fumarates and Multiple-Sclerosis--Relapsing-Remitting

Diroximel fumarate (Vumerity

Topics: Administration, Oral; Adult; Animals; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Therapeutic Equivalency

Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.

Topics: Animals; Dimethyl Fumarate; Esters; Fumarates; Humans; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Psoriasis

Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera® by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm®; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994.. This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report.. DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.

Topics: Dimethyl Fumarate; Esters; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

The efficacy and safety of the three oral agents approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS) are reviewed.. Limitations to parenteral disease-modifying therapies (DMTs) (interferon beta-1a, interferon beta-1b, and glatiramer acetate) for the treatment of RRMS have been addressed by the approval of three oral DMTs: fingolimod, teriflunomide, and dimethyl fumarate. In clinical trials, each of the oral DMTs was superior to placebo in annualized relapse rate, a key indicator of clinical efficacy, and in neuroradiological efficacy. A reduction in disability progression was evident with higher doses of teriflunomide but was not consistently demonstrated with fingolimod or dimethyl fumarate. Each of the oral DMTs demonstrated acceptable safety in clinical trials, with adverse-effect profiles that differ from injectable agents. The safety of both teriflunomide and dimethyl fumarate is supported by long-term use of related agents for other diseases; however, postmarketing surveillance studies are needed to determine the safety of each of the oral DMTs in patients with RRMS. Dimethyl fumarate seems to have the most innocuous safety profile of the three agents. Fingolimod requires first-dose inpatient monitoring due to cardiac safety concerns and multiple laboratory tests prior to initiation of therapy, while teriflunomide has been associated with hepatotoxicity and teratogenicity.. With the approval of three oral drugs for RRMS-fingolimod, teriflunomide, and dimethyl fumarate-the therapeutic strategy for RRMS has evolved to include options that are efficacious and appear to have administration advantages over established parenteral treatments.

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Disease Progression; Drug Approval; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Sphingosine; Toluidines; United States; United States Food and Drug Administration

Dimethyl fumarate (DMF) is a novel oral therapy that has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate shows anti-inflammatory and cytoprotective properties that are thought to be mediated primarily via activation of the nuclear factor (erythroid-derived 2)-like 2- Nrf2 transcriptional pathway, which up-regulates the genes involved in the cellular response to oxidative stress. The drug was evaluated in 2 large, randomized, double-blind, multicentric, multinational, 2-year, phase III clinical trials. The DEFINE and CONFIRM trials, conducted with over 2600 adult patients suffering from RRMS, unequivocally confirmed the efficacy of DMF (2 x 240 mg daily) in reducing the annualized relapse rate (ARR) and reducing the proportion of patients with MS relapse at 2 years. Significantly reduced sustained disability progression was observed with the drug versus placebo in DEFINE, while the same tendency was seen in CONFIRM. The MRI results of the studies were also convincing: DMF significantly reduced the number of new/enlarging T2-hyperintense lesions and the number of Gd-enhancing lesions compared to placebo. Dimethyl fumarate was generally well tolerated and no safety concern has been raised. Adverse events that occurred most frequently 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 the same results as the two previous studies. In conclusion, although further, mostly comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, dimethyl-fumarate is a valuable addition to the therapeutic options available for RRMS.

Topics: Administration, Oral; Adult; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Disabled Persons; Disease Progression; Drug Administration Schedule; Fumarates; Humans; Immunosuppressive Agents; Multicenter Studies as Topic; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic; Treatment Outcome

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).. 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. . 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.. 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.. 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.. 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.. 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.

