Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Abstract

Objective:To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study.Methods:CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort).Results:DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance.Conclusions:The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS.Classification of evidence:This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

“…Reductions in brain atrophy with dimethyl fumarate (DMF) in comparison to placebo did not reach statistical significance in the CONFIRM study [103], while in the DEFINE study a relative reduction in the progression of brain atrophy from baseline to year 2 (21% reduction; p = 0.0449) and from month 6 to year 2 (30% reduction; p = 0.0214) was observed and was statistically significant [104].…”

Treating relapsing–remitting multiple sclerosis: therapy effects on brain atrophy

“…Neither the TID dose nor glatiramer acetate significantly reduced BV loss at any point compared to placebo, although a trend towards statistical significance was observed from year 1 to year 2 for both drugs [32] ( Tables 1b, 2). Regarding teriflunomide, BV measures were only reported for the phase III TEMSO clinical trial: both doses of teriflunomide (7 and 14 mg.) failed to demonstrate a reduction in BV loss as compared to placebo [33] (Tables 1b, 2).…”

“…Results of brain atrophy for both phase III clinical trials with dimethyl-fumarate have been recently published [31,32]. In the DEFINE clinical trial, comparing dimethyl-fumarate versus placebo in RRMS, and using the 6-month MRI as baseline for BV estimation, dimethyl-fumarate administered twice a day (BID) significantly reduced BV loss as compared to placebo; surprisingly, results for the three times a day (TID) posology on brain atrophy resulted negative [31].…”

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

“…In a post hoc comparisons of BG-12 versus GA, differences were significant for the ARR (thrice-daily BG-12), new or enlarging T2 lesions (both BG-12 doses) and new T1 hypointense lesions (thrice-daily BG-12) (nominal p < 0.05 for each comparison) [87]. While statistically significant treatment effects of DMF on magnetization transfer ratio outcomes and brain atrophy were observed in DEFINE, magnetization transfer ratio outcomes and brain atrophy results with DMF did not reach statistical significance in CONFIRM [88].…”