Dimethyl fumarate in the treatment of relapsing–remitting multiple sclerosis: an overview

Abstract

Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.

Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway

“…Its mode of action as an anti-oxidant is attributed to its ability to activate the nuclear factor (erythroid – derived 2) – like 2 (Nrf2) genetic pathway and so reduce oxidative stress 23, 24 . In normal cells, Nrf2 is sequestered by the Kelch like –ECH- associated protein 1 (Keap-1) to form a Nrf2-Keap 1 complex.…”

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…DMF is currently used as an oral therapeutic agent for the treatment of relapsing forms of multiple sclerosis (9,32). DMF exerts anti-inflammatory and cytoprotective effects through activation of the Nrf-2 pathway in neuronal cells (2).…”

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

“…Recent evidence indicates that DMF acts at the core of the immunological synapse by inhibiting dendritic cell maturation and differentiation of Th cells into autoreactive Th1 and Th17 cells [81,82]. NF-kB signaling in dendritic cells is suppressed by DMF leading to the generation of type II dendritic cells that produce IL-10 instead of IL-12 and IL-23.…”