Topics: Administration, Oral; Adult; Dimethyl Fumarate; Drug Administration Schedule; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic

Multiple sclerosis (MS) is a chronic inflammatory disease, affecting more than 2.5 million people worldwide with more 400,000 cases in the United States alone. There has been considerable improvement in the treatment of MS, with the introduction of disease-modifying drugs; however, new oral therapies may provide additional benefit by providing an alternative treatment modality and the potential for improved adherence by avoiding the injection-associated side effects and anxiety encountered with some first-line agents. BG-12 (dimethyl fumarate) is an oral agent approved in the United States for the treatment of relapsing forms of MS.. We review published literature about what is known about the mechanism of action of BG-12, and key efficacy and safety findings from three clinical studies in patients with relapsing-remitting MS (RRMS).. Data from preclinical studies have demonstrated that BG-12 may promote anti-inflammatory and cytoprotective activities that are mediated, at least in part, by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway. Studies in animals have shown a protective effect of BG-12 on neuronal, axonal and myelin integrity. Results from a phase 2 study and two randomized double-blind placebo-controlled phase 3 studies, CONFIRM and DEFINE, have shown that BG-12 provides clinical and radiologic efficacy in patients with RRMS. At 2 years, BG-12 240 mg twice and three times daily reduced annualized relapse rate (CONFIRM primary endpoint) by 44% and 51% and the risk of relapse (DEFINE primary endpoint) by 49% and 50%, respectively, compared with placebo (all p < 0.001). BG-12 was generally well tolerated and had an acceptable safety profile, with a similar incidence of adverse events across treatment groups.. BG-12 may have cytoprotective and anti-inflammatory properties that contribute to its efficacy among patients with RRMS. Findings from phase 2 and 3 studies further support BG-12 as an effective initial therapy. ClinicalTrials.gov ID: NCT00168701; NCT00420212: NCT00451451.

Topics: Adult; Animals; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Mice; Multiple Sclerosis, Relapsing-Remitting; NF-E2-Related Factor 2; Rats

Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for relapsing-remitting multiple sclerosis (RRMS).. A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed.. BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (rate ratio: 0.529 [95% CI: 0.451-0.620]), IFNs (0.76 [95% CI: 0.639-0.904]), GA (0.795 [95% CI: 0.668-0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610-0.970] and 0.775 [95% CI: 0.614-0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes.. Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled and the variability in the definition of outcomes in included trials.

Topics: Antibodies, Monoclonal, Humanized; Crotonates; Dimethyl Fumarate; Disease Progression; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Interferon beta-1a; Interferon beta-1b; Interferon-beta; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Nitriles; Propylene Glycols; Randomized Controlled Trials as Topic; Recurrence; Sphingosine; Toluidines

As a case study of patent coverage for a repurposed drug, Biogen Idec's approach for Tecfidera(®), an oral formulation of dimethyl fumarate, was analyzed. While mixtures of fumarates have been used for over 50 years to treat psoriasis, Tecifidera is approved for the treatment of relapsing-remitting multiple sclerosis. Biogen pursued claims to pharmaceutical formulations and useful doses for treating multiple sclerosis, an approach that is relevant to pharmaceutical lifecycle management in general. A survey of recent US, EP, and PCT patent applications indicate other companies are developing competing fumarate formulations. While it is possible to pursue secondary patents for compounds without composition of matter coverage, regulatory data exclusivity provides additional protection to delay competitors.

Topics: Animals; Dimethyl Fumarate; Drug Repositioning; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Patents as Topic

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.

Topics: Animals; Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

After the approval of fumaric acid in February 2014 another first line agent is now available for the treatment of multiple sclerosis (MS). Along with the various beta interferon preparations, glatiramer acetate, teriflunomide and fumaric acid add to the repertoire of oral therapeutics for the initial treatment of relapsing remitting MS in daily practice. In order to employ these drugs in an individualized and precise medical manner and considering their efficacy and side effects, it seems worthwhile to learn the so far known mode of action and background history. Fumaric acid, as one of the newest drugs approved for MS, reveals the longest history as it was in use for decades as a treatment in psoriasis patients. Furthermore, fumaric acid is a good example for so far not extensively exploited option of drug reposition in medicine in general. The current review summarizes the outcomes of the clinical approval studies of fumaric acid in MS and discusses the dual mode of action, the immunomodulatory and tissue protective effect, as well as the reported adverse events under fumaric acid treatment. This review aims to serve an aid in the daily decision-making practice when choosing the baseline therapy for MS patients.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Flushing; Fumarates; Gastrointestinal Diseases; Humans; Immunologic Factors; Kidney Diseases; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Treatment Outcome

Our current treatment algorithms include only IFN-β and glatiramer as available first-line disease-modifying drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved in Europe and nine in the United States making the choice of therapy more complex. The purpose of the review has been to work out new management algorithms for treatment of relapsing-remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies.. Recent large placebo-controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-β and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-β 1a, has been approved in Europe, but not yet in the United States.. In de novo-treated patients, the injectables, IFN-β and glatiramer acetate, will to a great extent be replaced by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a second-line therapy.

