Safety and efficacy of delayed-release dimethyl fumarate in multiple sclerosis patients treated in routine medical practice: interim analysis of ESTEEM

2018 ◽  
Author(s):  
Nicholas J. Everage
Keyword(s):  
Multiple Sclerosis ◽  
Medical Practice ◽  
Interim Analysis ◽  
Dimethyl Fumarate ◽  
Safety And Efficacy ◽  
Delayed Release ◽  
Routine Medical Practice ◽  
Multiple Sclerosis Patients

Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies

2017 ◽  
Vol 23 (14) ◽  
pp. 1875-1883 ◽  
Author(s):  
Sreeja Gopal ◽  
Alvydas Mikulskis ◽  
Ralf Gold ◽  
Robert J Fox ◽  
Katherine T Dawson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ex Vivo ◽  
Dimethyl Fumarate ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Phase 3 ◽  
Potent Inducer ◽  
Nrf2 Pathway ◽  
Delayed Release ◽  
Multiple Sclerosis Patients

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: These data provide the first evidence of Nrf2 pathway activation from two large pivotal Phase 3 studies of DMF-treated MS patients.

scholarly journals Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Raed Alroughani ◽  
Peter Huppke ◽  
Maria Mazurkiewicz-Beldzinska ◽  
Astrid Blaschek ◽  
Martin Valis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pediatric Patients ◽  
Dimethyl Fumarate ◽  
Relative Reduction ◽  
Hyperintense Lesion ◽  
Safety And Efficacy ◽  
Delayed Release ◽  
T2 Lesions ◽  
Relapsing Remitting Multiple Sclerosis

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

scholarly journals Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

2016 ◽  
Vol 23 (2) ◽  
pp. 253-265 ◽  
Author(s):  
Ralf Gold ◽  
Douglas L Arnold ◽  
Amit Bar-Or ◽  
Michael Hutchinson ◽  
Ludwig Kappos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Interim Analysis ◽  
Dimethyl Fumarate ◽  
Long Term Effects ◽  
Serious Adverse Events ◽  
Treatment Benefit ◽  
Delayed Release ◽  
Magnetic Resonance Imaging Mri

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

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