Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis

Izanne Roos¹, Sifat Sharmin¹, Charles Malpas¹, Serkan Ozakbas², Jeannette Lechner-Scott³, Suzanne Hodgkinson⁴, Raed Alroughani⁵, Sara Eichau Madueño⁶, Cavit Boz⁷, Anneke van der Walt⁸, Helmut Butzkueven⁸, Katherine Buzzard^{9

10

11}, Olga Skibina^{12

10

11}, Matteo Foschi^{13

14}, Francois Grand'Maison¹⁵, Nevin John^{16

17}, Pierre Grammond¹⁸, Murat Terzi¹⁹, Julie Prévost²⁰, Michael Barnett²¹, Guy Laureys²², Liesbeth Van Hijfte²², Jose Luis Sanchez-Menoyo²³, Yolanda Blanco²⁴, Jiwon Oh²⁵, Pamela McCombe²⁶, Cristina Ramo Tello²⁷, Aysun Soysal²⁸, Alexandre Prat²⁹, Pierre Duquette²⁹, Bassem I Yamout³⁰, Samia Khoury³⁰, Vincent van Pesch³¹, Richard Macdonell³², Maria José Sá³³, Mark Slee³⁴, Jens Kuhle³⁵, Davide Maimone³⁶, Daniele LA Spitaleri³⁷, Barbara Willekens^{38

39}, Abdallah Al Asmi⁴⁰, Emma Tallantyre⁴¹, Neil P Robertson⁴¹, Alasdair Coles⁴², J William L Brown⁴², Tomas Kalincik¹

Affiliations

¹ CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
² Dokuz Eylul University, Konak, Izmir, Turkey.
³ Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia/John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia.
⁴ Immune Tolerance Laboratory Ingham Institute and Department of Medicine, UNSW, Sydney, NSW, Australia.
⁵ Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait.
⁶ Hospital Universitario Virgen Macarena, Sevilla, Spain.
⁷ Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.
⁸ Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
⁹ Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁰ Department of Neurology, Box Hill Hospital, Melbourne, VIC, Australia.
¹¹ Department of Neurosciences, Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia.
¹² Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia.
¹³ Department of Neuroscience, Multiple Sclerosis Center, S. Maria delle Croci Hospital of Ravenna, Ravenna, Italy.
¹⁴ Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, L'Aquila, Italy.
¹⁵ Neuro Rive-Sud, Greenfield Park, QC, Canada.
¹⁶ Department of Neurology, Monash Health, Melbourne, VIC, Australia.
¹⁷ Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
¹⁸ CISSS de Chaudière-Appalache, Sainte-Marie, QC, Canada.
¹⁹ Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
²⁰ CSSS de Saint-Jérôme, Saint-Jerome, QC, Canada.
²¹ Brain and Mind Centre, Sydney, NSW, Australia.
²² Department of Neurology, Ghent University Hospital, Ghent, Belgium.
²³ Department of Neurology, Hospital de Galdakao-Usansolo, Biocruces-Bizkaia Health Research Institute, Galdakao, Spain.
²⁴ Center of Neuroimmunology, Service of Neurology, Hospital Clinic de Barcelona, Barcelona, Spain.
²⁵ St. Michael's Hospital, Toronto, ON, Canada.
²⁶ The University of Queensland, Brisbane, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, OLD, Australia.
²⁷ Hospital Germans Trias i Pujol, Badalona, Spain.
²⁸ Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
²⁹ CHUM MS Center and Universite de Montreal, Montreal, QC, Canada.
³⁰ Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
³¹ Cliniques Universitaires Saint-Luc, Brussels, Belgium.
³² Austin Health, Melbourne, VIC, Australia.
³³ Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto, Portugal; Faculty of Health Sciences, University Fernando Pessoa, Porto, Portugal.
³⁴ College of Medicine and Public Health, Flinders University, Adelaide, Australia.
³⁵ Neurology, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
³⁶ Centro Sclerosi Multipla, UOC Neurologia, ARNAS Garibaldi, Catania, Italy.
³⁷ Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy.
³⁸ Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
³⁹ Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
⁴⁰ College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Sultan Qaboos University, Al-Khodh, Oman.
⁴¹ Department of Neurology, University Hospital of Wales; Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

PMID: 39087208
DOI: 10.1177/13524585241267211

Comparative Study

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis

Izanne Roos et al. Mult Scler. 2024 Aug.

. 2024 Aug;30(9):1163-1175.

doi: 10.1177/13524585241267211. Epub 2024 Aug 1.