Topics: Alemtuzumab; Algorithms; Antibodies, Monoclonal, Humanized; Clinical Protocols; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Glatiramer Acetate; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Nitriles; Peptides; Propylene Glycols; Sphingosine; Toluidines

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, encompassing both neuroinflammatory as well as prominent neurodegenerative aspects. A significant proportion of MS patients will develop neurological disability over time and up until recently licensed drugs could not satisfactorily halt this process. However, in the last years MS treatment has raised a stage of rapid progress. Several new drugs with significantly improved efficacy have entered the therapeutic field and several others are currently undergoing phase III clinical trials. In this review, we will summarize efficacy data as well as safety and tolerability issues of currently licensed drugs for relapsing-remitting MS and will give a short update on new drugs currently undergoing late-stage clinical trials.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Dimethyl Fumarate; Fumarates; Glatiramer Acetate; Humans; Interferon-beta; Mitoxantrone; Multiple Sclerosis, Relapsing-Remitting; Peptides

Relapsing-remitting multiple sclerosis (RRMS) management has dramatically changed over the past decade. New drugs have arrived on the market, allowing for more individualised treatment selection. However, this diversity has increased the complexity of RRMS patient follow-up. In this review, we provide summarised information about treatment efficacy, potential side-effects, follow-up recommendations, vaccinations, and pregnancy safety issues for all currently available disease modifying therapies and those awaiting approval.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Crotonates; Daclizumab; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Nitriles; Propylene Glycols; Sphingosine; Toluidines

Multiple sclerosis was without effective disease-modifying therapy for many years. The introduction of the injectable therapies (interferon and glatiramer acetate) some 20 years ago was considered a major advance. Recent years have heralded a revolution in treatment options with the introduction of intravenous natalizumab and, even more recently, three oral agents. We are currently in a period of determining the best use of these therapies to ensure prevention of disease progression while maintaining patient safety. Despite these new treatments, there are still many patients living with disability as a result of multiple sclerosis and significant attention must be given to symptomatic management.

Topics: Administration, Intravenous; Administration, Oral; Alemtuzumab; Antibodies, Monoclonal, Humanized; Crotonates; Dimethyl Fumarate; Disease Progression; Drug Administration Schedule; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Mitoxantrone; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Nitriles; Propylene Glycols; Risk Assessment; Sphingosine; Toluidines

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms.

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Treatments for multiple sclerosis (MS) are only partially effective and most require a parenteral route of administration and/or may have severe side effects. Dimethyl fumarate is the active compound of BG-12 recently licensed for the treatment of relapsing-remitting MS. The pivotal Phase III trials have demonstrated an approximately 50% reduction of relapse rates compared with placebo paralleled by a reduction in new lesion formation on MRI. A dose of 240 mg two-times a day had an optimal effect. Flushing and gastrointestinal symptoms (diarrhea, abdominal pain, nausea) were common adverse events in the first month(s) of treatment. Severe side effects were not more common than in the placebo group for a treatment period of 2 years. The mode of action is not exactly clear and both immunomodulatory effects and an activation of the transcription factor Nrf2 are suggested. This new oral drug will be a welcome addition to existing MS treatments.

Topics: Animals; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; NF-E2-Related Factor 2; Treatment Outcome

In March 2013, BG-12 was approved by the US FDA and EMA for the treatment of relapsing-remitting multiple sclerosis (RRMS) after meeting the primary and most secondary end points in two global phase III trials (CONFIM and DEFINE). From these data, the optimal BG-12 dosage for the treatment of RRMS is 240 mg twice daily. In the DEFINE and CONFIRM trials, the relative reduction of annual relapse rates were 53 and 44% in the approval-relevant dosages, respectively. Moreover, in the DEFINE trial, progression of disability was significantly ameliorated with a relative risk reduction of 38%. In both studies, administration of BG-12 was generally well-tolerated and safe. Most common adverse events were flushing and gastrointestinal events, including diarrhea, nausea and upper abdominal pain, which were particularly common in the early phases of treatment. At present, the introduction of BG-12 into the European market and its position among current MS treatment regimens is awaited with great interest.

