Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study.

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

Effects of delayed-release dimethyl fumarate on MRI measures in the Phase 3 DEFINE study.

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing-remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study.

In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing­remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68% [hazard ratio 0.32 (95% confidence interval (CI) 0.16-0.62)] to 26% [0.74 (0.51-1.09)] and from 66% [0.34 (0.23-0.50)] to 25% [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing­remitting multiple sclerosis with varied demographic and disease characteristics.