BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety

References

• Ford HL, Gerry E, Johnson M, et al. A prospective study of the incidence, prevalence and mortality of multiple sclerosis in Leeds. J Neurol 2002;249:260-5
   PubMed Web of Science ®Google Scholar
• Sloka JS, Pryse-Phillips WE, Stefanelli M. Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador. Can J Neurol Sci 2005;32:37-42
   PubMed Web of Science ®Google Scholar
• Asche CV, Singer ME, Jhaveri M, et al. All-cause health care utilization and costs associated with newly diagnosed multiple sclerosis in the United States. J Manag Care Pharm 2010;16:703-12
   PubMed Web of Science ®Google Scholar
• Goldberg LD, Edwards NC, Fincher C, et al. Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis. J Manag Care Pharm 2009;15:543-55
   PubMed Web of Science ®Google Scholar
• Cohen BA, Rieckmann P. Emerging oral therapies for multiple sclerosis. Int J Clin Pract 2007;61:1922-30
   PubMed Web of Science ®Google Scholar
• Gasperini C, Ruggieri S. Emerging oral drugs for relapsing–remitting multiple sclerosis. Expert Opin Emerg Drugs 2011;16:697-712
   PubMed Web of Science ®Google Scholar
• Fox EJ. Emerging oral agents for multiple sclerosis. Am J Manag Care 2010;16:S219-26
   PubMed Web of Science ®Google Scholar
• Turner AP, Williams RM, Sloan AP, et al. Injection anxiety remains a long-term barrier to medication adherence in multiple sclerosis. Rehabil Psychol 2009;54:116-21
   PubMed Web of Science ®Google Scholar
• Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing–remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;372:1463-72
   PubMed Web of Science ®Google Scholar
• Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107
   PubMed Web of Science ®Google Scholar
• Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97
   PubMed Web of Science ®Google Scholar
• Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007;17:210-18
   PubMed Web of Science ®Google Scholar
• Steinman L. Nuanced roles of cytokines in three major human brain disorders. J Clin Invest 2008;118:3557-63
   PubMed Web of Science ®Google Scholar
• De Stefano N, Narayanan S, Matthews PM, et al. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999;122:1933-9
   PubMed Web of Science ®Google Scholar
• Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393-9
   PubMed Web of Science ®Google Scholar
• Silber E, Sharief MK. Axonal degeneration in the pathogenesis of multiple sclerosis. J Neurol Sci 1999;170:11-18
   PubMed Web of Science ®Google Scholar
• Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-85
   PubMed Web of Science ®Google Scholar
• Witherick J, Wilkins A, Scolding N, et al. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune Dis 2011;164608
   Google Scholar
• Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92
   PubMed Web of Science ®Google Scholar
• Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the Nrf2 pathway. J Pharmacol Exp Ther 2012;341:274-84
   PubMed Web of Science ®Google Scholar
• Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233-60
   PubMed Web of Science ®Google Scholar
• Lukashev M, Zeng W, Goelz S, et al. Activation of Nrf2 and modulation of disease progression in EAE models by BG00012 (dimethyl fumarate) suggests a novel mechanism of action combining anti-inflammatory and neuroprotective modalities. Mult Scler 2007;13:S149, P503.
   Google Scholar
• Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997;236:313-22
   PubMed Web of Science ®Google Scholar
• Venugopal R, Jaiswal AK. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 1998;17:3145-56
   PubMed Web of Science ®Google Scholar
• Chen XL, Dodd G, Thomas S, et al. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol 2006;290:H1862-70
   PubMed Web of Science ®Google Scholar
• McMahon M, Itoh K, Yamamoto M, et al. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 2001;61:3299-307
   PubMed Web of Science ®Google Scholar
• Lin SX, Lisi L, Dello RC, et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 2011;3:75-84
   Web of Science ®Google Scholar
• Itoh K, Tong KI, Yamamoto M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 2004;36:1208-13
   PubMed Web of Science ®Google Scholar
• Li W, Kong AN. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 2009;48:91-104
   PubMed Web of Science ®Google Scholar
• Kwak MK, Wakabayashi N, Itoh K, et al. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 2003;278:8135-45
   PubMed Web of Science ®Google Scholar
• Lee JM, Calkins MJ, Chan K, et al. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 2003;278:12029-38
   PubMed Web of Science ®Google Scholar
• Bista P, Zeng W, Ryan S, et al. Dimethyl fumarate suppresses inflammation in vitro via both Nrf2-dependent and Nrf2-independent pathways. Neurology 2012;78:P02.108.
   Web of Science ®Google Scholar
• Loewe R, Pillinger M, de Martin R, et al. Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner. J Invest Dermatol 2001;117:1363-8
   PubMed Web of Science ®Google Scholar
• Wierinckx A, Breve J, Mercier D, et al. Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol 2005;166:132-43
   PubMed Web of Science ®Google Scholar
• Gerdes S, Shakery K, Mrowietz U. Dimethylfumarate inhibits nuclear binding of nuclear factor kappaB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein beta in activated human T cells. Br J Dermatol 2007;156:838-42
   PubMed Web of Science ®Google Scholar
• Ghoreschi K, Bruck J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011;208:2291-303
   PubMed Web of Science ®Google Scholar
• Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003;421:744-8
   PubMed Web of Science ®Google Scholar
• Frohman EM, Racke MK, Raine CS. Multiple sclerosis – the plaque and its pathogenesis. N Engl J Med 2006;354:942-55
   PubMed Web of Science ®Google Scholar
• Moharregh-Khiabani D, Linker RA, Gold R, et al. Fumaric acid and its esters: an emerging treatment for multiple sclerosis. Curr Neuropharmacol 2009;7:60-4
   PubMed Web of Science ®Google Scholar
• Schilling S, Goelz S, Linker R, et al. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006;145:101-7
   PubMed Web of Science ®Google Scholar
• Arnold HM, Huang C, Engber TM, et al. Neuroprotective effects of BG-12 on malonate-induced striatal lesion size in Sprague–Dawley rat brain. Mult Scler 2011;17:S432, P958.
