DEFINE Study Investigators.DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.

Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany.
New England Journal of Medicine (Impact Factor: 55.87). 09/2012; 367(12):1098-107. DOI: 10.1056/NEJMoa1114287
Source: PubMed


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 number, NCT00420212.).

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Available from: Lekha Pandit, Oct 22, 2014
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    • "DMF has been demonstrated to be an essential component of Fumaderm® [18]. Results on BG-12/Tecfidera® are consistent with this data [4] [5] [6]. However, pharmacokinetic studies have shown that DMF undergoes to a large pre-systemic conversion to MMF and adduction to GSH [19]. "
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    ABSTRACT: Fumaric acid esters (FAEs) exert therapeutic effects in patients with psoriasis and multiple sclerosis, however their mode of action remains elusive. Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death, mediated by the activation of inflammasomes. To understand the pharmacological basis of the therapeutic effects of FAEs, the anti-pyroptotic activity of dimethyl fumarate (DMF) and its hydrolysis metabolite monomethyl fumarate (MMF) was studied in a model of NLRP3 inflammasome-mediated pyroptosis of human macrophages. Phorbol myristate acetate-differentiated THP-1 cells were exposed to lipopolysaccharide (5 μg/ml; 4 h), then pulsed with ATP (5 mM; 1 h). MMF, DMF, or parthenolide (positive control) were added 1 h before the ATP pulse. The pyroptotic cell death was evaluated by morphological examination and quantified by measuring the lactate dehydrogenase leakage. The ATP-triggered death of THP-1 cells (60.4 ± 4.0%) was significantly (P < 0.01) prevented by DMF, in a time- and concentration-dependent manner (pIC50 and maximal effect were 6.6 and 67.6±1.2%, respectively). MMF was less efficacious than DMF. These effects were accompanied by a decreased intracellular activation of caspase-1 and interleukin-1β release from ATP-treated cells, thus suggesting that FAEs antagonise the effects of ATP by preventing the activation of the pyroptotic molecular cascade leading to cell death. These results indicate that FAEs are endowed with anti-pyroptotic activity, which may contribute to their therapeutic effects.
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    • "Dimethyl fumarate (DMF) is an oral anti-inflammatory, antioxidative and neuroprotective drug which was recently tested clinically on patients with relapsing-remitting multiple sclerosis . DMF 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 [3]. Although both multiple sclerosis and AD are neurodegenerative disorders in which inflammatory processes in the brain contribute to the pathology, there is no study on DMF application in AD or animal models of AD. "

    Full-text · Article · Sep 2015
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    • "An oral formulation of FAE (Fumaderm®), for example, constitutes a well-established therapy for psoriasis, a dermatological disorder with immune dysfunction , with a comprehensive safety profile of over 160,000 patient years (Lee et al., 2012; Mrowietz et al., 1998, 1999; Rostami Yazdi and Mrowietz, 2008). Furthermore, very recently, BG-12 (Panaclar, BG00012, FAG-201), an oral second-generation fumaric acid derivative containing DMF as main ingredient, was successfully tested in phase II and III studies of MS and shown to decrease the frequency of relapses and the time to disability progression (Fox et al., 2012; Gold et al., 2012; Kappos et al., 2008). "
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    ABSTRACT: Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema. Copyright © 2015. Published by Elsevier Inc.
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