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Molecular Vision 2019Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a...
PURPOSE
Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation.
METHODS
Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS.
RESULTS
In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis.
CONCLUSIONS
This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.
Topics: Animals; Dimethyl Fumarate; Eye Proteins; Female; Male; Mice, Inbred C57BL; Motor Activity; Optic Neuritis; Retinal Ganglion Cells; Vision, Ocular; Visual Acuity
PubMed: 31523122
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Aug 2020In recent years there has been a dramatic rise in available disease-modifying therapies for the treatment of relapsing multiple sclerosis (MS). Dimethyl fumarate (DMF)... (Review)
Review
INTRODUCTION
In recent years there has been a dramatic rise in available disease-modifying therapies for the treatment of relapsing multiple sclerosis (MS). Dimethyl fumarate (DMF) is an oral drug approved by the FDA for relapsing MS with unique immunomodulatory and cytoprotective effects.
AREAS COVERED
Herein, the authors provide the reader with a review of the literature obtained via a PubMed database search and provide their expert opinion on the use of DMF in clinical practice. The article details DMF's mechanism of action, long-term data on efficacy, tolerability and safety.
EXPERT OPINION
Since approval, growing experience with DMF in clinical practice demonstrates a combination of efficacy, ease of administration along with an acceptable safety profile. The authors believe that DMF is a valuable long-term treatment option in patients with relapsing MS. However, long-term follow up studies are needed to provide further data on progressive multifocal leukoencephalopathy (PML) risk stratification for MS patients on treatment with DMF. Indeed, despite the strong association with lymphopenia, not all patients with DMF associated PML experienced prolonged overall lymphopenia, suggesting that additional predictive metrics are still needed.
Topics: Administration, Oral; Clinical Trials as Topic; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Leukopenia; Long-Term Care; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome
PubMed: 32543241
DOI: 10.1080/14656566.2020.1763304 -
Expert Review of Neurotherapeutics Apr 2015Dimethyl 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... (Review)
Review
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.
Topics: Anti-Inflammatory Agents; Dimethyl Fumarate; Humans; Multiple Sclerosis, Relapsing-Remitting
PubMed: 25800129
DOI: 10.1586/14737175.2015.1025755 -
Journal of Molecular Medicine (Berlin,... Apr 2019Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, details regarding its mode of... (Review)
Review
Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, details regarding its mode of action are still emerging. It is believed that the mode of action of DMF involves both nuclear factor erythroid-derived 2-related factor (Nrf2)-dependent and independent pathways, which lead to an anti-inflammatory immune response due to type II myeloid cell and Th2 cell differentiation and neuroprotection. In this review, we will focus on the molecular and signaling effects of DMF that lead to changes in peripheral immune cell composition and function, alteration in CNS cell-specific functions, and effect on the blood-brain barrier.
Topics: Animals; Dimethyl Fumarate; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; NF-E2-Related Factor 2; Th2 Cells
PubMed: 30820593
DOI: 10.1007/s00109-019-01761-5 -
Journal of Translational Medicine Nov 2023Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of...
BACKGROUND
Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.
METHODS
The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats. The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.
RESULTS
We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats. Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.
CONCLUSIONS
Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.
Topics: Humans; Rats; Animals; Dimethyl Fumarate; NF-E2-Related Factor 2; Drug Repositioning; Epilepsy; Seizures; Status Epilepticus; Disease Models, Animal
PubMed: 37940957
DOI: 10.1186/s12967-023-04695-2 -
Neurotherapeutics : the Journal of the... Sep 2023In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for... (Meta-Analysis)
Meta-Analysis
In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for relapsing-remitting multiple sclerosis, namely, dimethyl fumarate (DMF) and teriflunomide (TRF). We searched scientific databases to identify real-world studies reporting a direct comparison of DMF versus TRF. We fitted inverse-variance weighted meta-analyses with random effects models to estimate the risk ratio (RR) of relapse, confirmed disability worsening (CDW), and treatment discontinuation. Quantitative synthesis was accomplished on 14 articles yielding 11,889 and 8133 patients treated with DMF and TRF, respectively, with a follow-up ranging from 1 to 2.8 years. DMF was slightly more effective than TRF in reducing the short-term relapse risk (RR = 0.92, p = 0.01). Meta-regression analyses showed that such between-arm difference tends to fade in studies including younger patients and a higher proportion of treatment-naïve subjects. There was no difference between DMF and TRF on the short-term risk of CDW (RR = 0.99, p = 0.69). The risk of treatment discontinuation was similar across the two oral drugs (RR = 1.02, p = 0.63), but it became slightly higher with DMF than with TRF (RR = 1.07, p = 0.007) after removing one study with a potential publication bias that altered the final pooled result, as also confirmed by a leave-one-out sensitivity analysis. Discontinuation due to side effects and adverse events was reported more frequently with DMF than with TRF. Our findings suggest that DMF is associated with a lower risk of relapses than TRF, with more nuanced differences in younger naïve patients. On the other hand, TRF is associated with a lower risk of treatment discontinuation for side effects and adverse events.
Topics: Humans; Dimethyl Fumarate; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 37528262
DOI: 10.1007/s13311-023-01416-x -
Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity.Brain : a Journal of Neurology Nov 2021Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we...
Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.
Topics: Adult; Animals; Antioxidants; Autoimmunity; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Young Adult
PubMed: 34849598
DOI: 10.1093/brain/awab307 -
Neurology(R) Neuroimmunology &... Sep 2021To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS).
METHODS
In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set.
RESULTS
Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups.
DISCUSSION
Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment.
TRIAL REGISTRATION INFORMATION
Clinicaltrials.gov identifier NCT02959658.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.
Topics: Adult; Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Neurofilament Proteins
PubMed: 34429340
DOI: 10.1212/NXI.0000000000001037 -
Drug and Therapeutics Bulletin Dec 2017Dimethyl fumarate (Skilarence - Almirall) was licensed by the European Medicines Agency in June 2017 for the treatment of moderate to severe plaque psoriasis in adults...
Dimethyl fumarate (Skilarence - Almirall) was licensed by the European Medicines Agency in June 2017 for the treatment of moderate to severe plaque psoriasis in adults in need of systemic therapy. An unlicensed formulation of dimethyl fumarate has been used in the UK for the management of psoriasis for several years. Here, we consider the evidence for the new product and how it fits with current strategies for the management of adults with psoriasis.
Topics: Adult; Dimethyl Fumarate; Humans; Practice Guidelines as Topic; Psoriasis
PubMed: 29237700
DOI: 10.1136/dtb.2017.12.0565 -
Frontiers in Immunology 2023Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity...
BACKGROUND AND OBJECTIVE
Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response.
MATERIAL AND METHODS
PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively.
RESULTS
In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes).
CONCLUSIONS
Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
Topics: Humans; Dimethyl Fumarate; Multiple Sclerosis; Immunosuppressive Agents; Leukocytes, Mononuclear; Killer Cells, Natural; Biomarkers
PubMed: 37483622
DOI: 10.3389/fimmu.2023.1209923