Treatment with Dimethyl Fumarate Produces Sustained Long-term Benefits

A well-tolerated oral medication for some forms of multiple sclerosis (DMF) appears to provide sustained benefit for patients, and favorable outcomes were seen on a composite outcome measure over a five-year period, according to a study presented at the 2014 Joint ACTRIMS-ECTRIMS Meeting, held in Boston, MA.

Gavin Giovannoni, MD, of Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK presented five-year findings from this follow-on outcomes study of dimethyl fumarate (DMF), an oral disease-modifying agent approved in the US to treat relapsing-remitting multiple sclerosis (RRMS).

An increasingly common measure of treatment efficacy for patients with MS is no evident disease activity, or NEDA. It is a composite measure consisting of relapse rate, disability outcomes, and neuroimaging findings. Change over time can be captured in tracking NEDA outcomes when data are broken out by yearly interval and subjects are re-baselined at each year. Giovannoni reported long-term NEDA for patients with RRMS who either continued DMF or switched to the drug to participate in the ENDORSE study.

ENDORSE, the study reported here, is an extension of the DEFINE and CONFIRM studies, which compared DMF to placebo and to glatiramer acetate (GA), respectively. In transitioning patients to the extension study for years 3-5, patients who had been on placebo or GA were re-randomized to DMF BID or TID. The DMF BID subset was assessed for this study, since this is the dosage of DMF that was eventually approved for the treatment of RRMS. The group was further narrowed to include only those patients who had both clinical and magnetic resonance imaging (MRI) data.

At the beginning of ENDORSE, 211 patients were continued on BID DMF, while 104 were transitioned from placebo to BID DMF and 48 switched from GA to BID DMF. Delayed-release DMF, also known as gastro-resistant DMF, was used for the ENDORSE study. Demographics, number of relapses in prior year and EDSS scores were similar across groups, while mean number of gadolinium (GD) enhancing lesions was slightly higher for the DMF group, at 2.1 vs. 1.4 each for the other two groups.

Breaking out findings into yearly assessment of absence of measured clinical activity, absence of measured MRI activity, and NEDA, Giovannoni reported that both the placebo and GA groups showed improvement when transitioning to DMF. All three subgroups showed sustained improvement by the end of year five, with 86% of the DMF/DMF group, 90.1% of the placebo/DMF group, and 84.5% of the GA/DMF group having absence of measured clinical activity by the end of year five. These figures showed modest improvement over clinical activity just before enrollment in ENDORSE, when 81.0%, 71.1%, and 77.6% showed no clinical activity, respectively.

No measured MRI activity was seen by the end of year five in 62.1% of the DMF/DMF group; 62.9% had been free of MRI activity at the end of year two. For the placebo group, 66.1% were free of MRI abnormalities at the end of ENDORSE data collection, while only 33.7% had no MRI activity at the end of year two. The GA acetate group improved, similarly, with 56.7% of patients having no measured MRI activity at the end of year five, in contrast with 40.9% at enrollment in ENDORSE.

Finally, the composite measure of NEDA showed that 42.5% of BID/BID enrollees had NEDA by year five, as did 43.2% of placebo/BID patients and 31.6% of GA/BID patients. By contrast, NEDA was seen in 50.2% of BID/BID patients, 43.2% of placebo/BID patients, and 31.6% of GA/BID patients by the end of year two.

In comments during his presentation and in answering questions afterward, Giovannoni noted that study subjects who had been on DMF for the entire five-year period had higher NEDA scores over that time span, faring better overall than the patients who had switched to DMF after a period of time on placebo or GA. Individuals who only began DMF at the beginning of ENDORSE, however, did show improvement on the new regime after re-baselining. Informal discussion after the presentation highlighted the relatively small numbers of subjects enrolled in various arms of the study, which Giovannoni feels may have accounted for some of the data showing less robust improvement in NEDA scores.