An integrated analysis of relapses requiring intravenous steroid use and multiple sclerosis (MS)-related hospitalizations from the BG-12 (dimethyl fumarate) phase 3 define and confirm studies
Gavin GiovannoniRalf GoldR.J. FoxM. KitaM. YangR. ZhangKatherine DawsonVissia VigliettaSarah SheikhEva Havrdová
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Dimethyl fumarate
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Dimethyl fumarate
Relapsing remitting
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Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the central nervous system. It is one of the leading causes of neurologic disability, particularly in young adults, and is presumed to be autoimmune. This chapter discusses the evidence supporting the use of the MS therapies. It presents clinical scenarios for the following: clinically isolated syndrome, interferon-beta and glatiramer acetate for relapsing-remitting multiple sclerosis, natalizumab and fingolimod, teriflunomide and dimethyl fumarate, secondary progressive MS, primary progressive MS, and dalfampridine. Disease-modifying therapies are all effective for reducing the annual relapse rate of relapsing-remitting disease (RRMS). In summary, substantial progress has been made toward halting inflammatory disease activity in RRMS but future therapies will need to focus on SPMS and PPMS in order to meet the major unmet needs, particularly accumulation of neurological disability, of patients with multiple sclerosis.
Teriflunomide
Glatiramer acetate
Natalizumab
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Relapsing remitting
Demyelinating disease
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Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.
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Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing–remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.
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Dimethyl fumarate
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Dimethyl fumarate
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Multiple sclerosis (MS) is a disease that is caused when the patient’s own immune cells attack the central nervous system, i.e. an autoimmune disease. The disease has a prevalence of 1-2.5 million people worldwide, but there is no known cure. Dimethyl fumurate (DMF), also known as Tecfidera®, is an oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, how DMF works in RRMS patients is not fully understood. The main goal of this study is to explore the effects of DMF treatment on the immune cells, as well as on their functionality. This study has provided valuable evidence on the effect of DMF on the immune system in MS and may contribute to revealing an underlying mechanism for the beneficial effects of the therapy which have been demonstrated by phase III trials. Funded by Biogen Nederland
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Dimethyl fumarate (DMF, Tecfidera®) is a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis. Lymphopenia is a frequent reason for discontinuation in fumarate-treated patients. Management strategies to minimize risk of lymphopenia are warranted.The aims of this study were to investigate the correlation of body mass index (BMI), baseline absolute lymphocyte count (ALC), age and sex with risk of DMF-induced lymphopenia in MS patients.The study was a retrospective cohort study of 452 MS patients who had been prescribed DMF at six clinics in two Danish regions between May 2014 and September 2017. Data on lymphocyte counts, BMI, age, sex, and reason for discontinuation of DMF were collected through the Danish Multiple Sclerosis Registry, with follow- up to two years after treatment start.28.5% of patients had lymphopenia grade II or higher at some time in the first two years of DMF treatment. Increased risk of lymphopenia was observed in patients with baseline ALC of 1.00-1.49×109 cells/L (odds ratio, OR 5.48, p<0.0001) and 1.50-1.99×109 cells/L (OR 2.08, p = 0.0009). Reduced risk of lymphopenia was observed in patients with ALC of 2.00-2.49×109 cells/L (OR 0.51, p< 0.01) and ≥ 2.50×109 cells/L (0.12, p<0.0001). Patients aged ≥ 56 years had an increased risk of lymphopenia (OR 3.58, p<0.001), and patients with BMI ≥ 30 kg/m2 had a decreased risk of lymphopenia (OR 0.53, p value = 0.03).Low baseline ALC and older age were risk factors for DMF-induced lymphopenia, while BMI ≥ 30 kg/m2 and high baseline ALC were protective factors for developing lymphopenia in MS patients treated with DMF.
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The use of dimethyl fumarate has not been reported in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis.The purpose of this study was to evaluate the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis.APEX was a phase 3, multinational trial, which consisted of a 24-week, randomized (1:1), double-blind study where patients received dimethyl fumarate 240 mg or placebo twice daily, followed by an open-label extension where all patients received dimethyl fumarate 240 mg. The primary endpoints were the total number of new gadolinium-enhancing (Gd+) lesions in Weeks 12-24 (Part I) and long-term safety (Part II). This post-hoc subgroup analysis evaluated the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis (n=52) up to Week 72 (24 weeks Part I and 48 weeks Part II).Dimethyl fumarate reduced the mean total number of new gadolinium-enhancing lesions at Weeks 12-24 by 94% versus placebo; the number of patients who had a relapse over 24 weeks was reduced by 72%. Adverse events leading to discontinuation of the study drug were reported in 9% of patients receiving placebo/dimethyl fumarate and 4% of patients in dimethyl fumarate/dimethyl fumarate.Dimethyl fumarate demonstrated sustained efficacy and acceptable tolerability in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis for 72 weeks.
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