Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study
- 2k Downloads
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.
KeywordsBG-12 Dimethyl fumarate Multiple sclerosis Randomized controlled trial Subgroup analysis
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.
- 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 367:1098–1107PubMedCrossRefGoogle 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 367:1087–1097PubMedCrossRefGoogle 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 58:840–846PubMedCrossRefGoogle 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 18:314–321PubMedCrossRefGoogle 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 10:338–348PubMedCrossRefGoogle 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 11:420–428PubMedCrossRefGoogle 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 10:329–337PubMedCrossRefGoogle 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 256:405–415PubMedCrossRefGoogle 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 18:1625–1632PubMedCrossRefGoogle Scholar