Fumarate In Relapsing-remitting Multiple Sclerosis Research Articles

Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. EVOLVE-MS-1-an open-label, 96-week, phase3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. ClinicalTrials.gov identifier NCT02634307.

The US FDA-Approved Drug Dimethyl Fumarate, an Nrf2 Activator, for Treating Multiple Sclerosis: The Mechanisms of Action Revisited

Dimethyl fumarate, a potent Nrf2 activator and antioxidant-inducing compound, has been approved by the US Food and Drug Administration (FDA) as a first-line drug for treating relapsing forms of multiple sclerosis (MS). Two latest studies published in Nat Commun demonstrated that the efficacy of the drug in treating MS may be associated with increased reactive oxygen species production instead. REFERENCES Rothstein JD. Edaravone: a new drug approved for ALS. Cell 2017; 171(4):725. doi: https://dx.doi.org/10.1016/j.cell.2017.10.011. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, Mitchell SJ, et al. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab 2012; 15(3):361–71. doi: https://dx.doi.org/10.1016/j.cmet.2012.01.017. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367(12):1098–107. doi: https://dx.doi.org/10.1056/NEJMoa1114287. Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci USA 2016; 113(17):4777–82. doi: https://dx.doi.org/10.1073/pnas.1603907113. Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 2018; 360(6387):449–53. doi: https://dx.doi.org/10.1126/science.aan4665. Carlstrom KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, et al. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun 2019; 10(1):3081. doi: https://dx.doi.org/10.1038/s41467-019-11139-3. Luckel C, Picard F, Raifer H, Campos Carrascosa L, Guralnik A, Zhang Y, et al. IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nat Commun 2019; 10(1):5722. doi: https://dx.doi.org/10.1038/s41467-019-13731-z.

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study

PurposeTo describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-naïve DMF patients and patients switching to DMF from other multiple sclerosis disease-modifying treatments (DMTs).MethodsA population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to other DMTs. Persistence was measured as the number of days until either DMF discontinuation (treatment gap ≥ 60 days) or switching to another DMT.ResultsThe study included 400 patients (median follow-up = 2.5 years). The majority had previously been treated with other DMTs (61%). Throughout the follow-up period, 124 patients (31%) discontinued DMF and 114 patients (29%) switched treatment. Overall, 34% of patients initiating DMF stopped treatment within 1 year and only 43% of patients remained on DMF at 2 years from treatment initiation.ConclusionsDMF had a rapid market uptake likely due to high expectations held by both patients and clinicians. However, persistence with DMF in routine clinical practice was found to be low.

Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM

PurposeIn Phase III studies (DEFINE [Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS]/CONFIRM [Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis]), delayed-release dimethyl fumarate (DMF) demonstrated significant efficacy and a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Post hoc analyses of integrated data from DEFINE/CONFIRM were conducted to evaluate the effect of DMF in patients previously treated with interferon (IFN) beta. MethodsPatients (age 18–55 years; Expanded Disability Status Scale score, 0–5.0) were randomized to receive DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Previous IFN users received at least 1 IFN treatment >3 months before randomization. Data for DMF 240 mg BID (approved dosing regimen) are reported. FindingsIn the integrated intention-to-treat population, 172 and 169 patients receiving DMF or placebo, respectively, had received ≥1 prior IFN. In this subgroup, significant reductions with DMF versus placebo were observed for the annualized relapse rate (rate ratio, 0.55 [95% CI, 0.40–0.77]), new/newly enlarging T2-hyperintense lesions (lesion mean ratio, 0.16 [95% CI, 0.09–0.29]), odds of having more gadolinium-enhancing lesions (odds ratio, 0.17 [95% CI, 0.07–0.44]), and new T1-hypointense lesions (lesion mean ratio, 0.25 [95% CI, 0.14–0.45]). Median Expanded Disability Status Scale scores remained stable during the study period. Adverse events associated with DMF included flushing and gastrointestinal events. ImplicationsIn this post hoc analysis in patients with previous IFN treatment, DMF demonstrated significant efficacy over 2 years versus placebo and an adverse event profile consistent with the overall population of DEFINE/CONFIRM. ClinicalTrials.gov identifiers: DEFINE, NCT00420212; and CONFIRM, NCT00451451.

