Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis

Abstract

Background and ObjectiveTo study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS).MethodsIn the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set.ResultsFifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0–6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI −292 to 491 ng/L). MBP in CSF decreased in the treatment group (−182 ng/L, 95% CI −323 to −41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups.DiscussionDimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment.Trial Registration InformationClinicaltrials.gov identifier NCT02959658.Classification of EvidenceThis study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.

Intrathecal CD8 + CD20 + T Cells in Primary Progressive Multiple Sclerosis

“… 9 Recently, we performed a randomized, placebo-controlled trial investigating dimethyl fumarate (DMF) treatment in patients with PPMS. 10 Like many of the previous studies of disease-modifying therapies in patients with PPMS, we found no effect of DMF after 48 weeks of treatment. 10 Concurrent with the clinical trial, we investigated the immunologic effects of DMF treatment.…”

“… 10 Like many of the previous studies of disease-modifying therapies in patients with PPMS, we found no effect of DMF after 48 weeks of treatment. 10 Concurrent with the clinical trial, we investigated the immunologic effects of DMF treatment. This showed substantial effects of DMF on circulating B cells and T cells and a reduced number of CD4 + T cells CSF in PPMS but no clear effects on other biomarkers of intrathecal inflammation.…”

“…This showed substantial effects of DMF on circulating B cells and T cells and a reduced number of CD4 + T cells CSF in PPMS but no clear effects on other biomarkers of intrathecal inflammation. 10 , 11 Why the substantial effect of DMF on T cells did not translate into a positive clinical treatment effect is unknown.…”

Protein biomarkers in multiple sclerosis

“…Serum Simoa NfL levels remained high in nonresponders with clinical relapse, whereas NfL decreased significantly during follow-up (24 months) in patients with a relapse-free course [27] DMF (RRMS, 52; HC, 23; placebo, 52) CSF Simoa RRMS patients had higher NfL levels at baseline compared to HC (mean, 2,368 pg/mL vs. 417 pg/mL; p < 0.001), and 72% of samples showed a reduction to levels comparable to HCs after 1 year of treatment [25] DMF (DMF, 27; placebo, 27) CSF ELISA Mean change in CSF NfL level did not differ between groups (mean difference, 99 ng/L; 95% CI, -292 to 491; p = 0.61) [28] Fingolimod (RRMS, 36) CSF ELISA Fingolimod proved effective in decreasing NfL levels in RRMS (-326 pg/mL, 83.3% with reduction, p = 0.002), and the NfL levels one year after treatment were higher in patients with relapse during the study vs. those without (mean, 1,448 pg/mL vs. 384 pg/mL; p = 0.014) [29] Natalizumab (RRMS, 96) Serum Simoa…”

Ocrelizumab associates with reduced cerebrospinal fluid B and CD20dim CD4+ T cells in primary progressive multiple sclerosis

“… 15 Since OCR did and dimethyl fumarate did not show significant effects in clinical trials for people with primary progressive multiple sclerosis, divergent effects on the intrathecal lymphocyte composition could reveal important mechanisms in the modulation of primary progressive multiple sclerosis. 5 , 28 Studying lymphocyte fractions in the CSF is especially relevant, since the pathology of primary progressive multiple sclerosis has been argued to be more dependent on compartmentalized inflammatory and degenerative processes and not on CNS recruitment of circulating lymphocytes. 29 Additionally, phenotypically distinct populations have been reported to patrol the intrathecal compartment in people with advanced progressive multiple sclerosis, and monoclonal antibodies as OCR do not cross the blood–brain barrier.…”