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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-014-7504-7) contains supplementary material, which is available to authorized users.
Highlights
Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system, characterized by inflammatory demyelination and neuroaxonal degeneration
The magnetic resonance imaging (MRI) cohort of the DEFINE study consisted of 540 patients, 448 (83 %) of whom had exploratory baseline magnetization transfer ratio (MTR) assessments, and 392 (73 %) of whom had both baseline and post-baseline MTR evaluations
There were mean percentage increases of 0.129 and 0.096 % in the delayed-release dimethyl fumarate (DMF) BID and times daily (TID) treatment groups, a significant improvement compared with placebo (p = 0.0027 and p = 0.0051, respectively), suggesting an increase in myelin density (Fig. 1a; Table 2)
Summary
Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system, characterized by inflammatory demyelination and neuroaxonal degeneration. In relapsing MS, patients experience episodic relapses associated with neurologic impairment and disability, affecting overall health and quality of life [1]. But are understood to be associated with focal inflammation, oxidative stress, and loss of integrity of the blood–brain barrier [2, 3]. Conventional magnetic resonance imaging (MRI) is a sensitive technique for visualizing the focal inflammatory lesions of MS. The number of focal lesions detected by MRI increases [4]. Decreases in the number of acute inflammatory lesions in response to treatment are predictive of the treatment effects of disease-modifying therapies on clinical relapses [5]
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