Topics: Animals; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified.

Topics: Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Potassium Channels, Inwardly Rectifying; Quinolones; Receptors, Tumor Necrosis Factor, Type I; T-Lymphocytes

Fumaric acid was originally therapeutically used in psoriasis. Several lines of evidence have demonstrated immunomodulatory but also neuroprotective effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4+ and CD8+ T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethylfumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-κB)-dependent transcription of tumor necrosis factor-alpha (TNF-α) induced genes in human endothelial cells. Animal experiments in the mouse model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis, revealed a clear preservation of myelin and axonal density in the plaque. Molecular studies showed that this is based on the antioxidative mechanism of action via induction of the transcription factor Nrf-2. A phase II clinical trial in relapsing-remitting multiple sclerosis (RRMS) patients with dimethylfumarate showed a significant reduction in the number of gadolinium enhancing lesions after 24weeks.

Topics: Animals; Clinical Trials as Topic; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is > 60%. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second-line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors-1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosen on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians.

Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cladribine; Dimethyl Fumarate; Drug Administration Schedule; Fingolimod Hydrochloride; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Peptides; Propylene Glycols; Quinolones; Sphingosine; Treatment Outcome

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs.. Positive results have been reported for five new oral drugs for RRMS--fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate--in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon. WHERE NEXT?: Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

Topics: Administration, Oral; Cladribine; Clinical Trials as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Biogen Idec Inc, following its acquisition of Fumapharm AG, is developing BG-12 (Panaclar, BG-00012, FAG-201), an oral second-generation fumarate derivative, for the potential treatment of multiple sclerosis (MS). In January 2007, a phase III program for relapsing-remitting MS patients was initiated. The company was also developing the drug for psoriasis and, in October 2003, Biogen Idec expected to commence phase III trials for psoriasis in the US in the following year. In April 2005, the drug met its European phase III psoriasis trial endpoint, with the data expected to be used to support a market authorization filing in Germany in 2005. It was later disclosed that while an application had been filed, this was subsequently withdrawn based on a joint decision by Fumapharm and Biogen Idec. No further development has been reported on BG-12 for psoriasis in the US and it was not listed as a pursued indication on Biogen Idec's April 2007 pipeline.

Topics: Animals; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Drug Evaluation, Preclinical; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated.. EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1.. As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%).. After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs.. ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

Topics: Adult; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Recurrence

Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile.. The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis.. EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability.. DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).. DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events.. ClinicalTrials.gov (NCT03093324).

Topics: Adult; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Recurrence

Monomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability.. This was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability.. Inferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted.. Bafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.

Topics: Dimethyl Fumarate; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting

Diroximel fumarate (DRF) is a novel oral fumarate in development for patients with relapsing forms of multiple sclerosis (MS). Clinical findings from the DRF development program suggest that rates of gastrointestinal (GI) treatment-emergent adverse events (TEAEs) and discontinuation due to GI TEAEs are low, based on clinical and real-world observations of other fumaric acid esters, including dimethyl fumarate (DMF). The incidence of GI TEAEs varies from 40 to 88% in clinical and real-world studies of DMF. The objective of this study is to present GI tolerability findings from the EVOLVE-MS-1 study and present biologic hypotheses for the improved GI properties of DRF.. GI TEAEs and treatment discontinuation because of GI TEAEs were assessed in DRF-treated patients with relapsing-remitting MS who were participating in the ongoing, 96-week, open-label, phase 3 EVOLVE-MS-1 study.. As of March 30, 2018, a total of 696 patients were enrolled in EVOLVE-MS-1. GI TEAEs were reported in 30.9% (215/696) of patients; the vast majority (96%; 207/215) experienced events that were mild or moderate in severity. When GI AEs did occur, they occurred early in treatment, resolved (88.8%; 191/215), and were of short duration [median 7.5 (range 1-87) days] in most patients. GI TEAEs led to < 1% of patients discontinuing treatment.. We suggest that the distinct chemical structure of DRF contributes to the observed low rates of GI TEAEs and GI-associated treatment discontinuations, possibly due to a combination of several factors. We hypothesize that these factors may include less reactivity with off-target proteins and/or lower production of a methanol leaving group that may contribute to GI irritation. A direct comparison of GI tolerability with DRF versus DMF is being evaluated in the EVOLVE-MS-2 study.. ClinicalTrials.gov number NCT02634307.. Alkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).

