Showing papers on "Dimethyl fumarate published in 2015"
TL;DR: Dimethyl fumarate (DMF) was found to be the active principle in fumaric acid formulations and in vitro studies demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells.
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.
225 citations
TL;DR: A fatal case of progressive multifocal leukoencephalopathy in a 54-year-old woman in whom lymphocytopenia developed after treatment with delayed-release dimethyl fumarate for multiple sclerosis is reported.
Abstract: The authors report a fatal case of progressive multifocal leukoencephalopathy in a 54-year-old woman in whom lymphocytopenia developed after treatment with delayed-release dimethyl fumarate for multiple sclerosis.
176 citations
TL;DR: Subsets of peripheral blood leukocyte and lymphocyte subsets are differentially affected by DMF treatment of MS, and reduction of CD8+ T cells is more pronounced than that of CD4- T cells.
Abstract: Objective: To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets. Methods: Peripheral blood leukocyte and lymphocyte subsets, including CD3 1 ,C D4 1 , and CD8 1 T cells; CD19 1 B cells; and CD56 1 natural killer (NK) cells, were obtained at baseline and monitored at 3 months, 6 months, and 12 months after initiation of DMF treatment. Results: Total leukocyte and lymphocyte counts diminished after 6 months of DMF therapy. At 12 months, lymphocyte counts had decreased by 50.1% (p , 0.0001) and were below the lower limit of normal (LLN) in one-half of patients. CD3 1 T lymphocyte counts fell by 44.2% (p , 0.0001). Among subsets, CD8 1 T cell counts declined by 54.6% (p , 0.0001), whereas CD4 1 T cell counts decreased by 39.2% (p 5 0.0006). This disproportionate reduction of CD8 1 T cells relative to CD4 1 T cells was significant (p 5 0.007) and was reflected by a 35.5% increase in the CD4/CD8 ratio (p 5 0.007). A majority of CD8 1 T cell counts, but not CD4 1 T cell counts, were below the LLN even when total lymphocyte counts were greater than 500 cells/mL. CD19 1 B cell counts were reduced by 37.5% (p 5 0.035). Eosinophil levels decreased by 54.1% (p 5 0.006), whereas levels of neutrophils, monocytes, basophils, and NK cells were not significantly altered. Conclusion: Subsets of peripheral blood leukocytes and lymphocytes are differentially affected by DMF treatment of MS. Reduction of CD8 1 T cells is more pronounced than that of CD4 1 T cells. These findings may have implications for cell-mediated antiviral immunity during DMF
169 citations
TL;DR: Progressive multifocal leukoencephalopathy developed in a 64-year-old woman who was treated with compounded dimethyl fumarate for psoriasis andymphocytopenia in this patient was not as severe as in other patients with PML receiving fumaric acid esters.
Abstract: Progressive multifocal leukoencephalopathy developed in a 64-year-old woman who was treated with compounded dimethyl fumarate for psoriasis. Lymphocytopenia in this patient was not as severe as in other patients with PML receiving fumaric acid esters.
139 citations
TL;DR: DMF inhibited NF-κB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner and highlighted a key difference in the biological impact of related, yet distinct fumarate compounds.
132 citations
TL;DR: These studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions, which would be expected to result in divergent effects on downstream biology.
Abstract: Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.
125 citations
TL;DR: The effects of DMF and its metabolites mono‐methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved are investigated.
Abstract: Background and Purpose
Dimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved.
Experimental Approach
Cell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits.
Key Results
DMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability.
Conclusion and Implications
DMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.
108 citations
TL;DR: The potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons are reported and analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis.
Abstract: Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS) Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed Tecfidera™ (BG-12) is an oral formulation of the fumaric acid esters (FAE), containing the active metabolite dimethyl fumarate (DMF) Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide (H2O2) treatment In addition, utilizing the reactive oxygen species (ROS) assay, we showed that DMF reduced ROS production induced by H2O2 DMF also decreased oxidative stress-induced apoptosis Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress We further analyzed the expression of oxidative stress-induced genes in the NPC cultures and showed that DMF increased the expression of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) at both levels of RNA and protein Furthermore, we demonstrated the involvement of Nrf2-ERK1/2 MAPK pathway in DMF-mediated neuroprotection Finally, we utilized SuperArray gene screen technology to identify additional anti-oxidative stress genes (Gstp1, Sod2, Nqo1, Srxn1, Fth1) Our data suggests that analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis (MS)
106 citations
01 Jul 2015
TL;DR: Lymphopenia develops in a significant minority of DMF-treated patients, and if grade 2 or worse, is unlikely to resolve while on the drug, and increased vigilance in lymphocyte monitoring and infection awareness is particularly warranted in older patients and those switching from natalizumab.
