Rate of Brain Volume Loss Under Long-Term Delayed-Release Dimethyl Fumarate Treatment in Relapsing-Remitting Multiple Sclerosis Patients: Results from the Endorse Study

Background: Brain atrophy in MS has been shown to correlate with physical disability, cognitive deficits, and quality of life. Changes in brain volume, typically calculated by MRI techniques, may be used as indirect measures of brain atrophy.

Objectives: Evaluate the long-term effect on brain volume loss in patients receiving continuous delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) treatment compared with patients switching from placebo or glatiramer acetate (GA) in the ENDORSE study, an extension of the phase 3 DEFINE and CONFIRM studies.

Methods: Patients randomized to DMF 240 mg twice (BID) or three times (TID) daily in DEFINE/CONFIRM continued the same dosage in ENDORSE; patients randomized to placebo (PBO) or GA (CONFIRM only) were re-randomized 1:1 to DMF BID or TID. Data were analyzed (May 14, 2014 cutoff) by treatment in parent/extension study. At year 3 (week 144) of ENDORSE, BID/BID patients received ≥5 years continuous DMF treatment; PBO/BID and GA/BID patients received 2 years PBO (DEFINE/CONFIRM) or GA (CONFIRM), respectively, followed by ≥3 years DMF (ENDORSE). Percentage brain volume change (PBVC) was calculated at year 3 of ENDORSE relative to the predefined baseline for PBVC, week 24 of DEFINE/CONFIRM. Results from patients treated with DMF 240 mg BID are reported, as this represents the maintenance dose of DMF that is approved for the treatment of patients with relapsing MS.

Results: This analysis was conducted in the MRI cohort of ENDORSE. Normalized brain volume data was available for 195 (BID/BID), 87 (PBO/BID), and 42 (GA/BID) patients. Mean PBVC at year 3 (over 218 weeks or 4.5 years) of ENDORSE relative to week 24 of DEFINE/CONFIRM was -1.38 (BID/BID), -1.90 (PBO/BID), and -2.05 (GA/BID). In the BID/BID group in ENDORSE, the rate of brain volume loss was slowed compared with placebo (P=0.0304) and significantly slowed across all time points compared with PBO/BID and GA/BID.

Conclusions: This analysis suggests a continuous beneficial effect of DMF on brain atrophy and a higher impact of early DMF treatment compared with delayed DMF treatment.