Efficacy of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with MS Using a Composite Measure of Disability

Background: : Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) significantly reduced confirmed disability progression (CDP) as measured by Expanded Disability Status Scale (EDSS) in an integrated analysis of patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS) from the Phase 3 DEFINE and CONFIRM studies. A composite outcome, using multiple neuroperformance components, can potentially enhance the measurement of CDP.

Objectives: To assess the effect of DMF on multi-component composite endpoints in newly diagnosed patients with RRMS from DEFINE/CONFIRM.

Methods: Eligible patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Assessments were administered at baseline and 12-week intervals thereafter. Composite-CDP was defined by the first occurrence of worsening from baseline of any one of the following: ≥1.0- or ≥1.5-point increase in EDSS score (>0 or 0, respectively); or ≥20% on timed 25-foot walk (T25FW), 9-hole peg test (9HPT), or Paced Auditory Serial Addition Test (PASAT); or ≥10 letters on Visual Function Test (VFT), confirmed at 12 and 24 weeks. Statistical comparisons were based on a Cox proportional hazards model adjusted for baseline covariates. DMF BID (approved dosage) results are reported. “Newly diagnosed” was defined as diagnosis within 1 year prior to study entry and treatment-naïve or previously treated with corticosteroids alone.

Results: The newly diagnosed population included 221 DMF and 223 placebo patients. Compared with placebo at Year 2, DMF significantly reduced the risk for 12-week composite-CDP (hazard ratio [HR], 95% confidence interval [CI]: 0.68, 0.49-0.94) and 24-week composite-CDP (HR, 95% CI: 0.56, 0.37-0.84) as measured by worsening of any of the disability outcomes (EDSS, T25FW, 9HPT, PASAT, or VFT); this represented 32% (P=0.0198) and 44% (P=0.0053) reductions vs placebo, respectively. Analysis of a second composite-CDP measure (first occurrence of worsening from baseline of EDSS, T25FW, or 9HPT) showed significant benefits with DMF vs placebo at 12 weeks (HR, 95% CI: 0.56, 0.39-0.82) and at 24 weeks (HR, 95% CI: 0.55, 0.35-0.85), which represented 44% (P=0.0026) and 45% (P=0.0077) reductions vs placebo, respectively. Additional outcomes will also be presented.

Conclusions: DMF demonstrated significant benefits compared with placebo on a composite measure of disability progression in newly diagnosed patients with RRMS.

Study supported by: Biogen.