title: Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study.
abstract: 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.
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; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003692:Delayed-Action Preparations / Q000494:pharmacology; D000069462:Dimethyl Fumarate; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D010919:Placebos; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D005650:Fumarates; D007166:Immunosuppressive Agents; D010919:Placebos; D000069462:Dimethyl Fumarate