Over a long-term follow-up, a high proportion of patients were compliant to therapy, with adverse events mild-to-moderate in nature, regardless of individuals being on continuous treatment or switched from placebo.
Recently published findings of more than 1000 patients with relapsing-remitting multiple sclerosis (RRMS) in the ENDORSE extension study (NCT00835770) showed that treatment with dimethyl fumarate was shown to be safe and effective after follow-up of 13 years.1
All told, for patients continuously treated with 240 mg twice daily of dimethyl fumarate (n = 501), overall annualized relapse rates (AARs) remained consistent and low, ranging from 0.20 (95% CI, 0.16-0.25) in the first year to 0.11 (95% CI, 0.07-0.17) in years 9 to 10. After using a repeated measures negative binomial model, those who switched from placebo to dimethyl fumarate showed an ARR of 0.35 (95% CI, 0.29-0.43) during the first 2 years of placebo, which decreased to 0.15 (95% CI, 0.12-0.19) during years 3 to 10 after initiating dimethyl fumarate, otherwise a 56% reduction (rate ratio [RR], .044; 95% CI, 0.34-0.56).
Led by Ralf Gold, MD, director, Neurologic Clinic, St. Josef Hospital, Ruhr-Universitat Bochum, the ENDORSE study was a completed extension of the DEFINE/CONFIRM studies (NCT00420212; NCT00451451), designed to evaluate the long-term safety and efficacy of dimethyl fumarate in those with RRMS. The ENDORSE study detailed the longest clinical follow-up of dimethyl fumarate exposure to date. In addition to efficacy and safety, investigators keyed in on a subgroup of newly diagnosed patients, who were defined as those diagnosed with RRMS within 1 year before DEFINE/CONFIRM study entry who were naïve to disease-modifying therapies.
Of 2079 patients who completed DEFINE/CONFIRM, 1736 entered ENDORSE, and 759 (44%) completed the study. During the first 3 months of dimethyl fumarate treatment, 3% of those on continuous therapy discontinued, compared with 13% of those who switched from placebo, mainly because of adverse events (AEs; continuous: <1%; switching: 10%). Beyond 3 months, the most common reason was consent withdrawn (continuous: 15%; switching: 14%). At 10 years, the estimated proportion of patients with relapses was 54.9% (95% CI, 50.0-59.8) for those on continuous dimethyl fumarate and 58.1% (95% CI, 51.4-64.9) for those who switched from placebo.
Throughout the observation period, the reported AEs were mild to moderate in nature, with one notable case of progressive multifocal leukoencephalopathy occurring in a dimethyl fumarate-treated patient with prolonged, severe lymphopenia. The most common serious AEs were MS relapse (14%) and fall (2%). Gastrointestinal disorders were reported for 43% of patients and were higher for those who switched (51%) compared with continuous treatment (37%). Renal or urinary disorders led to less than 1% of discontinuations, and there was no evidence of increasing incidence of renal injury with dimethyl fumarate. All told, the overall incidence and type of AEs and serious AEs were otherwise consistent with those reported in DEFINE and CONFIRM and were generally similar across treatment groups, and those newly diagnosed with RRMS.
Patient-reported outcomes, measured using the Short Form Health Survey-36 and EuroQol 5-dimensions, remained generally stable during ENDORSE. Overall compliance to therapy was high, as more than 94% of those in the continuous dimethyl fumarate group and more than 90% of those who switched were at least 90% compliant to therapy.
Relapse rates for newly diagnosed patients were also similar to that of the overall population. In those who switched from placebo to treatment, the model-based ARR was 0.25 (95% CI, 0.17-0.36) during the placebo treatment period, and decreased by 64% to 0.09 (95% CI, 0.06-0.13) during the dimethyl fumarate treatment period (RR, 0.36; 95% CI, 0.24-0.55; P <.0001). After 8 years of dimethyl fumarate treatment, the mean Expanded Disability Status Scale scores were low for those on continuous dimethyl fumarate (2.0; SD, 2.0) and for those who switched (2.0; SD, 0.9).
Absolute lymphocyte count (ALC) analyses included patients treated with dimethyl fumarate in ENDORSE, as well as those who did not crossover from DEFINE and CONFIRM (n = 2263). Over the first 48 weeks, ALC decreased by a mean of 27.7% and remained generally stable for the duration of the study, remaining above the lower limit of normal for most patients (59%). While on treatment, 10.6% and 2.4% of patients developed prolonged moderate or prolonged severe lymphopenia, respectively.