Abstract: BackgroundDimethyl fumarate (DMF), a disease-modifying therapy for multiple sclerosis (MS), causes lymphopenia in a fraction of patients. The clinical significance of this is unknown. Several cases of progressive multifocal leukoencephalopathy in lymphopenic fumarate-treated patients have raised concerns about drug safety. Since lymphocytes contribute to MS pathology, lymphopenia may also be a biomarker for response to the drug.ObjectiveThe objective of this manuscript is to evaluate risk factors for DMF-induced lymphopenia and drug failure in a real-world population of MS patients.MethodsWe conducted a retrospective cohort study of 221 patients prescribed DMF at a single academic medical center between March 2013 and February 2015.ResultsGrade 2–3 lymphopenia developed in 17% of the total cohort and did not resolve during DMF treatment. Older age (>55), lower baseline absolute lymphocyte count and recent natalizumab exposure increased the risk of developing moderate to severe lymphopenia while on DMF. Ly...
101 citations
TL;DR: Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not NRF2 knockout, mice showed a 24 h window of therapeutic opportunity.
Abstract: Background and Purpose— Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage. Methods— Male rats and mice, including Nrf2 knockouts, were subjected to intracerebral injection of blood (to mimic ICH) and then treated with DMF. Neurological deficit, brain edema, gene induction profile and hematoma resolution were evaluated. Phagocytic functions of primary microglia in culture were used to study hematoma resolution. Results— Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not Nrf2 knockout, mice. Most importantly, the treatment of ICH with DMF showed a 24 h window of therapeutic opportunity. Conclusions— A clinically relevant dose of DMF demonstrates potent therapeutic efficacy and impressive 24 h therapeutic window of opportunity. This study merits further evaluation of this compound as potential treatment for ICH in humans.
92 citations
TL;DR: DMF is suggested to be beneficial for the treatment of neurodegenerative diseases like PD as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum.
TL;DR: It is suggested that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema.
TL;DR: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.
Abstract: Introduction
Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.
TL;DR: Meta-analyses showed that dimethyl fumarate both three times daily and twice daily reduced the number of patients with a relapse and the risk for drug discontinuation due to adverse events over two years, compared to placebo.
Abstract: Background
Multiple sclerosis (MS) often leads to severe neurological disability and a serious decline in quality of life. The ideal target of disease-modifying therapy for MS is to prevent disability worsening and improve quality of life. Dimethyl fumarate is considered to have an immunomodulatory activity and neuroprotective effect. It has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency as a first-line therapy for adult patients with relapsing-remitting MS (RMSS).
Objectives
To assess the benefit and safety of dimethyl fumarate as monotherapy or combination therapy versus placebo or other approved disease-modifying drugs (interferon beta, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, alemtuzumab) for patients with MS.
Search methods
The Trials Search Co-ordinator searched the Trials Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (4 June 2014). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to June 2014) from the MS societies in Europe and America. We also communicated with investigators participating in trials of dimethyl fumarate and the Biogen Idec Medical Information.
Selection criteria
We included randomised, controlled, parallel-group clinical trials (RCTs) with a length of follow-up equal to or greater than one year evaluating dimethyl fumarate, as monotherapy or combination therapy, versus placebo or other approved disease-modifying drugs for patients with MS without restrictions regarding dosage, administration frequency and duration of treatment.
Data collection and analysis
We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.
