Dimethyl fumarate in relapsing–remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety

Abstract

Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing–remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.

Keywords:

• dimethyl fumarate
• experimental autoimmune encephalomyelitis
• immunology
• multiple sclerosis
• pharmacology

Financial & competing interests disclosure

T Menge has received travel grants and speaker honoraria from Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, and Teva. O Stüve has received grant support from Teva Pharmaceuticals. B Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis, and TEVA Pharmaceuticals. H Hartung has received honoraria for consulting and speaking from Bayer Healthcare, Biogen Idec, Genzyme, MerckSerono, Novartis, Roche, and Sanofi Aventis Teva, and was a co-investigator on the two Phase III trials CARE-MS I and CARE-MS II. Genzyme, from which all authors have received honoraria, has financial interests in alemtuzumab. 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 apart from those disclosed.

Key issues

• Based on data from an extensive clinical trials program, dimethyl fumarate (DMF) is an efficacious oral disease modifying agents for patients with relapsing–remitting multiple sclerosis.

• Experimental data suggest that DMF regulates the nuclear factor (erythroid-derived 2)-like 2 pathway, and that it might have neuroprotective effects.

• DMF appears to have acceptable safety profile, good bioavailability and limited drug interactions.

• The induction of lymphocyte apoptosis may be one of the mechanisms by which DMF may increase the risk of progressive multifocal leukoencephalopathy, and potentially that of other opportunistic infections.

Notes