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Dimethyl fumarate, the methyl ester of fumaric acid, is also known by its chemical name, dimethyl (E) butenedioate, (C6H8O). It was initially used as a fungicide to prevent the growth of mold on furniture. Due to allergic skin reactions, this application was banned in Europe in 1988. Dimethyl fumarate was discovered to be effective as treatment for psoriasis in 1959 in Germany. Fumaderm®, a proprietary formulation of fumaric acid in combination with three other esters, is approved in Europe as an oral therapy for psoriasis. In 2013, the FDA approved dimethyl fumarate as a first-line oral treatment for relapsing forms of multiple sclerosis. Approval was granted by the European Commission in 2014. Diroximel fumarate is a novel oral fumarate approved in 2019 for the treatment of patients with relapsing multiple sclerosis, and it undergoes esterase cleavage to monomethyl fumarate, the same pharmacologically active metabolite as the previously approved delayed-release formulation of dimethyl fumarate.
Pharmacodynamics. The exact mechanism of therapeutic effect of dimethyl fumarate in multiple sclerosis is unknown, but there are some explanations for the beneficial effect. According to one study, dimethyl fumarate and the metabolite, monomethyl fumarate, have been shown to have direct neuroprotective effects through upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with subsequent induction of an antioxidant response (24). Data from two large pivotal phase 3 studies of multiple sclerosis patients treated with dimethyl fumarate, DEFINE and CONFIRM, provide the first evidence of Nrf2 pathway activation (08). Dimethyl fumarate induced NADPH:quinone oxidoreductase-1 gene expression in ex vivo-stimulated peripheral blood mononuclear cells.
Dimethyl fumarate exerts antiinflammatory effects by modifying glutathione levels that can induce expression of the antiinflammatory protein haem oxygenase-1, which is one of the mechanisms responsible for the immunomodulatory actions (16). Dimethyl fumarate regulates expression of histone deacetylases in astrocytes, which could contribute to Nrf2 activation and suppression of inflammatory responses that can cause long-lasting changes in gene expression (11). Dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase, thereby downregulating aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its antiinflammatory effects (15).
Findings from clinical trials are consistent with cytoprotective and antiinflammatory properties of dimethyl fumarate that contribute to its efficacy as initial therapy for patients with relapsing multiple sclerosis (05). Evidence from recent studies indicates that the working mechanism of dimethyl fumarate treatment in multiple sclerosis is multifactorial, leading to a restored immune balance (20).
Pharmacokinetics. After oral administration, dimethyl fumarate undergoes rapid hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate. Dimethyl fumarate is not quantifiable in plasma following oral administration. All pharmacokinetic studies have been performed with plasma monomethyl fumarate concentrations.
Absorption. The median Tmax of monomethyl fumarate is 2 to 2.5 hours. The peak plasma concentration (Cmax) and area under the curve (AUC) increase approximately proportionally to the dose. Following administration of dimethyl fumarate 240 mg twice a day with food, the mean Cmax of monomethyl fumarate was 1.87 mg/L and AUC was 8.21 mg.hr/L in patients with multiple sclerosis.
Distribution. Volume of distribution of monomethyl fumarate varies between 53 and 73 L in healthy subjects. Human plasma protein binding of monomethyl fumarate is 27% to 45% and independent of concentration.
Metabolism. In humans, dimethyl fumarate is extensively metabolized by esterases in tissues before it reaches the systemic circulation. Further metabolism of dimethyl fumarate occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 system. Monomethyl fumarate, fumaric and citric acid, and glucose are the major metabolites in plasma.
Elimination. Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the dimethyl fumarate dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose, respectively. The terminal half-life of monomethyl fumarate is approximately 1 hour, and it disappears from the circulation within 24 hours in most individuals. Accumulation of monomethyl fumarate does not occur with multiple doses of dimethyl fumarate. Delayed-release dimethyl fumarate is well tolerated over 4 days of dosing in healthy volunteers, with a pharmacokinetic profile consistent with that of nondelayed release formulation and with no evidence of accumulation (25).
Clinical trials of dimethyl fumarate under the name BG-12 for multiple sclerosis are listed in Table 1.
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, placebo-controlled phase IIb trial.
Antiinflammatory effects indicated by reduction of new lesions and favorable safety profile justified further long-term phase III studies (12).
Retrospective study of MRI scans from a phase IIb trial for the effect of 240 mg BG-12 orally 3 times daily for 24 weeks on evolution of new Gd+ lesions to T1-hypointense lesions.
In addition to reducing new Gd+ lesions, BG-12 reduced their evolution to T1-hypointense lesions in patients with multiple sclerosis compared with placebo (17).
The effect of BG-12 240 mg 3 times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics of patients in a phase IIb trial.
BG-12 demonstrated efficacy in patients with relapsing-remitting multiple sclerosis by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics (13).
Placebo-controlled phase III study of oral BG-12 versus glatiramer in relapsing-remitting multiple sclerosis (CONFIRM trial).
BG-12 and glatiramer significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo (06). Subgroup analyses indicate that these treatments were effective against relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics (10).
A randomized, double-blind, placebo-controlled phase III study on patients with relapsing-remitting multiple sclerosis randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg 3 times daily, or placebo (DEFINE study).
Both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI (07).
CONFIRM: A 2-year, placebo-controlled study of the efficacy and safety of dimethyl fumarate 240 mg (twice or 3 times daily) in patients with relapsing-remitting multiple sclerosis.
Consistent reductions vs. placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment (19).
EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study for evaluating the gastrointestinal tolerability of diroximel fumarate vs dimethyl fumarate in patients with relapsing-remitting MS.
Diroximel fumarate has an improved gastrointestinal tolerability profile with less severe gastrointestinal events and lower discontinuation rates due to gastrointestinal adverse events (22).
An ongoing phase III extension study, ENDORSE, is evaluating the long-term efficacy and safety of dimethyl fumarate as a monotherapy in approximately 1700 patients with relapsing-remitting multiple sclerosis who completed the DEFINE and CONFIRM studies. Interim data from ENDORSE in 2012 showed that safety and tolerability of dimethyl fumarate was consistent with that seen in the DEFINE and CONFIRM studies, with no new or worsening safety signals identified among patients with continued exposure to the drug. An integrated analysis of the phase 3 DEFINE and CONFIRM studies on patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate showed that 26% of patients achieved “no evidence of disease activity” compared to 12% in the placebo group over a period of 2 years (09). Results of the latest clinical trials show that dimethyl fumarate shifted the immunophenotype of circulating absolute lymphocyte and counts were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance (18). Monitoring of absolute lymphocyte counts is used to identify patients at risk of subsequently developing prolonged moderate to severe lymphopenia, which is a risk factor for progressive multifocal leukoencephalopathy in patients treated with dimethyl fumarate.
Dimethyl fumarate is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
Dimethyl fumarate, as an immune modulator and inducer of the antioxidant response, suppresses HIV replication and neurotoxin release, making it a potential candidate as a neuroprotectant in HIV (02).
The aim of treatment is to reduce the number of lesions in relapsing-remitting multiple sclerosis. The longest period of follow-up in clinical trials is 4 years.
The starting dose for dimethyl fumarate in delayed-release capsules is 120 mg twice a day orally. After 7 days, the recommended dose is increased to 240 mg twice a day orally.
Because dimethyl fumarate has been reported to decrease lymphocyte counts by approximately 30%, a recent (within 6 months) complete blood count should be reviewed before starting treatment and should be repeated annually and as clinically indicated. Dimethyl fumarate has not been studied in patients with preexisting low lymphocyte counts, and caution should be exercised when treating these patients.
Pediatric. Safety and effectiveness of dimethyl fumarate in pediatric patients have not been established.
Geriatric. Clinical trials of dimethyl fumarate did not include enough patients aged 65 and over to determine whether they respond differently from younger patients.
Pregnancy. Dimethyl fumarate is designated Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring were observed when dimethyl fumarate was administered during pregnancy and lactation at clinically relevant doses. Dimethyl fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether this drug is excreted in human milk; therefore, caution should be exercised when it is administered to a nursing woman.
Anesthesia. No information is available about the use of anesthesia in patients on dimethyl fumarate therapy.
No potential drug interactions with dimethyl fumarate have been identified.
The most common adverse reactions for dimethyl fumarate as reported during clinical trials are flushing, mostly mild to moderate in nature, and gastrointestinal events such as diarrhea, nausea, abdominal pain, etc. These events are most common at the start of therapy and usually decrease over time.
Liver injury. In the postmarketing phase, cases of clinically significant hepatocellular injury have been reported to develop as early as a few days after the first dose of dimethyl fumarate, but none of the cases resulted in liver failure (21).
Multifocal leukoencephalopathy. Two cases of progressive multifocal leukoencephalopathy were reported in patients with psoriasis treated with oral dimethyl fumarate. One patient in the Netherlands and another in Germany developed progressive multifocal leukoencephalopathy after several years of treatment with European formulations of the drug approved as psoriasis treatment (04; 28). The manufacturer responded to these reports with the following statement (27):
Among patients treated with BG-12 (dimethyl fumarate for multiple sclerosis) to date, there has been no evidence of an increased risk of serious or opportunistic infections, and no reports of PML. Fumarates are distinct products with different active ingredients, metabolites, and formulations, and they are used in different populations with varying coexisting conditions. These factors may lead to important differences in the safety profiles among the various products.
Dimethyl fumarate produces significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts, which are relevant to cases of progressive multifocal leukoencephalopathy in patients receiving this drug (14). Another patient with multiple sclerosis who was treated with delayed-release dimethyl fumarate died from complications of aspiration pneumonia and progressive multifocal leukoencephalopathy with severe, prolonged lymphocytopenia, which is considered a risk factor (23). One fatal case of West Nile encephalitis has been reported in a multiple sclerosis patient with grade 3 lymphopenia who had been on dimethyl fumarate for 5 months (01). Another case of progressive multifocal leukoencephalopathy was reported in a patient treated with dimethyl fumarate for psoriasis (03). The authors pointed out that this adverse effect can occur in patients with lymphocyte counts between 450 and 700/μl, can produce only faint symptoms, and is not excluded by negative JC virus–polymerase chain reaction in cerebrospinal fluid. Therefore, incidence of progressive multifocal leukoencephalopathy may be underestimated, and a more careful surveillance of patients is necessary. Periodic monitoring of absolute lymphocyte counts as well as lymphocyte subsets is recommended to identify patients at increased risk for leukoencephalopathy. CD4 and CD8 lymphocytopenia with a total lymphocyte count above 500 cells per cubic millimeter with dimethyl fumarate is relevant because CD8 lymphocytopenia might confer a predisposition to JC virus replication (26). If there is severe, prolonged lymphocytopenia, interruption of treatment should be considered in these patients to reduce the risk.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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