Topics: Adult; Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting

Delayed-release dimethyl fumarate (DMF) is an approved oral treatment for relapsing forms of multiple sclerosis (MS). Preclinical studies demonstrated that DMF activated the nuclear factor E2-related factor 2 (Nrf2) pathway. DMF and its primary metabolite monomethyl fumarate (MMF) were also shown to promote cytoprotection of cultured central nervous system (CNS) cells via the Nrf2 pathway.. To investigate the activation of Nrf2 pathway following ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with DMF or MMF, and in DMF-treated patients from two Phase 3 relapsing MS studies DEFINE and CONFIRM.. Transcription of Nrf2 target genes NADPH:quinone oxidoreductase-1 (NQO1) and heme-oxygenase-1 (HO1) was measured using Taqman® assays. RNA samples were isolated from ex vivo-stimulated PBMCs and from whole blood samples of 200 patients each from placebo, twice daily (BID) and three times daily (TID) treatments.. DMF and MMF induced NQO1 and HO1 gene expression in ex vivo-stimulated PBMCs, DMF being the more potent inducer. Induction of NQO1 occurred at lower DMF concentrations compared to that of HO1. In DMF-treated patients, a statistically significant induction of NQO1 was observed relative to baseline and compared to placebo. No statistical significance was reached for HO1 induction.. These data provide the first evidence of Nrf2 pathway activation from two large pivotal Phase 3 studies of DMF-treated MS patients.

Topics: Adult; Delayed-Action Preparations; Dimethyl Fumarate; Female; Fumarates; Heme Oxygenase-1; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Signal Transduction

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.. 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.. 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).. In phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing-remitting multiple sclerosis.

Topics: Adult; Delayed-Action Preparations; Dimethyl Fumarate; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome

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.. 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).. 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.. 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.. 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.

Topics: Adolescent; Adult; Delayed-Action Preparations; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Internationality; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Young Adult

Multiple sclerosis (MS) has a significant impact on health-related quality of life (HRQoL) with symptoms adversely affecting many aspects of everyday living. BG-12 (dimethyl fumarate) demonstrated significant efficacy in the phase III studies DEFINE and CONFIRM in patients with relapsing-remitting MS. In CONFIRM, HRQoL was worse in patients with greater disability at baseline, and who relapsed during the study, and improved with BG-12 treatment. Mean Short Form-36 Physical Component Summary scores for BG-12 increased over 2 years and scores for placebo decreased. Coupled with clinical and neuroradiological benefits, these HRQoL results further support BG-12 as an effective oral treatment for relapsing MS.

Topics: Adult; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Quality of Life; Surveys and Questionnaires; Treatment Outcome

Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies.. To evaluate the health-related quality of life (HRQoL) impairment that is associated with RRMS and to assess the effects of BG-12 on HRQoL in the DEFINE study.. Patients with RRMS were randomized to BG-12 240 mg twice (BID) or three times (TID) daily, or placebo, for 2 years. HRQoL was assessed by the Short Form-36 (SF-36), global assessment of well-being visual analog scale and the EuroQol-5D.. In the 1237 patients from DEFINE, HRQoL impairment was greatest in patients who had higher disability scores and in those who had experienced relapse. Change in SF-36 physical component summary scores during 2 years' treatment significantly favored BG-12 over placebo (both doses: p < 0.001). We saw similar benefits in other measures of functioning and general well-being as early as Week 24. These benefits were maintained during the study.. Our results add to evidence for a negative impact of RRMS on HRQoL and they demonstrate the benefits of BG-12 on HRQoL measures, which coupled with significant clinical efficacy, further support its use as a new treatment for RRMS.