Main results
Two RCTs were included, involving 2667 adult patients with RRMS to evaluate the efficacy and safety of two dosages of dimethyl fumarate (240 mg orally three times daily or twice daily) by direct comparison with placebo for two years. Among them, a subsample of 1221 (45.8%) patients were selected to participate in MRI evaluations by each study site with MRI capabilities itself. No powered head-to-head study with an active treatment comparator has been found. Meta-analyses showed that dimethyl fumarate both three times daily and twice daily reduced the number of patients with a relapse (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.50 to 0.66, P < 0.00001 and 0.64, 95% CI 0.54 to 0.77, P < 0.00001, respectively) or disability worsening (RR 0.70, 95% CI 0.57 to 0.87, P = 0.0009 and 0.65, 95% CI 0.53 to 0.81, P = 0.0001, respectively) over two years, compared to placebo. The treatment effects were decreased in the likely-case scenario analyses taking the effect of dropouts into consideration. Both dosages also reduced the annualised relapse rate. Data of active lesions on MRI scans were not combined because there was a high risk of selection bias for MRI outcomes and imprecision of MRI data in both studies, as well as an obvious heterogeneity between the studies. In terms of safety profile, both dosages increased the risk for adverse events and the risk for drug discontinuation due to adverse events. The most common adverse events included flushing and gastrointestinal events (upper abdominal pain, nausea and diarrhoea). Uncommon adverse events included lymphopenia and leukopenia, but they were more likely to happen with dimethyl fumarate than with placebo (high dosage: RR 5.25, 95% CI 2.20 to 12.51, P = 0.0002 and 5.23, 95% CI 2.47 to 11.07, P < 0.0001, respectively; low dosage: RR 5.69, 95% CI 2.40 to 13.46, P < 0.0001 and 6.53, 95% CI 3.13 to 13.64, P < 0.00001, respectively). Both studies had a high attrition bias resulting from the unbalanced reasons for dropouts among groups. Quality of evidence for relapse outcome was moderate, but for disability worsening was low.
Authors' conclusions
There is moderate-quality evidence to support that dimethyl fumarate at a dose of 240 mg orally three times daily or twice daily reduces both the number of patients with a relapse and the annualised relapse rate over two years of treatment in comparison with placebo. However, the quality of the evidence to support the benefit in reducing the number of patients with disability worsening is low. There is no high-quality data available to evaluate the benefit on MRI outcomes. The common adverse effects such as flushing and gastrointestinal events are mild-to-moderate for most patients. Lymphopenia and leukopenia are uncommon adverse events but significantly associated with dimethyl fumarate. Both dosages of dimethyl fumarate have similar benefit and safety profile, which supports the option of low-dose administration. New studies of high quality and long-term follow-up are needed to evaluate the benefit of dimethyl fumarate on prevention of disability worsening and to observe the long-term adverse effects including progressive multifocal leukoencephalopathy.
TL;DR: 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.
Abstract: 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.
TL;DR: The evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation is summarized and the mechanisms underlying the beneficial effects of H CA2 activation in neuroinflammatory diseases are discussed.
TL;DR: Dimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.
TL;DR: Investigating the neuroprotective role of monomethyl fumarate (MMF), the biologically active metabolite of DMF, in retinal ischemia-reperfusion (I/R) injury, and examining the role of Nrf2 in mediating MMF action indicated that fumaric acid esters (FAEs) exert a neuronal protective function in the retinal I/R model.
Abstract: Retinal ischemia results in neuronal degeneration and contributes to the pathogenesis of multiple blinding diseases. Recently, the fumaric acid ester dimethyl fumarate (DMF) has been FDA-approved for the treatment of multiple sclerosis, based on its neuroprotective and anti-inflammatory effects. Its potential role as a neuroprotective agent for retinal diseases has received little attention. In addition, DMF’s mode of action remains elusive, although studies have suggested nuclear factor erythroid 2-related factor 2 (Nrf2) activation as an important mechanism. Here we investigated the neuroprotective role of monomethyl fumarate (MMF), the biologically active metabolite of DMF, in retinal ischemia-reperfusion (I/R) injury, and examined the role of Nrf2 in mediating MMF action. Wild-type C57BL/6J and Nrf2 knockout (KO) mice were subjected to 90 min of retinal ischemia followed by reperfusion. Mice received daily intraperitoneal injection of MMF. Inflammatory gene expression was measured using quantitative reverse transcription PCR (qRT-PCR) at 48 h after I/R injury. Seven days after I/R, qRT-PCR for Nrf2 target gene expression, immunostaining for Muller cell gliosis and cell loss in the ganglion cell layer (GCL), and electroretinography for retinal function were performed. The results of this study confirmed that MMF reduces retinal neurodegeneration in an Nrf2-dependent manner. MMF treatment significantly increased the expression of Nrf2-regulated antioxidative genes, suppressed inflammatory gene expression, reduced Muller cell gliosis, decreased neuronal cell loss in the GCL, and improved retinal function measured by electroretinogram (ERG) after retinal I/R injury in wild-type mice. Importantly, these MMF-mediated beneficial effects were not observed in Nrf2 KO mice. These results indicate that fumaric acid esters (FAEs) exert a neuronal protective function in the retinal I/R model and further validate Nrf2 modulation as a major mode of action of FAEs. This suggests that DMF and FAEs could be a potential therapeutic agent for activation of the Nrf2 pathway in retinal and possibly systemic diseases.
