Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies

Ralf Gold, Gavin Giovannoni, J Theodore Phillips, Robert J Fox, Annie Zhang, Jing L Marantz, Ralf Gold, Gavin Giovannoni, J Theodore Phillips, Robert J Fox, Annie Zhang, Jing L Marantz

Abstract

Introduction: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in the extension study (ENDORSE), in patients with relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up.

Methods: Patients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone.

Results: The newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates [ARR; 95% confidence interval (CI)] were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (P = 0.3988). PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0-2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3-6 (ENDORSE), representing 61% risk reduction for Years 3-6 versus Years 1-2 (P < 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (P = 0.0397).

Conclusion: Long-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population.

Funding: Biogen.

Trial registration: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

Keywords: Delayed-release dimethyl fumarate; Efficacy; Multiple sclerosis; Newly diagnosed; Safety.

Figures

Fig. 1
Fig. 1
Cumulative ARR. ARR was calculated using a negative binomial regression model, adjusted for baseline Expanded Disability Status Scale (≤2.0 vs. >2.0), baseline age (aDMF delayed-release dimethyl fumarate (also known as gastro-resistant DMF). bBased on a repeated negative binomial model for estimated 0–2/3–6 years ARR. ARR annualized relapse rate, CI confidence interval, PBO placebo
Fig. 2
Fig. 2
Proportion of patients with 24-week confirmed disability progression. Confirmed progression of disability is defined as >1.0-point increase on EDSS from a baseline EDSS >1.0 confirmed for 24 weeks or >1.5-point increase on EDSS from a baseline EDSS of 0 confirmed for 24 weeks. Patients were censored if they withdrew from the study or switched to alternative MS medication without a progression. aDMF delayed-release dimethyl fumarate (also known as gastro-resistant DMF). EDSS Expanded Disability Status Scale, HR hazard ratio, PBO placebo

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