Topics: Adult; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Quality of Life; Surveys and Questionnaires

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing-remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.

Topics: Adolescent; Adult; Atrophy; Brain; Delayed-Action Preparations; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Young Adult

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

Topics: Adolescent; Adult; Brain; Delayed-Action Preparations; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Placebos; Treatment Outcome; Young Adult

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

Topics: Adult; Dimethyl Fumarate; Disease Progression; Dose-Response Relationship, Drug; Female; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides; Secondary Prevention

In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68% [hazard ratio 0.32 (95% confidence interval (CI) 0.16-0.62)] to 26% [0.74 (0.51-1.09)] and from 66% [0.34 (0.23-0.50)] to 25% [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.

Topics: Administration, Oral; Adult; Dimethyl Fumarate; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides; Secondary Prevention

In a phase 2b study in patients with relapsing-remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo.. In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics.. Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo.. BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05).. BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics.

Topics: Adolescent; Adult; Brain; Contrast Media; Dimethyl Fumarate; Female; Fumarates; Gadolinium; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Young Adult

BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).. In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.. At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.. In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

Topics: Administration, Oral; Adult; Brain; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Infections; Intention to Treat Analysis; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Peptides

BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.. We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.. The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.. In patients with relapsing-remitting multiple sclerosis, 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. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).

Topics: Administration, Oral; Adult; Brain; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Infections; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting

Topics: Administration, Oral; Dimethyl Fumarate; Dose-Response Relationship, Drug; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis.. 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701.. Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot.. The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Topics: Administration, Oral; Adolescent; Adult; Dimethyl Fumarate; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Patient Dropouts

Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS). Clinical and real-world studies of DRF have demonstrated improved gastrointestinal (GI) tolerability and low (< 1%) GI-related treatment discontinuation versus dimethyl fumarate (DMF) and high rates of treatment adherence. Our aim was to conduct a concept elicitation study to identify treatment-related concepts most meaningful to patients and to evaluate how these concepts shape the patient perspective of DRF.. In-depth qualitative interviews were conducted with patients from October to December 2020. US adults who had been prescribed DRF through routine clinical care and had taken DRF for ≥ 3 weeks in the past 6 months were eligible to participate. Semi-structured interviews explored patient perceptions on treatment selection and impact.. Seventeen patients participated in the study. Mean (SD) age was 49.3 (12.0) years. Sixteen patients reported prior disease-modifying therapy, while 10 (58.8%) had prior DMF. DRF treatment duration ranged from ~ 6 weeks to 10 months. Four key concepts emerged: (1) overall wellness and quality of life, (2) ease of administration, (3) minimal and manageable side effects, and (4) patient optimism due to MS treatments. Mode of administration (82.4%), no/mild side effects (70.6%), convenience over injectable/infusion medications (58.8%), and effectiveness (64.7%) were cited as positive aspects of DRF treatment. Frequent dosing (52.9%) and food requirements (41.2%) were cited as negative attributes; however, 94.1% had no dietary changes since starting treatment.. The patient perspective is a key aspect when considering a disease-modifying therapy for MS, given the multitude of options currently available. Overall wellness, ease of administration, and minimal and manageable side effects were DRF-related concepts most meaningful to patients on therapy. Acknowledging these patient perceptions in shared decision-making may lead to greater patient adherence and optimal treatment outcomes.. Multiple sclerosis (MS), an immune-related disease, may present with neurological symptoms that come and go. Diroximel fumarate (DRF) is a next-generation oral treatment for MS, which has been shown in clinical trials to have fewer gastrointestinal side effects compared to dimethyl fumarate (DMF), another oral treatment. Patients’ perspective can shed light on what they value when choosing a treatment, so we interviewed 17 people with MS about how DRF treatment affects their daily life and work. The study participants (49.3 years old on average) received DRF for ~ 6 weeks to 10 months. Around 5 in 10 people had positive feelings about their current health following treatment with DRF. Most felt there was either improvement or no negative change in quality of life since starting DRF treatment; DRF did not affect their work or daily obligations. Treatment characteristics of DRF that were perceived as most important included ease of administration, minimal and manageable side effects, and the facilitation of overall wellness and quality of life. While the oral dosing of DRF was more convenient than injectable or infusion therapy options, about half of the respondents preferred a less frequent treatment regimen than the twice daily dosing of DRF which needs to be taken with food. However, those who switched to DRF from DMF (or other oral medications for MS) expressed that the transition was smooth. Understanding factors that are important to patients can guide treatment choices and help patients stay on treatment longer and have better MS outcomes.

