Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: An overview

Therapeutic Advances in Neurological Disorders

Volumn 8, Issue 1, 2015, Pages 20-30

  Bomprezzi, Roberto ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

clinical trial results; dimethyl fumarate; DMF mechanism of action; DMF metabolism; MS therapy; safety and efficacy

Indexed keywords

ACETYLSALICYLIC ACID; FUMADERM; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; NONSTEROID ANTIINFLAMMATORY AGENT; PLACEBO;

ABDOMINAL DISCOMFORT; ABDOMINAL PAIN; BACKACHE; CELL PROTECTION; DEPRESSION; DIARRHEA; DISEASE ACTIVITY; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG SAFETY; EUROPEAN MEDICINES AGENCY; EXPANDED DISABILITY STATUS SCALE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; FATIGUE; FLUSHING; FOOD AND DRUG ADMINISTRATION; GASTROINTESTINAL SYMPTOM; GLIA CELL; HEADACHE; HUMAN; IMMUNOMODULATION; INFECTION; LOW DRUG DOSE; MULTIPLE SCLEROSIS; NAUSEA; NERVE CELL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OLIGODENDROGLIA; PATIENT COMPLIANCE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEINURIA; PRURITUS; PSORIASIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RELAPSE; REMISSION; REVIEW; SKIN MANIFESTATION; TREATMENT OUTCOME; URINARY TRACT INFECTION; VOMITING;

EID: 84921047168     PISSN: 17562856     EISSN: 17562864     Source Type: Journal    
DOI: 10.1177/1756285614564152     Document Type: Review

References (56)

