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Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation

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Abstract

Background

Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce.

Objective

To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ.

Methods

We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation.

Results

195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12–4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04–57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26–4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74–13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time).

Conclusion

Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.

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Acknowledgements

The study was financially supported by Sanofi Genzyme (ALAIN01 to Sven G. Meuth and Tobias Ruck) and the Competence Network Multiple Sclerosis (01GI1603D, PROGRAMMS to Sven G. Meuth and Heinz Wiendl).

Funding

The study was financially supported by Sanofi Genzyme (ALAIN01 to Sven G. Meuth and Tobias Ruck) and the Competence Network Multiple Sclerosis (01GI1603D, PROGRAMMS to Sven G. Meuth and Heinz Wiendl).

Author information

Author notes

  1. Tobias Ruck and Sven G. Meuth contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Neurology and Institute for Translational Neurology, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany

    Steffen Pfeuffer, Frederike Anne Straeten, Luisa Klotz, Heinz Wiendl, Tobias Ruck & Sven G. Meuth

  2. Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany

    Rene Schmidt

  3. Department of Neurology, University Duisburg-Essen, Duisburg, Germany

    Refik Pul & Christoph Kleinschnitz

  4. Department of Neurology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany

    Marinus Wieshuber, De-Hyung Lee & Ralf A. Linker

  5. Department of Neurology, University of Wuerzburg, Wuerzburg, Germany

    Sebastian Doerck

  6. Department of Neurology, Johannes-Wesling-Hospital Minden, Minden, Germany

    Vera Straeten

  7. Department of Neurology, Clinics Osnabrueck, Osnabrueck, Germany

    Susanne Windhagen

  8. Department of Neurology, University Medical Center Magdeburg, Magdeburg, Germany

    Marc Pawlitzki

  9. Department of Neurology, Herz-Jesu-Hospital Muenster-Hiltrup, Muenster, Germany

    Christoph Aufenberg

  10. Center for Neurology, Ulm, Germany

    Michael Lang

  11. Department of Neurology, University of Giessen-Marburg, Marburg, Germany

    Christian Eienbroeker & Björn Tackenberg

  12. Department of Neurology, Cologne General Hospitals, University of Cologne, Cologne, Germany

    Volker Limmroth

  13. Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany

    Brigitte Wildemann & Jürgen Haas

Authors
  1. Steffen Pfeuffer
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Contributions

SP: study concept and design, acquisition of data, analysis and interpretation of data, writing of the manuscript. RS: analysis and interpretation of data, writing of the manuscript. FAS: acquisition of data, analysis and interpretation of data. RP: acquisition of data, critical revision of manuscript for intellectual content. CK: acquisition of data, critical revision of manuscript for intellectual content. MW: acquisition of data. DL: acquisition of data, critical revision of manuscript for intellectual content. RL: acquisition of data, critical revision of manuscript for intellectual content. SD: acquisition of data, critical revision of manuscript for intellectual content. VS: acquisition of data, critical revision of manuscript for intellectual content. SW: acquisition of data, critical revision of manuscript for intellectual content. MP: acquisition of data, critical revision of manuscript for intellectual content. CA: acquisition of data, critical revision of manuscript for intellectual content. ML: acquisition of data, critical revision of manuscript for intellectual content. CE: acquisition of data, critical revision of manuscript for intellectual content. BT: acquisition of data, critical revision of manuscript for intellectual content. VL: acquisition of data, critical revision of manuscript for intellectual content. BW: acquisition of data, critical revision of manuscript for intellectual content. JH: acquisition of data, critical revision of manuscript for intellectual content. LK: acquisition of data, critical revision of manuscript for intellectual content. HW: critical revision of manuscript for intellectual content. TR: study concept and design, acquisition of data, analysis and interpretation of data, critical revision of manuscript for intellectual content. SGM: study concept and design, analysis and interpretation of data, critical revision of manuscript for intellectual content.

Corresponding author

Correspondence to Sven G. Meuth.