Topics: Adult; Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Fumarates; Humans; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Qualitative Research; Quality of Life; Recurrence

Dimethyl fumarate (DMF) is a disease-modifying therapy for patients with relapsing-remitting multiple sclerosis (RRMS). T cells are major contributors to the pathogenesis of RRMS, where they regulate the pathogenic immune response and participate in CNS lesion development.. In this study we evaluate the therapeutic effects of DMF on T cell subpopulations, their CNS migration potential and effector functions.. Blood and CSF from untreated and DMF-treated patients with RRMS and healthy donors were analyzed by flow cytometry.. DMF reduced the prevalence of circulating proinflammatory CD4+ and CD8+ memory T cells, whereas regulatory T cells were unaffected. Furthermore, DMF reduced the frequency of CD4+ T cells expressing CNS-homing markers. In coherence, we found a reduced recruitment of CD4+ but not CD8+ T cells to CSF. We also found that monomethyl fumarate dampened T cell proliferation and reduced the frequency of TNF-α, IL-17 and IFN-γ producing T cells.. DMF influences the balance between proinflammatory and regulatory T cells, presumably favoring a less proinflammatory environment. DMF also reduces the CNS migratory potential of CD4+ T cells whereas CD8+ T cells are less affected. Altogether, our study suggests an anti-inflammatory effect of DMF mainly on the CD4+ T cell compartment.

Topics: Adult; Cell Proliferation; Cohort Studies; Cytokines; Dimethyl Fumarate; Female; Fumarates; Humans; Immunologic Factors; Inflammation; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; T-Lymphocytes; Young Adult

Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile.. To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study.. EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory.. As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%;. Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) effectively lead to reduction in disease relapses and active magnetic resonance imaging (MRI) lesions. DMF and MMF are known to be effective in modulating T- and B-cell responses; however, their effect on the phenotype and function of human myeloid dendritic cells (mDCs) is not fully understood.. To investigate the role of MMF on human mDCs maturation and function.. mDCs from healthy controls were isolated and cultured in vitro with MMF. The effect of MMF on mDC gene expression was determined by polymerase chain reaction (PCR) array after in vitro MMF treatment. The ability of mDCs to activate T cells was assessed by in vitro co-culture system. mDCs from DMF-treated multiple sclerosis (MS) patients were analyzed by flow cytometry and PCR.. MMF treatment induced a less mature phenotype of mDCs with reduced expression of major histocompatibility complex class II (MHC-II), co-stimulatory molecules CD86, CD40, CD83, and expression of nuclear factor κB (NF-κB) subunits RELA and RELB. mDCs from DMF-treated MS patients also showed the same immature phenotype. T cells co-cultured with MMF-treated mDCs showed reduced proliferation with decreased production of interferon gamma (IFN-γ), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to untreated cells.. We report that MMF can modulate immune response by affecting human mDC function.

Topics: Dendritic Cells; Dimethyl Fumarate; Fumarates; Humans; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Myeloid Cells; T-Lymphocytes

Dimethyl fumarate (DMF) is a disease-modifying therapy used for patients with relapsing-remitting multiple sclerosis (RRMS). B cells are important contributors to the pathogenesis of RRMS, where they regulate the inflammatory immune responses and participate in development of lesions in the central nervous system (CNS). The impact of DMF on B cell subpopulations remains incompletely understood.. In this study, we evaluated the effects of DMF on B cell subpopulations and their effector functions.. Blood from 21 DMF-treated and 18 untreated patients with RRMS was analyzed by flow cytometry.. We found that DMF reduces the frequency of circulating antigen-experienced B cells, a reduction likely related to a reduced frequency of follicular helper T (T. In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.

