Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study
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In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical 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. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34 % [rate ratio 0.664 (95 % confidence interval 0.422–1.043)] to 53 % [0.466 (0.313–0.694)] and from 13 % [0.870 (0.551–1.373)] to 67 % [0.334 (0.226–0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.
KeywordsBG-12 Dimethyl fumarate Glatiramer acetate Multiple sclerosis Randomized controlled trial Subgroup analysis
This study was supported by Biogen Idec Inc. (Weston, MA, USA). EH was supported by the Czech Ministry of Education, VZ MSM 0021620849 and PRVOUK-P26/LF1/4. The authors would like to thank the CONFIRM study investigators. Medical writing support and editorial assistance were provided by Samantha Holmes (CircleScience, Tytherington, UK), funded by Biogen Idec Inc.
Conflict of interest
Michael Hutchinson serves on a medical advisory board [BG00012] for Biogen Idec, is an assistant editor of Multiple Sclerosis Journal, and reports having received speaker’s honoraria from Bayer Schering, Biogen Idec, and Novartis, and research support from Dystonia Ireland and the Health Research Board of Ireland. Robert J. Fox reports having received consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva, and grant and research support from Novartis. David H. Miller reports having received honoraria from Bayer Schering Pharma, Biogen Idec, and GlaxoSmithKline and research grants from Apitope, Biogen Idec, GlaxoSmithKline, Novartis, Richmond Pharma, and Schering AG. J. Theodore Phillips reports having received honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva, and research support from Biogen Idec and Roche. Mariko Kita reports having received research support from Biogen Idec. Eva Havrdova reports having received honoraria from Bayer, Biogen Idec, Genzyme, Novartis, Serono, and Teva. John O’Gorman, Ray Zhang, Mark Novas, Vissia Viglietta, and Katherine T. Dawson are employees of Biogen Idec.
- 1.US Food and Drug Administration (2013) TECFIDERA™ prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf. Accessed 2 April 2013
- 2.Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O’Neill GN (2008) Efficacy and safety of oral fumarate in patients with relapsing–remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372:1463–1472PubMedCrossRefGoogle Scholar
- 3.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 367:1098–1107PubMedCrossRefGoogle Scholar
- 4.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 367:1087–1097PubMedCrossRefGoogle Scholar
- 16.Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302PubMedCrossRefGoogle Scholar
- 18.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 March 2011
- 19.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
- 20.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
- 21.Bar-Or A, Gold R, Kappos L, Arnold DL, Giovannoni G, Selmaj K, O’Gorman J, Stephan M, Dawson KT (2012) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study. Submitted to J NeurolGoogle Scholar
- 22.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 (2011) Effect of BG-12 on contrast-enhancing lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler 18:314–321PubMedCrossRefGoogle Scholar
- 23.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 10:338–348PubMedCrossRefGoogle Scholar
- 24.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 11:420–428PubMedCrossRefGoogle Scholar
- 25.Giovannoni G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, 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 10:329–337PubMedCrossRefGoogle Scholar
- 26.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 256:405–415PubMedCrossRefGoogle Scholar
- 27.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 18:1625–1632PubMedCrossRefGoogle Scholar