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Conflicts of interest

Steffen Pfeuffer: received travel reimbursements from Sanofi-Genzyme and Merck and honoraria for lecturing from Sanofi Genzyme, Biogen and Mylan. Rene Schmidt: declares no conflicts of interest. Frederike Anne Straeten: declares no conflicts of interest. Refik Pul: received travel reimbursements from Merck, research support by Novartis, speaker honoraria from Merck Serono, Biogen, Novartis, Sanofi-Genzyme, Mylan and Roche. Christoph Kleinschnitz: received travel reimbursements, honoraria for lecturing and research support from Ablynx, Amgen, Bayer Vital, Bristol-Mayers Squibb, Biotronik, Boehringer Ingelheim, Biogen, CSL Behring, Daiichi-Sankyo, Desitin, Eisai, Ever Pharma, Sanofi Genzyme, Merck Serono, Mylan, Medday, Novartis, Pfizer, Roche, Siemens, Stago and Teva. Marinus Wieshuber: declares no conflict of interest. De-Hyung Lee: received compensation for activities with Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Ralf A. Linker: received compensation for activities with Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Sebastian Doerck: reports no conflicts of interest. Vera Straeten: received travel reimbursements from Novartis, Merck and Biogen and honoraria for lecturing from Sanofi Genzyme, Biogen and Novartis. Susanne Windhagen: declares no conflict of interest. Marc Pawlitzki: received honoraria for lecturing and travel reimbursements from Biogen, Sanofi Genzyme, Merck Serono, Roche and Novartis. Christoph Aufenberg: received travel reimbursements from Bayer. Michael Lang: received travel grants, honoraria for lecturing, financial research support and consultancy fees from Teva, Merck Serono, Sanofi Genzyme, Novartis, Bayer and Biogen. Christian Eienbroeker: received honoraria for lecturing from Bayer, Biogen, and CSL Behring. Björn Tackenberg: received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA and UCB Pharma. Volker Limmroth: received honoraria as speaker, AD-Board member or research support from Antisense, Bayer, Biogen, Boehringer, Sanofi Genzyme, Novartis, Pfizer, Roche and Teva. Brigitte Wildemann: received grants and personal fees from Biogen, Merck Serono, Sanofi Genzyme, Novartis and Teva, and personal fees from Bayer Healthcare. Jürgen Haas: declares no conflict of interest. Luisa Klotz: received compensation for serving on scientific advisory boards from Sanofi Genzyme and Novartis, honoraria for lecturing and travel reimbursements from CSL Behring, Merck Serono, Biogen, Sanofi Genzyme, Novartis, and research support from Biogen and Novartis. Heinz Wiendl: received compensation for serving on Scientific Advisory Boards/Steering Committees from Bayer, Biogen, Sanofi Genzyme, Merck Serono and Novartis, honoraria for lecturing and travel reimbursements Bayer, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Sanofi Genzyme, Merck Serono, Omniamed, Novartis and Sanofi Aventis. He received compensation as a consultant from Biogen, Merck Serono, Novartis, Roche and Sanofi Genzyme and research support from Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme and Teva. Tobias Ruck: received travel reimbursements from Merck Serono and financial research support from Sanofi Genzyme and Novartis and honoraria for lecturing from Sanofi Genzyme, Roche, Biogen, Merck Serono and Teva. Sven G. Meuth: received honoraria for lecturing, travel reimbursements and financial research support from Bayer, Biogen, Sanofi Genzyme, Merck Serono, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi Aventis, UCB and Teva. The submitting author hereby declares that he takes responsibility for conduction and analysis of the data and that he had full access to all study data. The submitting author furthermore declares that there are no competing interests concerning these data and that the authors have all rights to publish the data. The submitted manuscript does not contain data that have been published in any other journal. The authors have no related articles under submission.

Ethical standards

The local institutional review board (IRB) has approved the conduction of this trial. Further details are listed in the “Methods” chapter.

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Pfeuffer, S., Schmidt, R., Straeten, F.A. et al. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. J Neurol 266, 165–173 (2019). https://doi.org/10.1007/s00415-018-9117-z

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  • DOI: https://doi.org/10.1007/s00415-018-9117-z

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