TL;DR: Results suggest that although CDDO-Im,CDDO-Me and DMF all activate the Nrf2 pathway, they target distinct genes and signaling pathways, resulting in opposite effects for the prevention of experimental lung cancer.
Abstract: Lung cancer accounts for the highest number of cancer-related deaths in the USA, highlighting the need for better prevention and therapy Activation of the Nrf2 pathway detoxifies harmful insults and reduces oxidative stress, thus preventing carcinogenesis in various preclinical models However, constitutive activation of the Nrf2 pathway has been detected in numerous cancers, which confers a survival advantage to tumor cells and a poor prognosis In our study, we compared the effects of two clinically relevant classes of Nrf2 activators, dimethyl fumarate (DMF) and the synthetic oleanane triterpenoids, CDDO-imidazolide (CDDO-Im) and CDDO-methyl ester (CDDO-Me) in RAW 2647 mouse macrophage-like cells, in VC1 lung cancer cells and in the A/J model of lung cancer Although the triterpenoids and DMF both activated the Nrf2 pathway, CDDO-Im and CDDO-Me were markedly more potent than DMF All of these drugs reduced the production of reactive oxygen species and inhibited nitric oxide production in RAW2647 cells, but the triterpenoids were 100 times more potent than DMF in these assays Microarray analysis revealed that only 52 of 99 Nrf2-target genes were induced by all three compounds, and each drug regulated a unique subset of Nrf2 genes These drugs also altered the expression of other genes important in lung cancer independent of Nrf2 Although all three compounds enhanced the phosphorylation of CREB, only DMF increased the phosphorylation of Akt CDDO-Me, at either 125 or 50mg/kg of diet, was the most effective drug in our lung cancer mouse model Specifically, CDDO-Me significantly reduced the average tumor number, size and burden compared with the control group (P < 005) Additionally, 52% of the tumors in the control group were high-grade tumors compared with only 14% in the CDDO-Me group Though less potent, CDDO-Im had similar activity as CDDO-Me In contrast, 61-63% of the tumors in the DMF groups (400-1200mg/kg diet) were high-grade tumors compared with 52% for the controls (P < 005) Additionally, DMF significantly increased the average number of tumors compared with the controls (P < 005) Thus, in contrast to the triterpenoids, which effectively reduced pathogenesis in A/J mice, DMF enhanced the severity of lung carcinogenesis in these mice Collectively, these results suggest that although CDDO-Im, CDDO-Me and DMF all activate the Nrf2 pathway, they target distinct genes and signaling pathways, resulting in opposite effects for the prevention of experimental lung cancer
TL;DR: Insight is provided into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography–mass spectrometry and shotgun lipidomics.
Abstract: Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography-mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis.
01 Jan 2015
TL;DR: 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.
Abstract: 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.
TL;DR: This study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocytes counts.
Abstract: Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug.
TL;DR: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS.
Abstract: Objective: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. Methods: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). Results: DMF BID and TID produced significant and 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 and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. Conclusions: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. Classification of evidence: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.
TL;DR: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.
Abstract: Background:Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.Objective:To evaluate delayed-release DMF in newly diagnosed relapsing–remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.Methods:Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.Results:The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions b...
TL;DR: It is indicated that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.
Abstract: Background: In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0−3) with the recommended DMF dosage (240 mg twice daily). Methods: Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks. Results: The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing an...
TL;DR: Clinicians should consider PML in the differential diagnosis of fumarate‐treated patients presenting with brain lesions or seizures even in the absence of severe lymphocytopenia, reports a psoriasis patient who presented with progressive neurologic dysfunction and seizures after 2.5 years offumarate therapy.
