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

Abstract

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.

Fig. 1

Patient disposition: MRI cohort. BID twice daily, MS multiple sclerosis, TID three times daily

Fig. 2

Mean number (±95 % CI) of new or enlarging T2-hyperintense lesions (a), Gd+ lesions (b), and new T1-hypointense lesions (c) at 6 months, 1 and 2 years. Patient numbers refer to those who provided data both at baseline and at each scheduled MRI analysis. Relative reductions (vs. placebo) in the risk of having a greater number of Gd+ lesions were based on the odds ratio from the pre-specified analysis model of ordinal logistic regression (a conservative method, chosen to minimize undue influence of outlier Gd+ lesion counts on the estimated treatment effect), for categories of patients with 0, 1, 2, 3–4, and ≥5 lesions. Comparisons vs. placebo were based on: (a) negative binomial regression, adjusted for region and baseline lesion volume; (b) ordinal regression, adjusted for region and baseline lesion number; (c) analysis of covariance on ranked data, adjusted for region and baseline lesion volume. *P < 0.05; **P < 0.01; ^‡ P < 0.001; ^§ P < 0.0001 vs. placebo. BID twice daily, CI confidence interval, DMF dimethyl fumarate, Gd+ gadolinium-enhancing, TID three times daily

Fig. 3

Median percentage change in volume of T2-hyperintense lesions (a), mean change from baseline in volume (mm³) of Gd+ lesions (b), and median percentage change in volume of T1-hypointense lesions (c) at 6 months, 1 and 2 years. Patient numbers refer to those who provided data both at baseline and at each scheduled MRI analysis. Comparisons vs. placebo were based on analysis of covariance on ranked data, adjusted for region and baseline lesion volume. *P < 0.05; **P < 0.01; ^‡ P < 0.001; ^§ P < 0.0001 vs. placebo. BID twice daily, DMF dimethyl fumarate, Gd+ gadolinium-enhancing, TID three times daily

Fig. 4

Median percentage change in whole brain volume at 2 years relative to baseline and 6 months. Comparisons vs. placebo were based on analysis of covariance on ranked data, adjusted for region and normalized brain volume at 6 months. *P < 0.05 vs. placebo. BID twice daily, DMF dimethyl fumarate, TID three times daily