Pharmacology and clinical efficacy of dimethyl fumarate (BG-12) for treatment of relapsing-remitting multiple sclerosis

Therapeutics and Clinical Risk Management

Volumn 10, Issue 1, 2014, Pages 229-238

  Ruggieri, Serena ^a   Tortorella, Carla ^b   Gasperini, Claudio ^c  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b UNIVERSITY OF BARI   (Italy)

^c SAN CAMILLO FORLANINI HOSPITAL   (Italy)

Author keywords

Disease modifying drugs; Neuroprotection; Nrf2; Nuclear factor erythroid derived 2 (E2) related factor; Oral treatment; Oxidative stress

Indexed keywords

CYTOKINE; FUMADERM; FUMARIC ACID; FUMARIC ACID DIMETHYL ESTER; PLACEBO; TRANSCRIPTION FACTOR NRF2;

CYTOKINE RELEASE; DRUG CLASSIFICATION; DRUG EFFICACY; DRUG FORMULATION; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; GASTROINTESTINAL DISEASE; HUMAN; IMMUNOMODULATION; LEUKOCYTE COUNT; MULTIPLE SCLEROSIS; NONHUMAN; REVIEW; RISK BENEFIT ANALYSIS;

EID: 84897969927     PISSN: 11766336     EISSN: 1178203X     Source Type: Journal    
DOI: 10.2147/TCRM.S53285     Document Type: Review

References (58)

1. Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin. 1995;13:119-146.
2. Murray TJ. Diagnosis and treatment of multiple sclerosis. BMJ. 2006;332:525-527.
3. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502-1517.
4. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133-146.
5. Trojano M, Pellegrini F, Fuiani A, et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol. 2007;61(4):300-306.
6. Bergamaschi R, Quaglini S, Tavazzi E, et al. Immunomodulatory therapies delay disease progression in multiple sclerosis. Mult Scler. Epub May 31, 2012.
7. Batoulis H, Addicks K, Kuerten S. Emerging concepts in autoimmune encephalomyelitis beyond the CD4/T(H)1 paradigm. Ann Anat. 2010;192(4):179-193.
8. Frohman EM, Racke MK, Raine CS. Multiple sclerosis-the plaque and its pathogenesis. N Engl J Med. 2006;354:942-955.
9. Peterson LK, Fujinami RS. Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2007;184:37-44.
10. Witte ME, Bo L, Rodenburg RJ, et al. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol. 2009;219;193-204.
11. Hendriks JJA, Alblas J, Van der Pol SM, van Tol EA, Dijkstra CD, de Vries HE. Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med. 2004;200: 1667-1672.
12. Vladimirova O, O'Connor J, Cahill A, Alder H, Butunoi C, Kalman B. Oxidative damage to DNA in plaques of MS brains. Mult Scler. 1998;4:413-418.
13. Miller DH, Thompson AJ, Morrissey SP, et al. High dose steroids in acute relapses of multiple sclerosis: MRI evidence for a possible mechanism of therapeutic effect. J Neurol Neurosurg Psychiatry. 1992;55(6):450-453.
14. Gallo P, Chiusole M, Sanzari M, et al. Effect of high-dose steroid therapy on T-cell subpopulations. A longitudinal study in MS patients. Acta Neurol Scand. 1994;89(2):95-101.
15. Goodkin DE. Interferon beta-1b. Lancet. 1994;344:1057-1060.
16. Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther. 2007;29: 2031-2048.
17. 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: 1268-1276.
18. Hartung HP, Gonsett R, König N, et al; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind randomized multicenter trial. Lancet. 2002;360:2018-2025.
19. Martinelli V, Cocco E, Capra R, et al; Italian Mitoxantrone Group. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology. 2011;77:1887-1895.
20. Polman CH, O'Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910.
21. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870-1880.
22. Kappos L, Radue EW, O'Connor P, et al. FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.
23. Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402-415.
24. Río J, Comabella M, Montalban X. Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol. 2009;5:553-560.
25. Schweckendiek W. [Treatment of psoriasis vulgaris]. Med Monatsschr. 1959;13:103-104. German.
26. Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol. 1999;141:424-429.
27. Mrowietz U, Rostami-Yazdi M, Neureither M, Reich K. [15 years of fumaderm: fumaric acid esters for the systemic treatment of moderately severe and severe psoriasis vulgaris]. J Dtsch Dermatol Ges. 2009;7 Suppl 2:S3-S16. German.
28. Werdenberg D, Joshi R, Wolffram S, Merkle HP, Langguth P. Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters. Biopharm Drug Dispos. 2003;24:259-273.
29. Litjens NH, Burggraaf J, van Strijen E, et al. Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004;58: 429-432.
30. Nibbering PH, Thio B, Zomerdijk TP, Bezemer AC, Beijersbergen RL, van Furth R. Effects of monomethylfumarate on human granulocytes. J Invest Dermatol. 1993;101:37-42.
31. 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;134:678-692.
32. Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012;341:274-284.
33. Lee DH, Gold R, Linker RA. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci. 2012;13(9):11783-11803.
34. Altmeyer P, Hartwig R, Matthes U. [Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients]. Hautarzt. 1996;47: 190-196. German.
35. Treumer F, Zhu K, Gläser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol. 2003;121: 1383-1388.
36. de Jong R, Bezemer AC, Zomerdijk TP, van de Pouw-Kraan T, Ottenhoff TH, Nibbering PH. Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. Eur J Immunol. 1996;26:2067-2074.
37. Litjens NH, Rademaker M, Ravensbergen B, et al. Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol. 2004;34: 565-575.
38. Asadullah K, Schmid H, Friedrich M, et al. Influence of monomethylfumarate on monocytic cytokine formation-explanation for adverse and therapeutic effects in psoriasis? Arch Dermatol Res. 1997;289: 623-630.
39. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun. 1997;234:19-23.
40. Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity. Trends Mol Med. 2005;11:43-48.
41. Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol. 2006;145: 101-107.
42. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006;13:604-610.
43. Kappos L, Gold R, Miller DH, et al; BG-12 Phase IIb Study Investigators. 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;372:1463-1472.
44. 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;258:449-455.
45. Gold R, Kappos L, Arnold DL, et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-1107.
46. Fox RJ, Miller DH, Phillips JT, et al; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-1097.
47. Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol. 2003;149:363-369.
48. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368:1657-1658.
49. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368:1658-1659.
50. Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med. 2013;368:1659-1661.
51. Schwab N, Ulzheimer JC, Fox RJ, et al. Fatal PML associated with efalizumab therapy: insights into integrin aLβ2 in JC virus control. Neurology. 2012;78:458-467.
52. 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 (P01.162). Neurology. 2013;80(Meeting Abstracts 1):P01.162.
53. US Food and Drug Administration. FDA approves new multiple sclerosis treatment: Tecfidera [press release]. Silver Spring, MD: US Food and Drug Administration; March 27, 2013 [updated March 28, 2013]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm. Accessed August 19, 2013.
54. Tecfidera [webpage on the Internet]. London, UK: European Medicines Agency; 2013 [updated March 22, 2013]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002601/smops/Positive/human_smop_000498.jsp&mid=WC0b01ac058001d127. Accessed August 19, 2013.
55. O'Connor P, Wolinsky JS, Confavreux C et al; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;36514:1293-1303.
56. Vermersch P, Czlonkowska A, Grimaldi LM et al; for the TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. November 21, 2013. [Epub ahead of print].
57. Comi G, Jeffery D, Kappos L et al; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-1009.
58. Vollmer T, Soelberg Sorensen P, Arnold D on behalf of the BRAVO Study Group. A placebo-controlled and active comparator phase III trial (BRAVO) for relapsing-remitting multiple sclerosis. In: 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Amsterdam, the Netherlands, October 19-22, 2011.