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Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study

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Abstract

In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68 % [hazard ratio 0.32 (95 % confidence interval (CI) 0.16–0.62)] to 26 % [0.74 (0.51–1.09)] and from 66 % [0.34 (0.23–0.50)] to 25 % [0.75 (0.42–1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.

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References

  1. US Food and Drug Administration (2013) TECFIDERA™ prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf. Accessed 2 Apr 2013

  2. Gold R, Kappos L, Arnold DL, Bar-Or A, Giavannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT, on behalf of the DEFINE Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107

    Article  PubMed  CAS  Google Scholar 

  3. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT, on behalf of the CONFIRM Study Investigators (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097

    Article  PubMed  CAS  Google Scholar 

  4. Chofflon M (2005) Mechanisms of action for treatments in multiple sclerosis: Does a heterogeneous disease demand a multi-targeted therapeutic approach? BioDrugs 19:299–308

    Article  PubMed  CAS  Google Scholar 

  5. Degenhardt A, Ramagopalan SV, Scalfari A, Ebers GC (2009) Clinical prognostic factors in multiple sclerosis: a natural history review. Nat Rev Neurol 5:672–682

    Article  PubMed  Google Scholar 

  6. Disanto G, Berlanga AJ, Handel AE, Para AE, Burrell AM, Fries A, Handunnetthi L, De Luca GC, Morahan JM (2010) Heterogeneity in multiple sclerosis: scratching the surface of a complex disease. Autoimmune Dis 2011:932351

    PubMed  Google Scholar 

  7. Mowry EM (2011) Natural history of multiple sclerosis: early prognostic factors. Neurol Clin 29:279–292

    Article  PubMed  Google Scholar 

  8. Renoux C (2011) Natural history of multiple sclerosis: long-term prognostic factors. Neurol Clin 29:293–308

    Article  PubMed  Google Scholar 

  9. Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164

    Article  PubMed  Google Scholar 

  10. Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–782

    Article  PubMed  Google Scholar 

  11. Losseff NA, Miller DH, Kidd D, Thompson AJ (2001) The predictive value of gadolinium enhancement for long term disability in relapsing-remitting multiple sclerosis—preliminary results. Mult Scler 7:23–25

    PubMed  CAS  Google Scholar 

  12. Scott TF, Schramke CJ, Novero J, Chieffe C (2000) Short-term prognosis in early relapsing-remitting multiple sclerosis. Neurology 55:689–693

    Article  PubMed  CAS  Google Scholar 

  13. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846

    Article  PubMed  Google Scholar 

  14. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    Article  PubMed  CAS  Google Scholar 

  15. ICH harmonised tripartite guideline—guideline for good clinical practice: E6 (R1) (1996) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, June 10, 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed 30 Mar 2011

  16. World Medical Association (2010) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/. Accessed 22 Nov 2010

  17. European Medicines Agency (EMA) (2006) Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003485.pdf. Accessed 11 Feb 2011

  18. Hutchinson M, Fox RJ, Miller DH, Phillips JT, Kita M, Havrdova E, O’Gorman J, Zhang R, Novas M, Viglietta V, Dawson KT (2013) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol. doi:10.1007/s00415-013-6968-1

  19. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, Meluzinova E, Dufek M, Yang M, Dawson K, O’Neill GN (2012) Effect of BG-12 on contrast-enhanced lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler 18:314–321

    Article  PubMed  CAS  Google Scholar 

  20. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA (2011) Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 10:338–348

    Article  PubMed  CAS  Google Scholar 

  21. Devonshire V, Havrdova E, Radue EW, O’Connor P, Zhang-Auberson L, Agoropoulou C, Haring DA, Francis G, Kappos L (2012) Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 11:420–428

    Article  PubMed  CAS  Google Scholar 

  22. Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sørensen PS, Vermersch P, Hamlett A, Viglietta V, Greenberg S (2011) Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post hoc and subgroup analysis. Lancet Neurol 10:329–337

    Article  PubMed  CAS  Google Scholar 

  23. Hutchinson M, Kappos L, Calabresi PA, Confavreux C, Giovannoni G, Galetta SL, Havrdova E, Lublin FD, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA (2009) The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol 256:405–415

    Article  PubMed  CAS  Google Scholar 

  24. Miller AE, O’Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, Truffinet P, Wang L, D’Castro L, Comi G, Freedman MS (2012) Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler 18:1625–1632

    Article  PubMed  Google Scholar 

  25. Tremlett H, Zhao Y, Joseph J, Devonshire V (2008) Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 79:1368–1374

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Biogen Idec Inc. (Weston, MA, USA). The authors would like to thank the DEFINE study investigators. Medical writing support and editorial assistance were provided by Samantha Holmes (CircleScience, Tytherington, UK), funded by Biogen Idec Inc.

Conflicts of interest

Amit Bar-Or reports having received honoraria and/or research support from Amplimmune, Aventis, Bayhill Therapeutics, Berlex, Biogen Idec, Diogenix, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, and Teva Neuroscience. Ralf Gold reports having received honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Ludwig Kappos reports having received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim, Eisai, Elan, Genmab, GlaxoSmithKline, Glenmark, MediciNova, Merck Serono, Novartis, Roche, Sanofi-Aventis, Santhera, Shire, Teva Neuroscience, UCB, Wyeth, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, and Novartis and Roche Research Foundations. Douglas L. Arnold reports having received honoraria from Bayer HealthCare, Biogen Idec, Coronado Biosciences, Eli Lilly, EMD Serono, Genentech, Genzyme, NeuroRx Research, Novartis, Roche, and Teva and research support from Bayer HealthCare and Biogen Idec. Gavin Giovannoni reports having received research support from Bayer Schering, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Sanofi-Aventis, and Teva and honoraria from Bayer Schering, Biogen Idec, Eisai, Elan, Fiveprime, Genentech, Genzyme, GlaxoSmithKline, GW Pharma, Ironwood, Merck Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. Krzysztof Selmaj reports having received honoraria from Biogen Idec, Genzyme, Novartis, Ono, Roche, Synthon, and Teva. John O’Gorman, Monica Stephan, and Katherine T. Dawson are employees of Biogen Idec.

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Authors and Affiliations

  1. Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada

    Amit Bar-Or & Douglas L. Arnold

  2. St. Josef Hospital, Ruhr University, Bochum, Germany

    Ralf Gold

  3. University Hospital Basel, Neurology, Basel, Switzerland

    Ludwig Kappos

  4. NeuroRx Research, Montreal, QC, Canada

    Douglas L. Arnold

  5. Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Gavin Giovannoni

  6. Medical University of Lodz, Lodz, Poland

    Krzysztof Selmaj

  7. Biogen Idec Inc., Weston, MA, USA

    John O’Gorman, Monica Stephan & Katherine T. Dawson

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  1. Amit Bar-Or
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  2. Ralf Gold
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  3. Ludwig Kappos
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  4. Douglas L. Arnold
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  9. Katherine T. Dawson
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Corresponding author

Correspondence to Amit Bar-Or.

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For the DEFINE study investigators.

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Bar-Or, A., Gold, R., Kappos, L. et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol 260, 2297–2305 (2013). https://doi.org/10.1007/s00415-013-6954-7

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  • DOI: https://doi.org/10.1007/s00415-013-6954-7

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