Abstract: Progressive multifocal leukoencephalopathy (PML) has recently been described in psoriasis or multiple sclerosis patients treated with fumaric acid esters (fumarates), who had developed severe and long-standing lymphocytopenia (<500/mm3). We report a psoriasis patient who presented with progressive neurologic dysfunction and seizures after 2.5 years of fumarate therapy. Despite absolute lymphocyte counts remaining between 500-1000/mm3, his CD4+ and CD8+ T-cell counts were markedly low. MRI showed right hemispheric and brainstem lesions and JC virus DNA was undetectable in his cerebrospinal fluid. Brain biopsy revealed typical features of PML as well as JC virus-infected neurons. Clinicians should consider PML in the differential diagnosis of fumarate-treated patients presenting with brain lesions or seizures even in the absence of severe lymphocytopenia. ANN NEUROL 2015;78:501–514
TL;DR: A more precise estimate of the efficacy of delayed‐release dimethyl fumarate in relapsing multiple sclerosis is obtained and the consistency of DMF's effects across patient subgroups stratified by baseline demographic and disease characteristics is examined.
Abstract: Objective
Obtain a more precise estimate of the efficacy of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) in relapsing multiple sclerosis (MS) and examine the consistency of DMF's effects across patient subgroups stratified by baseline demographic and disease characteristics.
Methods
A prespecified integrated analysis of the randomized, double-blind, placebo-controlled, Phase 3 DEFINE and CONFIRM trials was conducted.
Results
The intent-to-treat population comprised 2301 patients randomized to receive placebo (n = 771) or DMF 240 mg twice daily (BID; n = 769) or three times daily (TID; n = 761). At 2 years, DMF BID and TID reduced the annualized relapse rate by 49% and 49% (both P < 0.0001), risk of relapse by 43% and 47% (both P < 0.0001), risk of 12-week confirmed disability progression by 32% (P = 0.0034) and 30% (P = 0.0059), and risk of 24-week confirmed disability progression by 29% (P = 0.0278) and 32% (P = 0.0177), respectively, compared with placebo. In a subset of patients (MRI cohort), DMF BID and TID reduced the mean number of new/enlarging T2-hyperintense lesions by 78% and 73%, gadolinium-enhancing lesion activity by 83% and 70%, and mean number of new nonenhancing T1-hypointense lesions by 65% and 64% (all P < 0.0001 vs. placebo). Effects were generally consistent across patient subgroups.
Interpretation
The integrated analysis provides a more precise estimate of DMF's efficacy. DMF demonstrated a robust reduction in disease activity and a consistent therapeutic effect across patient subgroups.
TL;DR: Progressive multifocal leukoencephalopathy can occur in patients with lymphocyte counts between 450 and 700/μl, produce only faint symptoms and is not excluded by negative JC-virus-polymerase chain reaction in cerebrospinal fluid.
Abstract: Progressive multifocal leukoencephalopathy is a severe demyelinating disease caused by the polyoma JC virus in patients with reduced immunocompetence A few cases of progressive multifocal leukoencephalopathy have been reported in patients treated with fumaric acid esters A 53-year-old Caucasian woman reported to our clinic with a first focal epileptic seizure and mild cognitive impairment Since 15 years, she was treated with fumaderm for her psoriasis During that time, her lymphocyte counts ranged between 450 and 700/μl Cerebral magnet resonance imaging showed multifocal subcortical T2 hyperintense lesions with partial gadolinium enhancement She did not have antibodies against human immunodeficiency virus 1 and 2 and cerebrospinal fluid-polymerase chain reaction for viral infections including a sensitive JC-virus polymerase chain reaction were negative The diagnosis of progressive multifocal leukoencephalopathy was established by histological analysis and detection of JC-virus desoxyribonucleic acid in brain biopsy specimens Dimethyl fumarate was stopped and Mirtazapin and Mefloquin were initiated Neurological examination and imaging remained stable Progressive multifocal leukoencephalopathy can occur in patients with lymphocyte counts between 450 and 700/μl, produce only faint symptoms and is not excluded by negative JC-virus-polymerase chain reaction in cerebrospinal fluid The incidence of progressive multifocal leukoencephalopathy may thus be underestimated and a more careful surveillance of patients would be necessary
TL;DR: A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF.
Abstract: Background and purpose
Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing−remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF.
Methods
Eligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis.
Results
A total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0–12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post-baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo).
Conclusions
In phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing−remitting multiple sclerosis.
TL;DR: Consensus was reached among North American clinicians on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies.
Abstract: Introduction
Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy.