DMF on trial in PPMS

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Recently ProfG has been singing the praises of Nrf2 modulators as useful targets….but the proof is in the pudding. Here we have a DMF, a well known Nrf2 modulator, trial and and the taste of the pudding does not seem good.

It is looking in PPMS and using neurofilament as the outcome and there is nothing positive to say, I am sorry to say. However, I think the issue is neurofilament light. The majority of this is produced due to active inflammation and so this disappears when you block inflammation say with natalizumab. A small part of the neurofilament signal comes from progression and this may not respond to inhibition of inflammation, especially if the agent is not protent enough. Maybe ProfG or NDG may have something to say as they are the NFL gurus.

Højsgaard Chow H, Talbot J, Lundell H, Gøbel Madsen C, Marstrand L, Lange T, Mahler MR, Buhelt S, Holm Hansen R, Blinkenberg M, Romme Christensen J, Soelberg Sørensen P, Rode von Essen M, Siebner HR, Sellebjerg F.

Background and objective: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS).

Methods: In 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.

Results: Fifty-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.

Discussion: Dimethyl 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.

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MouseDoctor

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  • Yes, I suspect not the right endpoints and that DMF would only have a significant effect if used as part of a combination treatment. I also find the fact that the comparator group was placebo instead of ocrelizumab to be absolutely reprehensible and immoral.

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