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

Gold, Ralf; Arnold, Douglas L.; Bar‐Or, Amit; Hutchinson, Michael; Kappos, Ludwig; Havrdová, Eva; MacManus, David; Yousry, Tarek; Pozzilli, Carlo; Selmaj, Krzysztof; Sweetser, Marianne T.; Zhang, Ray; Yang, Minhua; Potts, James; Novas, Mark; Miller, David H.; Kurukulasuriya, Nuwan; Fox, Robert J.; Phillips, T. J.

doi:10.1177/1352458516649037

Cited by 134 publications

(143 citation statements)

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“…The results indicated little difference between the early-and delayed-treatment groups for the annualized relapse rate during the extension phase and a lower proportion of participants with disability worsening in the early-treatment group. 66 Two trials compared fingolimod with placebo with 104 weeks' follow-up. 67,68 According to a meta-analysis of both trials (n = 2355), moderate-quality evidence showed that fingolimod was associated with a larger proportion of participants free from relapse (RR = 1.44, 95% CI: 1.28-1.63), a lower annualized relapse rate (MD = −0.21, 95% CI: −0.25 to −0.16), lower risk of disability worsening (RR = 0.71, 95% CI: 0.56-0.90) and a trend in favour of fingolimod for all MRI outcomes.…”

Section: Efficacy Of Dmdsmentioning

confidence: 99%

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

et al. 2018

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Background and scopeMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination and degenerative changes. MS usually begins around the age between 20 and 40 years and affects two to three times as many women as men; it also constitutes the most frequent cause of non-traumatic disability in the young adult population. 1 The incidence of MS varies across regions, with rates as high as 8 to 10 new cases per 100,000 in high latitudinal regions. 2,3 Current estimates suggest that over 700,000 people are affected in Europe, with over 2.5 million cases worldwide, 4 which represent a significant burden in terms of impact on quality of life, societal costs and personal expenses. 5,6 Most patients (85%-90%) have a relapsing course from onset that is characterized by relapses and remissions of neurological symptoms Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion:The present guideline will enable homogeneity of treatment decisions across Europe. associated with areas of CNS inflammation, and over the course of two decades, more than half of untreated patients transition to a phase of gradual worsening independent of acute attacks. 7,8 Progressive forms of MS can be present as the initial disease course (primary-progressive MS) in approximately 10%-15% of patients. 9,10 There is no curative treatment available for MS, and the current therapeutic strategy is aimed at reducing the risk of relapses and potentially disability progression. The treatment era for MS began in 1993, when the first interferon became available, and recent years have seen a large expansion in the therapeutic options for MS, with 11 disease-modifying therapies (DMTs) approved by the European Medicine Agency (EMA) in both injectable and oral formulations by the beginning of 2017. 11 The growing armamentarium of therapies brings new opportunities for individualized therapy where patients and providers must balance considerations around efficacy,...

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Section: Efficacy Of Dmdsmentioning

confidence: 99%

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

et al. 2018

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“…11,13,14 The clinical and magnetic resonance imaging efficacy of DMF was maintained over 5 years in the ENDORSE (A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis) study, an ongoing, 8-year extension study of DEFINE and CON-FIRM. 15 Head-to-head comparative studies of disease-modifying therapies in RRMS are limited. Glatiramer acetate was included as a reference comparator in CONFIRM.…”

Section: Dmf For Ms Efficacymentioning

confidence: 99%

“…7,8 Consistent findings have been observed in ENDORSE; hepatic AEs occurred in 3% or less of patients in any treatment group, and 3% or less of patients treated with DMF for a minimum of 5 years had alanine aminotransferase or aspartate aminotransferase levels of at least 3× ULN; no case fulfilled Hy's law criteria for drug-induced liver injury. 15 Limited pregnancy outcomes from clinical trials and postmarketing data suggest no increased risk of adverse pregnancy outcomes during the first trimester. However, DMF should be used during pregnancy only if the benefits outweigh the potential risks.…”

