Abstract
Dimethyl fumarate (DMF) was recently approved for treating patients with relapsing–remitting multiple sclerosis (RRMS) based on two phase III clinical trials demonstrating its efficacy. This prompts the need for demonstrating the clinical efficacy and safety of DMF in the real world. By retrospective analysis of medical records at two German MS centers, 644 MS patients treated with DMF were identified. All were included in a safety analysis, and a subgroup of patients with available efficacy data during previous MS therapies (n = 352) was further analyzed for annualized relapse rate and disability progression assessed by the EDSS. In the overall DMF population studied, the annualized relapse rate decreased from 0.52 at baseline to 0.35, and the annualized disability progression from 0.15 to 0.10. Patients who were switched from interferons or glatiramer acetate to DMF revealed a greater benefit, whereas patients pretreated with more potent immunotherapies did not respond that well. Interestingly, patients with a lymphocyte count ≥2000/µl after 0.52 years (mean, SD 0.2) of DMF treatment did not benefit compared to those with lower lymphocyte counts. In total, 22.2 % of the patients withdrew from DMF due to side effects, with gastrointestinal discomfort (12.7 %) and lymphopenia (5.3 %) as most frequently reported reasons. Our study corroborates that DMF is an overall safe and effective drug that reduces relapse rate as well as disability progression in MS patients. Further prospective studies are warranted to establish the additional parameters predicting DMF response, especially in patients switching from other first-line immunotherapies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Noseworthy JH, Lucchinetti C, Rodriguez M et al (2000) Multiple sclerosis. N Engl J Med 343:938–952
Gilgun-Sherki Y, Melamed E, Offen D et al (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251:261–268
Scannevin RH, Chollate S, Jung MY et al (2012) 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 341:274–284
Gold R, Kappos L, Arnold DL et al (2012) Placebo-controlled phase 3 study of oral BG- 12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107
Fox RJ, Miller H, Phillips T et al (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097
Fox EJ, Vasquez A, Grainger W et al (2016) Gastrointestinal tolerability of delayed- release dimethyl fumarate in a multicenter, open-label study of patients with relapsing forms of multiple sclerosis (MANAGE). IJMSC 18:9–18
Pozzilli C, Philipps JT, Fox RJ et al (2014) Long-term follow-up of the safety of delayed-release dimethyl fumarate in RRMS: Interim results from the ENDORSE extension study. MSJ 20(S1):67–284
Fox RJ, Chan A, Gold R et al (2014) Lymphocyte count reductions in relapsing-remitting multiple sclerosis (RRMS) patients treated with delayed-release dimethyl fumarate: an integrated analysis of the placebo-controlled studies. EJoN 21(S1):343
Hoepner R, Faissner S, Klasing A et al (2015) Progressive multifocal leukoencephalopathy during fumarate monotherapy of psoriasis. Neurol Neuroimmunol Neuroinflamm 2:e85
Winkelmann A, Loebermann M, Reisinger EC et al (2016) Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 12:217–233
Anonymous. German AWMF MS Guidelines; www.awmf.org. Accessed 20/03/2016
Anonymous. Special product information; www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/002601/WC500162069.pdf. Accessed 17/03/2016
Anonymous. Cancer, Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS, http://ctep.cancer.gov. Accessed 26/03/2016
Cohan S, Calkwood J, LaGanke C et al (2015) Real-World Clinical Outcomes in Relapsing-Remitting Multiple Sclerosis Patients who Switch from Natalizumab to Delayed-Release Dimethyl Fumarate: A Multicenter, Retrospective, Observational Study (STRATEGY). Neurology 84(14 Supplement):P3–P293
Spelman T, Mekhael L, Burke T et al (2016) Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis. Eur J Neurol 23:729–736
Fox RJ, Chan A, Gold R et al (2015) Characterization of absolute lymphocyte count profiles in MS patients treated with delayed-release dimethyl fumarate: considerations for patient managment. Neurology 85(4):E48
Phillips JT, Selmaj K, Gold R et al (2015) Clinical significance of gastrointestinal and flushing events in patients with multiple sclerosis treated with delayed-release dimethyl fumarate. IJMSC 17(5):236–243
Acknowledgments
We thank Bernd C. Kieseier for critical discussion.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
A Miclea reports no disclosures. V Leussink received speaker’s and board honoraria from Biogen and Novartis as well as scientific grant support from Novartis. HP Hartung received honoraria for consulting and speaking at symposia from Bayer Schering Pharma, Biogen Idec, GeNeuro, Genzyme, MedImmune, Merck Serono, Novartis, Octapharma, Opexa, Roche, Teva, and Sanofi-Aventis, with approval by the rector of Heinrich Heine University. R Gold received speaker’s and board honoraria from Biogen Idec, Baxter, Bayer Schering, Chugai Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis, Talecris, and TEVA. He also received scientific grant support from Biogen Idec, Bayer Schering, Genzyme, Merck Serono, and TEVA. R Hoepner received research and travel grants from Novartis and Biogen Idec.
Funding
No funding.
Additional information
A. Miclea and V. I. Leussink contributed equally to the work.
Rights and permissions
About this article
Cite this article
Miclea, A., Leussink, V.I., Hartung, H.P. et al. Safety and efficacy of dimethyl fumarate in multiple sclerosis: a multi-center observational study. J Neurol 263, 1626–1632 (2016). https://doi.org/10.1007/s00415-016-8175-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-016-8175-3