Dimethyl Fumarate: A Review of Its Use in Patients with Relapsing-Remitting Multiple Sclerosis

Abstract

Dimethyl fumarate (Tecfidera®) is a novel oral therapy that has recently been approved for the treatment of relapsing forms of multiple sclerosis (MS) and relapsing-remitting MS (RRMS). In preclinical studies, dimethyl fumarate exhibited anti-inflammatory and cytoprotective properties that are generally thought to be mediated via activation of the nuclear factor (erythroid-derived 2)-like 2 transcriptional pathway, which is involved in the cellular response to oxidative stress. In the large, double-blind, multinational, 2-year DEFINE and CONFIRM trials conducted in over 2,600 adult patients with RRMS, twice-daily oral dimethyl fumarate 240 mg was effective in reducing the proportion of patients with MS relapse at 2 years (primary endpoint of DEFINE) and the annualized relapse rate (primary endpoint of CONFIRM) compared with placebo, with reduced disability progression also observed with the drug versus placebo in DEFINE. Dimethyl fumarate also reduced disease activity measures relative to placebo in these trials, as assessed by magnetic resonance imaging. Dimethyl fumarate was generally well tolerated in patients with RRMS; adverse events that occurred more frequently in dimethyl fumarate than in placebo recipients included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating that dimethyl fumarate was associated with continued efficacy for up to 4 years of treatment, with no new tolerability concerns. In conclusion, although more comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, oral dimethyl fumarate is an important addition to the therapeutic options available for RRMS.

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

“…Nrf2 deficiency exacerbates inflammation, such as sepsis, pleurisy, and emphysema, in a variety of murine models (20 -22). In human clinical studies, the Nrf2 inducer Tecfidera (dimethyl fumarate) has been approved for the treatment of multiple sclerosis (23,24)-at least in part based on its antiinflammatory function. Thus, Nrf2 is essential in controlling inflammation.…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…The best example is the multiple sclerosis drug BG-12 (dimethyl fumarate). BG-12 was repurposed from an older drug by Biogen Idec, who successfully developed and commercialized it using the use patent [141,143]. There are several strategies that could be used to obtain adequate IP protection to maximize the market exclusivity of a drug.…”

Novel Approaches of Oxidative Stress Mechanisms in the Multiple Sclerosis Pathophysiology and Therapy

“…The transcription factor Nrf2 is a key regulator of antioxidative defense (92,93). Oral dimethyl fumarate (DMF) activates antiinflammatory and antioxidative pathways to upregulate the expression of this molecule (94,95). A differential expression is involved in the defense against OS, predominantly in actively demyelinating white matter lesions (58,94,96).…”