Topics: Adult; B-Lymphocytes; Cytokines; Dimethyl Fumarate; Female; Fumarates; Humans; Immunologic Factors; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; T-Lymphocytes, Helper-Inducer; Treatment Outcome; Young Adult

Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.. 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.. Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.. 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 by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.. Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

Topics: Adult; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Dimethyl Fumarate; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome

Topics: Fumarates; Humans; Multiple Sclerosis, Relapsing-Remitting

Topics: Fumarates; Humans; Multiple Sclerosis, Relapsing-Remitting

The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-β(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS).. A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality-adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results.. Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-β(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One-way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost-effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values.. The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-β(1a), with an ICER of US$7,115.

Topics: Adolescent; Adult; Cohort Studies; Cost-Benefit Analysis; Dimethyl Fumarate; Disability Evaluation; Female; Fingolimod Hydrochloride; Fumarates; Humans; Immunologic Factors; Injections, Intramuscular; Interferon beta-1a; Interferon-beta; Male; Markov Chains; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Propylene Glycols; Randomized Controlled Trials as Topic; Sphingosine; Young Adult

Topics: Flushing; Fumarates; Gastrointestinal Diseases; Humans; Kidney Diseases; Multiple Sclerosis, Relapsing-Remitting

Topics: Flushing; Fumarates; Gastrointestinal Diseases; Humans; Kidney Diseases; Multiple Sclerosis, Relapsing-Remitting

Topics: Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Quality of Life; Self Report; Surveys and Questionnaires

Fumaric acid esters (FAEs) are effective in patients with moderate to severe psoriasis. Recent studies also report the efficacy of one FAE component, dimethylfumarate, in relapsing forms of multiple sclerosis (MS). We describe the case of a patient with MS who developed severe plaque psoriasis during interferon-β-1a treatment for MS. The psoriasis was unresponsive to usual topical treatments and phototherapy. The patient was started on FAE 720 mg daily, with complete remission of the psoriatic lesions and neurological stabilization at follow-up at 24 months. Our case suggests that FAEs could represent a therapeutic option for patients with MS who develop plaque psoriasis following exposure to immune-modulating agents.

Topics: Adjuvants, Immunologic; Drug Eruptions; Esters; Fumarates; Humans; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Psoriasis; Treatment Outcome

For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and ▼natalizumab). Recently, three oral drugs have become available. We have previously reviewed the use of ▼fingolimod for highly active relapsing-remitting MS1 and ▼teriflunomide for the management of relapsing-remitting MS in adults.2 Here, we review the evidence for ▼dimethyl fumarate (Tecfidera-Biogen Idec Ltd) for the treatment of adults with relapsing-remitting MS.

Topics: Administration, Oral; Adult; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fumarates; Humans; Hydroxybutyrates; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Therapies, Investigational; Toluidines; Treatment Outcome

Topics: Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Peptides

Topics: Female; Fumarates; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides

Topics: Female; Fumarates; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide.. This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing-remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups.. The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.

Topics: Female; Fumarates; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides

Topics: Administration, Oral; Dimethyl Fumarate; Drug Administration Schedule; Drug Costs; Drug Interactions; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome

Topics: Administration, Oral; Brain; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Dimethyl Fumarate; Female; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Peptides

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting

The currently licensed medications for relapsing-remitting multiple sclerosis (RRMS) are only partially effective and require a parenteral route of administration. Thus there is a need for new, preferably orally available therapeutics. Such a substance could be fumaric acid and its esters (FAE). These compounds are already in use for treatment of psoriasis and are known to have an immunomodulatory effect. In addition there is a potential for neuroprotective effects as suggested by in vitro studies and experiments in the animal model of experimental autoimmune encephalomyelitis. A phase II clinical study in RRMS patients with the modified fumaric acid ester BG-12 showed as "proof of principle" in a frequent MRI design that FAE significantly reduce the number of gadolinium-enhancing lesions after 24 weeks of treatment. Further phase III studies have been started to explore the long-term efficacy of this substance. The results of these studies will show if FAE can be another treatment option, maybe for combination therapy, in patients with MS.

Topics: Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Esters; Fumarates; Humans; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Treatment Outcome