Authors

Affiliations

¹ CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
² Dokuz Eylul University, Konak, Izmir, Turkey.
³ Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia/John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia.
⁴ Immune Tolerance Laboratory Ingham Institute and Department of Medicine, UNSW, Sydney, NSW, Australia.
⁵ Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait.
⁶ Hospital Universitario Virgen Macarena, Sevilla, Spain.
⁷ Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.
⁸ Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
⁹ Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁰ Department of Neurology, Box Hill Hospital, Melbourne, VIC, Australia.
¹¹ Department of Neurosciences, Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia.
¹² Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia.
¹³ Department of Neuroscience, Multiple Sclerosis Center, S. Maria delle Croci Hospital of Ravenna, Ravenna, Italy.
¹⁴ Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, L'Aquila, Italy.
¹⁵ Neuro Rive-Sud, Greenfield Park, QC, Canada.
¹⁶ Department of Neurology, Monash Health, Melbourne, VIC, Australia.
¹⁷ Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
¹⁸ CISSS de Chaudière-Appalache, Sainte-Marie, QC, Canada.
¹⁹ Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
²⁰ CSSS de Saint-Jérôme, Saint-Jerome, QC, Canada.
²¹ Brain and Mind Centre, Sydney, NSW, Australia.
²² Department of Neurology, Ghent University Hospital, Ghent, Belgium.
²³ Department of Neurology, Hospital de Galdakao-Usansolo, Biocruces-Bizkaia Health Research Institute, Galdakao, Spain.
²⁴ Center of Neuroimmunology, Service of Neurology, Hospital Clinic de Barcelona, Barcelona, Spain.
²⁵ St. Michael's Hospital, Toronto, ON, Canada.
²⁶ The University of Queensland, Brisbane, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, OLD, Australia.
²⁷ Hospital Germans Trias i Pujol, Badalona, Spain.
²⁸ Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
²⁹ CHUM MS Center and Universite de Montreal, Montreal, QC, Canada.
³⁰ Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
³¹ Cliniques Universitaires Saint-Luc, Brussels, Belgium.
³² Austin Health, Melbourne, VIC, Australia.
³³ Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto, Portugal; Faculty of Health Sciences, University Fernando Pessoa, Porto, Portugal.
³⁴ College of Medicine and Public Health, Flinders University, Adelaide, Australia.
³⁵ Neurology, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
³⁶ Centro Sclerosi Multipla, UOC Neurologia, ARNAS Garibaldi, Catania, Italy.
³⁷ Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy.
³⁸ Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
³⁹ Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
⁴⁰ College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Sultan Qaboos University, Al-Khodh, Oman.
⁴¹ Department of Neurology, University Hospital of Wales; Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

PMID: 39087208
DOI: 10.1177/13524585241267211

Abstract

Background: Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking.

Objectives: To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS.

Methods: Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes.

Results: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p < 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47-2.47) or alemtuzumab (HR 0.73, 95% CI 0.26-2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13-0.94) and ocrelizumab (HR 0.45, 95% CI 0.26-0.78). There was no evidence for a difference in disability improvement.

Conclusion: Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies.

Keywords: Cladribine; comparative effectiveness; multiple sclerosis; observational studies.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: I. Roos served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen.S. Sharmin reports no disclosures relevant to the manuscript.C. Malpas has received speaker honoraria and consulting fees from Biogen, Merck and Novartis.S. Ozakbas reports no disclosures relevant to the manuscript.J. Lechner-Scott received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis.S. Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering, Merck and Sanofi Genzyme and travel grants from Novartis, Biogen Idec and Bayer Schering.R. Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi Genzyme.S. Eichau-Madueño received speaker honoraria and consulting fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva.C. Boz received conference travel support from Biogen, Novartis, Bayer Schering, Merck and Teva and has participated in clinical trials by Sanofi-Aventis, Roche and Novartis.A. van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.H. Butzkueven received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee.K. Buzzard received honoraria and consulting fees from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck, CSL and Grifols.O. Skibina received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme.M. Foschi received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi Genzyme and Merck.F. Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences and ATARA Pharmaceuticals.N. John is primary investigator on MS trials sponsored by Novartis, Roche and Biogen.P. Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme and Pendopharm; has received grant support from Genzyme and Roche; has received research grants for his institution from Biogen Idec, Sanofi Genzyme and EMD Serono.M. Terzi received travel grants from Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi-Aventis, Roche and Novartis.J. Prevost accepted travel compensation from Novartis, Biogen, Genzyme and Teva and speaking honoraria from Biogen, Novartis, Genzyme and Teva.M. Barnett served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis.G. Laureys received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene and Biogen.L. Van Hijfte received travel compensation from Merck.J. L. Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche.Y. Blanco received speaker honoraria/consulting fees from Merck, Biogen, Roche, Brystol, Novartis, Sanofi and Sandoz.J. Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche and EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche and Sanofi Genzyme.P. McCombe received speaker fees and travel grants from Novartis, Biogen, Teva and Sanofi.C. Ramo-Tello received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Merck, Roche, Almirall, Bristol and Sanofi.A. Soysal reports no disclosures relevant to the manuscript.A. Prat reports no disclosures relevant to the manuscript.P. Duquette served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme.B. I. Yamout reports no disclosures relevant to the manuscript.S. J. Khoury received compensation for scientific advisory board activity from Merck and Roche and received compensation for serving on the IDMC for Biogen.V. van Pesch received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall, Alexion and Roche. His institution has received research grants and consulting fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma.R. Macdonell or his institution have received remuneration for his speaking engagements, advisory board memberships, research and travel from Biogen, Merck, Genzyme, Bayer, Roche, Teva, Novartis, CSL, BMS, MedDay and NHMRC.M. J. Sa received consulting fees, speaker honoraria and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva.M. Slee has participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis and Novartis.J. Kuhle received speaker fees, research support, travel support and/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Bayer, Biogen, Bristol Myers Squibb, Celgene, Merck, Novartis, Octave Bioscience, Roche and Sanofi.D. Maimone received speaker honoraria for advisory board and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva.D. L.A. Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva and Merck.B. Willekens received honoraria for acting as a member of scientific advisory boards/consultancy for Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi Genzyme and speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi Genzyme; research and/or patient support grants from Biogen, Janssen, Merck, Sanofi Genzyme, Roche. Honoraria and grants were paid to UZA/UZA Foundation. Furthermore, B.W. received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA.A. Al-Asmi reports no disclosures relevant to the manuscript.E. Tallantyre reports no disclosures relevant to the manuscript.N. P. Robertson reports no disclosures relevant to the manuscript.A. Coles reports no disclosures relevant to the manuscript.J. W.L. Brown reports speaking honoraria from The Corpus, Biogen and Novartis; and advisory board fees from Biogen and Intesso.T. Kalincik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck.

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Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis

Affiliations

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

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