Effect of Dimethyl Fumarate vs Interferon β-1a in Patients With Pediatric-Onset Multiple Sclerosis

Abstract

ImportanceWith few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).ObjectiveTo compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.Design, Setting, and ParticipantsThe CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.InterventionsPatients were randomized to DMF or IFNβ-1a.Main Outcomes and MeasuresThe primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.ResultsAmong 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.Conclusions and RelevanceThis study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.Trial RegistrationClinicalTrials.gov Identifier: NCT02283853

Initiation Patterns of Disease-Modifying Therapies for Multiple Sclerosis Among US Adults and Children, 2001 Through 2020

“…The pediatric labeling of fingolimod makes it the first and only currently US Food and Drug Administration–approved DMT for children. Of note, results from the CONNECT trial were published in 2022, which found dimethyl fumarate to be superior to interferon β in children with MS based on similar end points . How these new findings will affect future trends in DMT use in children remains to be seen.…”

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis

“…39 Herein, DMF was classified among MET based on the most conservative assumption because no robust RCT has yet shown that DMF is more effective than platform therapies or teriflunomide, neither in adults nor children. 4,40,41 Limiting long-term disability is critical, but no differences were found between strategies, possibly due to missing baseline EDSS scores and a relatively short follow-up duration, as in other studies. 10 Yet, we cannot rule out that patients initially treated with MET who escalated to HET were ultimately sufficiently protected against EDSS progression at 5 years.…”

“…1,2 Teriflunomide and DMF were recently approved by the US Food and Drug Administration and European Medicine Agency following the phase 3 Efficacy, Safety, and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS) and Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis (CONNECT) RCTs. [3][4][5] These successes paved the way for other ongoing RCTs with highly potent drugs like ocrelizumab, ofatumumab, and siponimod. 6,7 In the last decade, the availability of highly potent drugs led to a decrease in long-term disability accrual.…”

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies

“…In addition, the results suggested that delaying DMT at an early stage of MS could lead to a decrease in the cumulative efficacy of DMT treatment when patients are older [31]. In pediatric patients with MS aged 10-17 years, DMF has been shown to be more effective than IFNb-1a in that more patients were free of new or newly enlarging T2 lesions following 96 weeks of treatment with DMF compared with IFNb-1a (16% vs. 5%, respectively) [32]. These studies provide further evidence of the beneficial effects of early and consistent treatment with DMF.…”