Dataset Information

Effectiveness of Dimethyl Fumarate in Patients With Relapsing Multiple Sclerosis Switching After Suboptimal Response to Glatiramer Acetate, Including Patients With Early Multiple Sclerosis: Subgroup Analysis of RESPOND.

ABSTRACT:

Introduction

This post hoc subset analysis of RESPOND evaluated the effectiveness of dimethyl fumarate (DMF) 240 mg twice daily in patients with relapsing multiple sclerosis (RMS) after suboptimal response to glatiramer acetate (GA; "first switch" patients), including patients with early MS ("early MS switch" patients).

Methods

Patients had discontinued GA due to suboptimal response and initiated DMF treatment within 60 days after enrollment. Relapse data were collected from medical records. First switch patients had had one prior approved MS therapy (GA) before initiating DMF treatment. Early MS switch patients were first switch patients with baseline Patient-Reported Expanded Disability Status Scale (PR-EDSS) score ≤ 3.5, ≤ 1 relapses in the past 1 year, or both.

Results

Among first switch patients (n = 231), the annualized relapse rate (ARR) was 0.48 (95% confidence interval [CI] 0.40-0.58) for 12 months before DMF initiation and 0.11 (95% CI 0.06-0.18) for 12 months after DMF initiation, a 78% decrease in ARR. Among early MS switch patients with baseline PR-EDSS score ≤ 3.5 (n = 120), ≤ 1 relapses in the prior year (n = 219), or both (n = 114), the ARRs (95% CIs) for 12 months before DMF initiation were 0.47 (0.37-0.59), 0.37 (0.32-0.44), and 0.39 (0.31-0.49), respectively; values for 12 months after DMF initiation were 0.06 (0.02-0.19), 0.09 (0.05-0.17), and 0.06 (0.02-0.20), respectively, an 87, 75, and 83% decrease in ARR. The proportion of patients relapse-free 12 months after DMF initiation versus 12 months before were 94 versus 59% in first switch patients, and 97 versus 58%, 94 versus 63%, and 97 versus 61% in early MS switch patients in the PR-EDSS score ≤ 3.5, ≤ 1 relapses in the prior year, or PR-EDSS score ≤ 3.5 and ≤ 1 relapses subgroups, respectively. After 12 months of DMF treatment, most patient-reported outcomes scores showed significant improvement.

Conclusions

DMF may be an effective treatment option in first switch and early MS switch patients with RMS who experience a suboptimal response to GA.

Trial registration

ClinicalTrials.gov identifier: NCT01903291.

SUBMITTER: Repovic P

PROVIDER: S-EPMC8140000 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.