Top

Published in:

01-10-2018 | Original Research Article

Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study

Authors: Massimiliano Mirabella, Luca Prosperini, Matteo Lucchini, Laura Boffa, Giovanna Borriello, Maria Chiara Buscarinu, Diego Centonze, Antonio Cortese, Chiara De Fino, Laura De Giglio, Giorgia Elia, Roberta Fantozzi, Elisabetta Ferraro, Ada Francia, Simona Galgani, Claudio Gasperini, Shalom Haggiag, Doriana Landi, Girolama Alessandra Marfia, Enrico Millefiorini, Fabrizia Monteleone, Viviana Nociti, Marco Salvetti, Eleonora Sgarlata, Carlo Pozzilli

Published in: CNS Drugs | Issue 10/2018

Abstract

Background

Two phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real-world practice are still limited.

Objectives

The aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes.

Methods

We collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes.

Results

We collected data for 1089 patients with a mean on-treatment follow-up of 17 ± 8 months; 331 (30.4%) of these patients were treatment naïve. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (n = 103) and disease activity (n = 63), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08 ± 0.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; p < 0.001], higher EDSS score (HR 1.18; p < 0.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; p = 0.003) and prior exposure to MS treatments (HR 1.43; p = 0.02).

Conclusion

This post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS.

Available only for authorised users

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107. https://doi.org/10.1056/NEJMoa1114287.CrossRefPubMed

Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97. https://doi.org/10.1056/NEJMoa1206328.CrossRefPubMed

Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678–92. https://doi.org/10.1093/brain/awq386.CrossRefPubMed

Chaves C, Ganguly R, Ceresia C, Camac A. Lymphocyte subtypes in relapsing-remitting multiple sclerosis patients treated with dimethyl fumarate. Mult Scler J. 2017;3(2):2055217317702933. https://doi.org/10.1177/2055217317702933.CrossRef

Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L. Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler (Houndmills, Basingstoke, England). 2016;22(8):1061–70. https://doi.org/10.1177/1352458515608961.

Longbrake EE, Cantoni C, Chahin S, Cignarella F, Cross AH, Piccio L. Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count. Mult Scler (Houndmills, Basingstoke, England). 2017:1352458517707069. https://doi.org/10.1177/1352458517707069.

Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol. 2018;9:5. https://doi.org/10.3389/fneur.2018.00005.CrossRefPubMedPubMedCentral

Anon. Tecfidera, INN-dimethyl fumarate—WC500162069.pdf. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf. Accessed 16 Aug 2017.

Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med. 2015;372(15):1476–8. https://doi.org/10.1056/NEJMc1415408.CrossRefPubMed

10.

Gieselbach RJ, Muller-Hansma AH, Wijburg MT, de Bruin-Weller MS, van Oosten BW, Nieuwkamp DJ, et al. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol. 2017;264(6):1155–64. https://doi.org/10.1007/s00415-017-8509-9.CrossRefPubMed

11.

Miclea A, Leussink VI, Hartung HP, Gold R, Hoepner R. Safety and efficacy of dimethyl fumarate in multiple sclerosis: a multi-center observational study. J Neurol. 2016;263(8):1626–32. https://doi.org/10.1007/s00415-016-8175-3.CrossRefPubMed

12.

Smoot K, Spinelli KJ, Stuchiner T, Lucas L, Chen C, Grote L, et al. Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center. Mult Scler (Houndmills, Basingstoke, England). 2017:1352458517709956. https://doi.org/10.1177/1352458517709956.

13.

Giovannoni G, Tomic D, Bright JR, Havrdova E. “No evident disease activity”: The use of combined assessments in the management of patients with multiple sclerosis. Mult Scler (Houndmills, Basingstoke, England). 2017;23(9):1179–87. https://doi.org/10.1177/1352458517703193.

14.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. https://doi.org/10.1002/ana.22366.CrossRefPubMedPubMedCentral

15.

Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, et al. Effect of BG-12 on contrast-enhanced lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler (Houndmills, Basingstoke, England). 2012;18(3):314–21. https://doi.org/10.1177/1352458511421054.

16.

Kappos, Giovannoni G, Gold R, Phillips JT, Arnold DL, Hotermans C, et al. Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis. Eur J Neurol. 2015;22(4):664–71. https://doi.org/10.1111/ene.12624.

17.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, et al. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol. 2015;77(3):425–35. https://doi.org/10.1002/ana.24339.CrossRefPubMed

18.

http://www.regione.lazio.it/binary/rl_sanita/tbl_normativa/SAN_DCA_U00386_13_11_2014.pdf. Accessed 7 Sept 2017.

19.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.CrossRefPubMed

20.

Publication N. National Cancer Institute. Common terminology criteria for adverse events. 2009;4: #09–7473. p. 112.

21.

Rio J, Nos C, Tintore M, Tellez N, Galan I, Pelayo R, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344–52. https://doi.org/10.1002/ana.20740.CrossRefPubMed

22.

Fox RJ, Chan A, Gold R, Phillips JT, Selmaj K, Chang I, et al. Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: Patient management considerations. Neurol Clin Pract. 2016;6(3):220–9. https://doi.org/10.1212/cpj.0000000000000238.CrossRefPubMedPubMedCentral

23.

Alroughani R, Ahmed SF, Behbehani R, Al-Hashel J. Effectiveness and safety of dimethyl fumarate treatment in relapsing multiple sclerosis patients: real-world evidence. Neurol Ther. 2017;6(2):189–96. https://doi.org/10.1007/s40120-017-0080-x.CrossRefPubMedPubMedCentral

24.

Longbrake EE, Cross AH. Dimethyl fumarate associated lymphopenia in clinical practice. Mult Scler (Houndmills, Basingstoke, England). 2015;21(6):796–7. https://doi.org/10.1177/1352458514559299.

25.

Baharnoori M, Gonzalez CT, Chua A, Diaz-Cruz C, Healy BC, Stankiewicz J, et al. Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count. Mult Scler Relat Disord. 2017;20:51–7. https://doi.org/10.1016/j.msard.2017.12.003.CrossRefPubMed

Title: Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study
Authors: Massimiliano Mirabella
Luca Prosperini
Matteo Lucchini
Laura Boffa
Giovanna Borriello
Maria Chiara Buscarinu
Diego Centonze
Antonio Cortese
Chiara De Fino
Laura De Giglio
Giorgia Elia
Roberta Fantozzi
Elisabetta Ferraro
Ada Francia
Simona Galgani
Claudio Gasperini
Shalom Haggiag
Doriana Landi
Girolama Alessandra Marfia
Enrico Millefiorini
Fabrizia Monteleone
Viviana Nociti
Marco Salvetti
Eleonora Sgarlata
Carlo Pozzilli
Publication date: 01-10-2018
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 10/2018
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.1007/s40263-018-0543-3

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study

Abstract

Background

Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 10/2018

Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox–Gastaut Syndrome: A Systematic Review and Meta-Analysis

Antipsychotic-Associated Symptoms of Tourette Syndrome: A Systematic Review

Emergency First-Line Anti-Seizure Medication for Seizures and Status Epilepticus: What is Going Wrong, Doctor?

Cancer Risk in Patients with Multiple Sclerosis: Potential Impact of Disease-Modifying Drugs

Potential Role of Selective Serotonin Reuptake Inhibitors in Improving Functional Outcome after Stroke

Palliative Sedation for the Terminally Ill Patient