Section: Dmf For Ms Efficacymentioning

confidence: 99%

“…7,16 General Safety DEFINE and CONFIRM demonstrated that DMF 240 mg twice a day has a favorable risk/benefit profile in RRMS, which was confirmed by the long-term ENDORSE extension study; data from an interim analysis of this study have been published, with a minimum of 5-year follow-up data in patients initially randomized to receive DMF (treatment duration ≤7 years in some patients). 7,8,15 The most frequently occurring AEs in DEFINE and CONFIRM (incidence ≥2% higher than with placebo) were flushing, abdominal pain, diarrhea, and nausea. 7,8 In a recently published integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N = 2470), mean absolute lymphocyte counts (ALCs) decreased by approximately 30% during the first year of treatment, then plateaued, remaining higher than the lower limit of normal (0.91 × 10 9 /L) thereafter.…”

Section: Gi Tolerability Profilementioning

confidence: 99%

“…17 In the ENDORSE ongoing safety extension study, one case has been reported to date of progressive multifocal leukoencephalopathy (PML), an opportunistic infection, in a patient treated with DMF 240 mg three times daily in the setting of prolonged (≥6 months) severe lymphopenia (approximately <0.5 × 10 9 /L of 3.5 years' duration). 15 In addition, rare cases of PML also occurred in the postmarketing setting in the presence of prolonged moderate-to-severe lymphopenia. Aside from PML in the setting of prolonged (≥6 months) moderateto-severe lymphopenia, there is no overall increased risk of serious infections, including other opportunistic infections.…”

Section: Gi Tolerability Profilementioning

confidence: 99%

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Dimethyl Fumarate

Phillips¹,

Agrella²,

Fox³

2017

International Journal of MS Care

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Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for the treatment of relapsing multiple sclerosis. Flushing and gastrointestinal (GI) adverse events (AEs) are common within the first few months of starting DMF therapy. Although most symptoms are mild or moderate in severity, transient, and infrequently result in treatment discontinuation, they nevertheless present a challenge for patients to adhere to therapy and achieve an optimal treatment response. Methods: This review discusses management strategies for the prophylaxis and treatment of common DMF-associated AEs based on clinical trial evidence and real-world experience in clinical practice settings. Results: Before starting DMF therapy, patients should receive counseling on the importance of treatment adherence and the likely occurrence and severity of flushing and GI AEs (nausea, vomiting, diarrhea, and abdominal pain). Management strategies, such as administering DMF with food, using a slower-dose titration schedule, applying temporary dose reductions, and using symptomatic therapies, provide clinicians with several approaches to address DMF tolerability. In particular, DMF coadministration with certain foods (eg, sausage, peanut butter) may prevent or reduce the severity of GI AEs. Taking aspirin 325 mg/day 30 minutes before administering DMF in the first month of therapy can reduce the incidence and severity of flushing without negatively affecting GI-related events. Conclusions: Through continual patient education and support and management of treatment-related flushing and GI AEs, clinicians can help patients adhere to and persist with DMF therapy, thus maximizing treatment benefit.

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Multiple Sclerosis

Pitts

Dyckman

2021

Burger's Medicinal Chemistry and Drug Discovery

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Several new medicines have been approved or entered development for the treatment of Multiple Sclerosis (MS) in the past few years. The sphingosine‐1‐phosphate (S1P) modulator fingolimod was the first FDA approved oral disease modifying therapy for MS, and it has inspired a number of additional agents directed at this clinically validated target. Fumarates (e.g. dimethyl fumarate), dihydroorotate dehydrogenase inhibitors (e.g. teriflunomide) and other agents which decrease lymphocyte proliferation (e.g. cladribine) represent additional clinically validated therapeutic approaches. While the mechanisms of action for these new agents may not be fully defined, they have demonstrated a good degree of efficacy in the treatment of relapsing forms of MS. It is of interest to note that biologic agents which target CD20 on B cells have also shown significant efficacy in the treatment of MS. This, in turn, has spurred MS clinical trials with Bruton's Tyrosine Kinase (BTK) inhibitors, which also act on B cell pathways. The introduction of each of these newer agents still requires careful consideration of the risk–benefit for individual patients, but has also set a higher bar in the treatment of MS for subsequent agents, as evidenced by the discontinuation of several agents in late stage clinical trials. This higher bar has also pushed some historic agents to second or third line agents. This speaks to an overall advancement in the treatment of MS, and provides hope for further advances in therapeutic options.

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

Cited by 134 publications

References 28 publications

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

Dimethyl Fumarate

Multiple Sclerosis

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