1. Altmeyer P. Matthes U. Pawlak F. Hoffmann K. Frosch P. Ruppert P. et al. (1994) Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 30: 977–981
2. Arnold D. Gold R. Kappos L. Bar-Or A. Giovannoni G. Selmaj K. et al. (2014 a) Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 DEFINE study. J Neurol 261: 1794–1802
3. Arnold D. Gold R. Kappos L. Bar-Or A. Giovannoni G. Selmaj K. et al. (2014 b) Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study. J Neurol. 1 October 2014. [Epub ahead of print].
4. Arnold P. Mojumder D. Detoledo J. Lucius R. Wilms H. (2014 c) Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways. Clin Pharmacol 6: 35–42.
5. Basketter D. White I. Burleson F. Burleson G. Kimber I. (2013) Dimethylfumarate: potency prediction and clinical experience. Contact Dermatitis 68: 269–272.
6. Biogen Idec (2013) Tecfidera (dimethyl fumarate): US prescribing information. Available at http://www.tecfidera.com/pdfs/full-prescribing-information.pdf [accessed 20 October 2014].
7. Bomprezzi R. Okuda D. Alderazi Y. Stüve O. Frohman E. (2012) From injection therapies to natalizumab: views on the treatment of multiple sclerosis. Ther Adv Neurol Disord 5: 97–104.
8. Bourdette D. Whitham R. (2010) Immunotherapy and multiple sclerosis: the devil is in the details. Neurology 74: 1410–1411.
9. Burness C. Deeks E. (2014) Dimethyl fumarate: a review of its use in patients with relapsing-remitting multiple sclerosis. CNS Drugs 28: 373–387.
10. Carrithers M. (2014) Update on disease-modifying treatments for multiple sclerosis. Clin Ther. 10 September 2014. pii: S0149-2918 (14)00537-2. doi: 10.1016/j.clinthera.2014.08.006. [Epub ahead of print].
11. Chen H. Assmann J. Krenz A. Rahman M. Grimm M. Karsten C. et al. (2014) Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest 124: 2188–2192.
12. de Jong R. Bezemer A. Zomerdijk T. van de Pouw-Kraan T. Ottenhoff T. Nibbering P. (1996) Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethyl fumarate. Eur J Immunol 26: 2067–2074.
13. Electronic Medicines Compendium (2014) Tecfidera 240 mg gastro-resistant hard capsules: summary of product characteristics. Available at http://www.medicines.org.uk/emc/medicine/28592/ [accessed 20 October 2014].
14. Ermis U. Weis J. Schulz J. (2013) PML in a Patient Treated with Fumaric Acid. N Engl J Med 368: 1657–1658.
15. European Medicines Agency (2013) Tecfidera. Summary of opinion (initial authorization). Available at http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002601/WC500140695.pdf [accessed 20 October 2014].
16. Fox R. Kita M. Cohan S. Henson L. Zambrano J. Scannevin R. et al. (2014) BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin 30: 251–262.
17. Fox R. Miller D. Phillips J. Hutchinson M. Havrdova E. Kita M. et al. (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367: 1087–1097.
18. Frohman E. Racke M. Raine C. (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 354: 942–955.
19. German Multiple Sclerosis Society (2014). Report of PML case and recommendations for monitoring patients on DMF [in German]. Available at http://www.dmsg.de/multiple-sklerose-news/index.php?w3pid=news&kategorie=therapien&anr=5473&suchbegriffe=tecfidera [accessed 8 November 2014].
20. Ghoreschi K. Brück J. Kellerer C. Deng C. Peng H. Rothfuss O. et al. (2011) Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 208: 2291–2303.
21. Gilgun-Sherki Y. Melamed E. Offen D. (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251: 261–268.
22. Gold R. Giovannoni G. Phillips J. Fox R. Zhang A. Meltzer L. et al. (2014 a) Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS). Mult Scler 2 July 2014. pii: 1352458514537013. [Epub ahead of print].
23. Gold R. Kappos L. Arnold D. Bar-Or A. Giovannoni G. Selmaj K. et al. (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367: 1098–1107.
24. Gold R. Phillips J. Havrdova E. Bar-Or A. Kappos L. Yuan H. et al. (2014 b) Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Joint ECTRIMS / ACTRIMS Meeting 2014: Abstract P839.
25. Haghikia A. Hohlfeld R. Gold R. Fugger L. (2013) Therapies for multiple sclerosis: translational achievements and outstanding needs. Mol Med 19: 309–319.
26. Hanson J. Gille A. Zwykiel S. Lukasova M. Clausen B. Ahmed K. et al. (2010) Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest 120: 2910–2919.
27. Havrdova E. Hutchinson M. Kurukulasuriya N. Raghupathi K. Sweetser M. Dawson K. et al. (2013) Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM. Evaluation of: Gold, R, Kappos, L, Arnold, D Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098–107; and Fox, RJ, Miller, DH, Phillips, JT. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087–97. Expert Opin Pharmacother 14: 2145–2156.
28. Hoefnagel J. Thio H. Willemze R. Bouwes Bavinck J. (2003) Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol 149: 363–369.
29. Hutchinson M. Fox R. Miller D. Phillips J. Kita M. Havrdova E. et al. (2013) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol 260: 2286–2296.
30. Johnson K. Brooks B. Cohen J. Ford C. Goldstein J. Lisak R. et al. (1995) 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 45: 1268–1276.
31. Kappos L. Gold R. Arnold D. Bar-Or A. Giovannoni G. Selmaj K. et al. (2014) Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: the DEFINE study. Mult Scler 20: 243–252.
32. Kappos L. Gold R. Miller D. Macmanus D. Havrdova E. Limmroth V. et al. (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: 1463–1472.
33. Kappos L. Gold R. Miller D. MacManus D. Havrdova E. Limmroth V. et al. (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.
34. Kawalec P. Mikrut A. Wiśniewska N. Pilc A. (2014) The effectiveness of dimethyl fumarate monotherapy in the treatment of relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. Curr Neuropharmacol 12: 256–268.
35. Kita M. Fox R. Phillips J. Hutchinson M. Havrdova E. Sarda S. et al. (2014) Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study. Mult Scler 20: 253–257.
36. Linker R. Lee D. Ryan S. van Dam A. Conrad R. Bista P. et al. (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf 2 antioxidant pathway. Brain 134: 678–692.
37. Litjens N. Rademaker M. Ravensbergen B. Rea D. van der Plas M. Thio B. et al. (2004) Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th 1 lymphocyte responses. Eur J Immunol 34: 565–575.
38. Litjens N. Rademaker M. Ravensbergen B. Thio H. van Dissel J. Nibbering P. (2006) Effects of monomethylfumarate on dendritic cell differentiation. Br J Dermatol 154: 211–217.
39. Lu E. Wang B. Alwan S. Synnes A. Dahlgren L. Sadovnick A. et al. (2014) A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. CNS Drugs 28: 89–94.
40. Meissner M. Valesky E. Kippenberger S. Kaufmann R. (2012) Dimethyl fumarate – only an anti-psoriatic medication? J Dtsch Dermatol Ges 10: 793–801.
41. Moharregh-Khiabani D. Linker R. Gold R. Stangel M. (2009) Fumaric acid and its esters: an emerging treatment for multiple sclerosis. Curr Neuropharmacol 7: 60–64.
42. Mrowietz U. Reich K. (2013) Case reports of PML in patients treated for psoriasis. N Engl J Med 369: 1080–1081.
43. National Multiple Sclerosis Society (2014) Pregnancy registries for MS medications. Available at http://www.nationalmssociety.org/Living-Well-With-MS/Family-and-Relationships/Pregnancy/Pregnancy-Registration [accessed 20 October 2014].
44. Nicholas J. Boster A. Imitola J. O'Connell C. Racke M. (2014) Design of oral agents for the management of multiple sclerosis: benefit and risk assessment for dimethyl fumarate. Drug Des Devel Ther 8: 897–908.
45. Papadopoulou A. D'Souza M. Kappos L. Yaldizli O. (2010) Dimethyl fumarate for multiple sclerosis. Expert Opin Investig Drugs 19: 1603–1612.
46. Phillips T. Fox R. Selmaj K. Zhang R. Novas M. Sweetser M. et al. (2014) Safety profile of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis (RRMS): long-term interim results from the ENDORSE Extension Study. Am Acad Neurol Abstract P2.200.
47. Reich K. Thaci D. Mrowietz U. Kamps A. Neureither M. Luger T. (2009) Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis–a retrospective study (FUTURE). J Dtsch Dermatol Ges 7: 603–611.
48. Salmen A. Gold R. (2014) Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol 262: 52–56.
49. Schilling S. Goelz S. Linker R. Luehder F. Gold R. (2006) Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 145: 101–107.
50. Schimrigk S. Brune N. Hellwig K. Lukas C. Bellenberg B. Rieks M. et al. (2006) Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 13: 604–610.
51. Strassburger-Krogias K. Ellrichmann G. Krogias C. Altmeyer P. Chan A. Gold R. (2014) Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther Adv Neurol Disord 7: 232–238.
52. Sweetser M. Dawson K. Bozic C. (2013) Manufacturer's response to case reports of PML. N Engl J Med 368: 1659–1661.
53. UK Multiple Sclerosis Society (2014) Case of PML in a patient taking Tecfidera. Available at http://www.mssociety.org.uk/ms-news/2014/10/case-pml-confirmed-someone-taking-tecfidera [accessed 8 November 2014].
54. US Food and Drug Administration (2013) TECFIDERA™ prescribing information. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf [accessed 20 October 2014].
55. van Oosten B. Killestein J. Barkhof F. Polman C. Wattjes M. (2013) PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 368: 1658–1659.
56. Werdenberg D. Joshi R. Wolffram S. Merkle H. Langguth P. (2003) Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters. Biopharm Drug Dispos 24: 259–273.