Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis

Abstract

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

“…The safety and efficacy of dimethyl fumarate (Tecfidera ® ) in the POMS population was recently investigated in a small, single-arm, open-label study that consisted of an initial 8-week off-treatment period followed by a 24-week treatment period (FOCUS study; NCT02410200) [ 74 ]. An additional 96-week extension termed CONNECTED further followed the same patients that completed the FOCUS study [ 75 ]. All patients started the treatment with 1 week of dimethyl fumarate 120 mg twice a day (BID) and later escalated to the full adult dose of 240 mg BID.…”

“…Over the entire 120-week follow-up through FOCUS and the CONNECTED extension, the ARR remained low at 0.2, an 84.5% reduction when compared with the year before entry into the study [ 75 ]. In the initial 24-week follow-up period, two patients had to discontinue the treatment due to an MS relapse and a case of urticaria, respectively [ 74 ].…”

“…In terms of serious adverse events, five patients experienced an MS relapse and one patient reported vertigo. Over the extension period, one more case of significant abdominal pain requiring hospitalization was reported [ 75 ]. Five patients had absolute lymphocyte count below the lower limit of normal and the total lymphocyte count decreased from baseline to week 24 by 18% [ 74 ].…”

“…Five patients had absolute lymphocyte count below the lower limit of normal and the total lymphocyte count decreased from baseline to week 24 by 18% [ 74 ]. An additional 3% decrease was seen through the extension period [ 75 ]. A major limitation to this study is the lack of a comparator arm and regression-to-the-mean effect as patients enrolled right after a recent relapse are not necessarily expected to maintain a high level of activity over the treatment period.…”

Therapy of Pediatric-Onset Multiple Sclerosis: State of the Art, Challenges, and Opportunities

“…In the CONNECTED study (26), extension of FOCUS, a long-lasting benefit of therapy, was observed: 12/17 participants (71%) had no new/enlarged T2 hyperintense lesions from weeks 16 to 24. Over a mean treatment period of 120 weeks, a significant reduction of ARR compared with the year before DMF initiation was observed (from 1.5 to 0.2, p < 0.0001).…”