1. Correspondence to Dr Mark C Genovese, Division of Immunology and Rheumatology, Stanford University Medical Center, 900 Blake Wilbur Drive, Palo Alto, CA 94305, USA; genovese{at}stanford.edu

Abstract

Objective Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

Methods Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK).

Results The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7–2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy.

Conclusions The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

  • Rheumatoid Arthritis
  • Autoantibodies
  • DMARDs (biologic)

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/annrheumdis-2016-210297

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    Footnotes

    • Handling editor Tore K Kvien

    • Contributors All authors contributed to the development of this manuscript.

    • Funding Clinical trials were funded by F. Hoffmann-La Roche, Ltd (Roche). MUSASHI was funded by Chugai Pharmaceuticals Co., Ltd. Roche sponsored the study; participated in the design of the study along with the academic centres involved in the trials; and participated in the collection, analysis and interpretation of the data. This article was reviewed by Roche, but the decision to submit was contingent only on the approval of the lead author and coauthors, including those employed by Roche and Chugai.

    • Competing interests MB, WR, TW, JP and MM are employed by Genentech, Inc. SL, AP-S, HB, KS and NLM are employed by F. Hoffmann-La Roche. AN is employed by Chugai Pharmaceutical. GRB has received grants and honoraria for consulting and lectures from Roche. EC has received research grant, speaker and consultancy fees from Roche and Chugai Pharmaceutical. AK has received research grants and consulted for Genentech, Inc. AO has received consulting fees, speaking fees and/or honoraria from Chugai Pharmaceutical. MCG has received grants and consulting fees and/or honoraria from Roche.

    • Provenance and peer review Not commissioned; externally peer reviewed.