Clinical guidelines for the use of dimethyl fumarate in relapsing-remitting multiple sclerosis

Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, in which autoimmune inflammation and oxidative stress play essential pathogenetic roles. Activation and infiltration of immune cells in brain tissues, lipid peroxidation products, mitochondrial dysfunction, defective antioxidant protection, and many other pathological factors result in demyelination, axonal injury and death, and apoptosis of oligodendrocytes and neurons, all of which causes constant progression of the disease. The new oral agent for the treatment of relapsing-remitting multiple sclerosis (RRMS), dimethyl fumarate (DMF), helps change the pathogenetic mechanisms of the disease, thus decreasing the rate of exacerbations, slowing down disease progression, and reducing the risk of radiological progression of the disease.

Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations.

Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy.

Five-Year Follow-up of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis: MRI Outcomes from DEFINE, CONFIRM, and ENDORSE (P7.262)

Five-Year Follow-up of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis: MRI Outcomes from DEFINE, CONFIRM, and ENDORSE (P7.262)

Safety Profile of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS): Long-term Interim Results From the ENDORSE Extension Study (P2.200)

Safety Profile of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS): Long-term Interim Results From the ENDORSE Extension Study (P2.200)

Clinical Efficacy of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients with Highly Active Disease: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies (P3.189)

Clinical Efficacy of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients with Highly Active Disease: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies (P3.189)

Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: The DEFINE study

Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM

Introduction: 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.Areas covered: 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.Expert opinion: 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.

Clinical Efficacy of BG-12 in Relapsing-Remitting Multiple Sclerosis (RRMS): Data from the Phase 3 CONFIRM Study (S01.003)

Objective: To describe the efficacy of BG-12 (dimethyl fumarate) in patients with RRMS in the Phase 3 CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) study. Background BG-12 demonstrated significant reductions in the proportion of patients relapsed, annualized relapse rate (ARR), and disability progression versus placebo in RRMS patients in DEFINE, the first of two Phase 3 studies. Design/Methods: CONFIRM was a multicenter, randomized, placebo-controlled, reference comparator study that evaluated the efficacy and safety of BG-12 over 2 years in RRMS patients. Patients (18–55 years) with a diagnosis of RRMS per McDonald criteria and an Expanded Disability Status Scale (EDSS) score of 0.0–5.0 were enrolled. CONFIRM evaluated BG-12 240 mg twice (BID) and three times daily (TID) versus placebo and included an active reference comparator arm with subcutaneous glatiramer acetate (GA) 20 mg/day. The primary endpoint was ARR at 2 years. Secondary clinical endpoints included the proportion of patients who relapsed and disability progression as measured by EDSS at 2 years. Results: A total of 1417 patients received treatment. Baseline demographic and clinical characteristics were similar across treatment groups. BG-12 BID (n=359) and TID (n=345) significantly reduced ARR by 44% (p Conclusions: Efficacy results from CONFIRM further support those from DEFINE and suggest that BG-12 has the potential to be a valuable treatment option for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Fox has received personal compensation for activities with Avanir, Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received research support from Biogen Idec and Genentech, Inc. Dr. Miller has received personal compensation for activities with UCL Institute of Neurology, Biogen Idec, GlaxoSmithKline, and Bayer Schering Pharma. Dr. Miller has received personal compensation in an editorial capacity for Journal of Neurology. Dr. Miller has received research support from GlaxoSmithKline, Biogen Idec, and Novartis. Dr. Phillips has received personal compensation for activities with Avanir, Biogen Idec, Genzyme, Novartis, and Teva as a speaker or consultant.Dr. Phillips has received research support from Biogen Idec and Roche. Dr. Kita has received personal compensation for activities with Biogen Idec as a speaker. Dr. Kita has received research support from Biogen Idec. Dr. Hutchinson has received personal compensation for activities with Biogen Idec as a speaker. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Ms. Yang has received personal compensation for activities with Biogen Idec as an employee. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Viglietta has received personal compensation for activities with Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.