Dimethyl fumarate (TECFIDERA) is an orally administered fumarate ester recently FDA approved for first-line monotherapy of multiple sclerosis. Because it is rapidly and completely hydrolyzed by esterases before reaching the systemic circulation, the pharmacologic activity of dimethyl fumarate is due to its active metabolite, monomethyl fumarate. Although the precise mechanism of action is incompletely characterized, monomethyl fumarate is thought to exert neuroprotective effects in patients with multiple sclerosis by activating the nuclear erythroid 2-related factor 2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptional pathway.[1,3,4,5] Using a model of endogenous neuronal oxidative stress, Albrecht, et al., studied time- and concentration-dependent effects of dimethyl fumarate and monomethyl fumarate and concluded that dimethyl fumarate causes a brief period of oxidative stress that results in the intraneuronal synthesis of the antioxidant glutathione (GSH) mediated through the Nrf2 pathway (see Figure 1). Others have proposed additional immunomodulatory actions for dimethyl fumarate mediated through nitric oxide, interleukins, tumor necrosis factor (TNF-α), or other cytokines.[7,8,9,10,11]
Proposed Mechanism of Action of Dimethyl Fumarate. Abbreviations used: ARE, antioxidant response element; GCLC, glutamate-cysteine ligase; GSH, glutathione; GstA2, glutathione S-transferase A2; HO-1, heme-oxygenase-1; Nqo1, NADPH quinone oxidoreductase 1; MMF, monomethyl fumarate; Nrf2, nuclear factor erythroid-derived 2-related factor 2.
Two randomized, controlled, phase 3 clinical trials (DEFINE and CONFIRM) of dimethyl fumarate administered at a dose of 240 mg twice daily by mouth over a period of 2 years were associated with a statistically significant reduction in clinical disease exacerbations (the primary efficacy endpoint), a reduction in the necessity for rescue therapy with intravenous corticosteroids, and improvements in other indicators of disease progression, including MRI images of brain lesions (see Table 1 ). To date studies have been insufficiently powered to detect a consistent effect on disability progression, but quality of life assessments are expected as a secondary outcome measure of the 5-year follow-on study (ENDORSE).
Monomethyl fumarate is metabolized through the tricarboxylic acid (TCA) cycle to fumarate, glucose, and CO2, with exhalation of CO2 being the primary route of elimination. Initiating therapy at a sub-maximal dose (120 mg twice daily for 7 days) and administering the drug with food are both recommended to minimize flushing and gastrointestinal intolerability, which are the most commonly reported side effects.[1,15] Other notable side effects include hypersensitivity, abnormal rise in hepatic enzymes, lymphopenia (sometimes accompanied by reductions in total WBC, neutrophils, hemoglobin, hematocrit, and platelets), and eosinophilia. Based on strong signals of nephrotoxicity in non-humans and the theoretical risk of renal cell cancer from intracellular accumulation of fumarate, post-marketing study of a large population of patients will be necessary to fully assess the long-term safety of dimethyl fumarate.[4,16]
In summary, multiple sclerosis is a chronic demyelinating disorder of the central nervous system that leads to progressive disability. The current treatment goals are to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability.[16,17] In this regard, dimethyl fumarate offers a promising alternative to orally administered fingolimod (GILENYA) or teriflunomide (AUBAGIO), which are currently marketed in the United States under FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) programs because of serious safety concerns. More clinical experience with all three agents will be necessary to differentiate the tolerability of long-term therapy for patients diagnosed with multiple sclerosis.
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