Dimethyl fumarate for treating relapsing multiple sclerosis

Abstract

Introduction: Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera® by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm®; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994.

Areas covered: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report.

Expert opinion: DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected.

Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.

Keywords:

• dimethyl fumarate
• fumarate
• lymphopenia
• monoethyl fumarate
• multiple sclerosis
• neuroprotection
• nuclear factor (erythroid-derived-2)-like 2
• progressive multifocal encephalopathy

Acknowledgements

The authors thank Biogen-Idec editorial staff for having provided a fact-check review of this manuscript. The generic term for the German product marketed as Fumaderm® in Europe is designated as ‘monoethyl fumarate’, although dimethyl fumarate constitutes 56% of the product and monoethyl fumarate 44%. In the USA, it is designated as ‘dimethyl fumarate and monoethyl fumarate’. The authors have abbreviated this generic designation as ‘DMF-MEF’.

Declaration of interest

KW Rammohan and W Sheremata have received research grants from the NIH, Biogen-Idec, Hoffman-La Roche, Novartis, Teva, GlaxoSmithKline, and EMD Serono through their University. KW Rammohan has also received compensation from Biogen-Idec, Teva, EMD Serono, Hoffman-La Riche, Novartis and Genzyme. W Sheremata has received honoraria for consultation from Biogen-Idec and Questcor, and will receive an honorarium from Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

¹ Based on ‘personal’, non-scientific meta-analysis, as practicing physicians typically do.

² The most recent communication from Biogen-Idec, just received, indicate that the company in referring to the Fumaderm® product sold in Europe, recommends use the generic term “Fumarate mixture”.