   Web of Science ®Google Scholar
• Arnold HM, Huang C, Huang R, et al. Neuroprotective effects of BG-12 on malonate-induced striatal lesion volume in Sprague–Dawley rat brain. Neurology 2012;78:P02.121.
   Web of Science ®Google Scholar
• Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria'. Ann Neurol 2005;58:840-6
   PubMed Web of Science ®Google Scholar
• Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-52
   PubMed Web of Science ®Google Scholar
• Macmanus DG, Miller DH, Kappos L, et al. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol 2011;258:449-56
   PubMed Web of Science ®Google Scholar
• Kappos L, Gold R, Miller DH, et al. Effect of BG-12 on contrast-enhancing lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler 2011;18:314-21
   PubMed Web of Science ®Google Scholar
• Bar-Or A, Gold R, Kappos L, et al. Effect of BG-12 in subgroups of patients with relapsing–remitting multiple sclerosis: findings from the DEFINE study. Neurology 2012;78:P01.130.
   Google Scholar
• Bar-Or A, Gold R, Kappos L et al. Effect of BG-12 in subgroups of patients with relapsing–remitting multiple sclerosis: findings from the DEFINE study. Poster presented at the American Academy of Neurology (AAN) 2012, New Orleans, LA, 21–28 April 2012:P01.130
   Google Scholar
• Bar-Or A, Gold R, Kappos L, et al. Effect of BG-12 on magnetic resonance imaging activity in subgroups of patients with relapsing-remitting multiple sclerosis: findings from the DEFINE study. Eur J Neurol 2012;19:356, P1685.
   Web of Science ®Google Scholar
• Giovannoni G, Gold R, Kappos L. Analysis of clinical and radiological disease activity-free status in patients with relapsing–remitting multiple sclerosis treated with BG-12: findings from the DEFINE study. J Neurol 2012;259:S106, P459.
   Web of Science ®Google Scholar
• Hutchinson M, Fox RJ, Miller D, et al. Effect of BG-12 in subgroups of patients with relapsing–remitting multiple sclerosis: findings from the CONFIRM (COmparator aNd an oral Fumarate In Relapsing-remitting Multiple sclerosis) study. Eur J Neurol 2012;19:355, P1684.
   Web of Science ®Google Scholar
• Miller D, Hutchinson M, Fox RJ, et al. Effect of BG-12 on magnetic resonance imaging activity in subgroups of patients with relapsing–remitting multiple sclerosis: findings from the CONFIRM study. Mult Scler 2012;18:189, P464.
   Google Scholar
• Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med 2013;368:1659-61
   PubMed Web of Science ®Google Scholar
• Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006;15:241-3
   PubMed Web of Science ®Google Scholar
• Phillips JT, Fox R, Selmaj K et al. Safety and tolerability of oral BG-12 (dimethyl fumarate) in relapsing–remitting multiple sclerosis (RRMS): interim results from ENDORSE Extension Study. Annual Meeting of the American Academy of Neurology, San Diego, CA, 16-23 March 2013:Poster P01.162
   Google Scholar
• Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285-94
   PubMed Web of Science ®Google Scholar
• Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45:1268-76
   PubMed Web of Science ®Google Scholar
• PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 2001;56:1628-36
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Southam E, Waubant E. Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler 2012;18:932-46
   PubMed Web of Science ®Google Scholar
• Girouard N, Theoret G. Management strategies for improving the tolerability of interferons in the treatment of multiple sclerosis. Can J Neurosci Nurs 2008;30:18-25
   PubMedGoogle Scholar
• O'Rourke KE, Hutchinson M. Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns. Mult Scler 2005;11:46-50
   PubMed Web of Science ®Google Scholar
• Rio J, Porcel J, Tellez N, et al. Factors related with treatment adherence to interferon beta and glatiramer acetate therapy in multiple sclerosis. Mult Scler 2005;11:306-9
   PubMed Web of Science ®Google Scholar
• Tremlett HL, Oger J. Interrupted therapy: stopping and switching of the beta-interferons prescribed for MS. Neurology 2003;61:551-4
   PubMed Web of Science ®Google Scholar
• Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15
   PubMed Web of Science ®Google Scholar
• Novartis Pharmaceuticals Corporation. Gilenya. Prescribing Information. 2012. Available at: www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf [Last accessed 17 July 2012]
   Google Scholar
• Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401
   PubMed Web of Science ®Google Scholar
• O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303
   PubMed Web of Science ®Google Scholar
• Calabresi PA, Goodin D, Jeffrey D et al. Efficacy and safety of fingolimod versus placebo: primary outcomes from the phase 3 FREEDOMS II study in patients with relapsing–remitting multiple sclerosis. European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Lyon, France, 10–13 October 2012:Poster P491
   Google Scholar
• Radue EW, Goodin D, Jeffrey D et al. Fingolimod reduces magnetic resonance imaging inflammatory lesion activity versus placebo in patients with relapsing–remitting multiple sclerosis: results from the phase 3 FREEDOMS II study. European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Lyon, France, 10–13 October 2012:Poster P724
   Google Scholar
• Sanofi. A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing multiple sclerosis (TENERE). 2013. Available at: http://clinicaltrials.gov/show/NCT00883337 [Last accessed 2 April 2013]
   Google Scholar
• Genzyme. Aubagio, US Prescribing Information. 2012. Available at: https://www.aubagio.com/[Last accessed 1 September 2012]
   Google Scholar