title: 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.
authors.affiliation: NeuroRx Research, Montreal, QC, Canada, darnold@neurorx.com.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
authors.forename: Minhua
authors.initials: M
authors.lastname: Yang
authors.forename: Ray
authors.initials: R
authors.lastname: Zhang
authors.forename: Monica
authors.initials: M
authors.lastname: Stephan
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Sheikh
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Dawson
mesh_terms: D000293:Adolescent; D000328:Adult; D001284:Atrophy / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D000069462:Dimethyl Fumarate; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D005650:Fumarates; D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate