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. 2015 Jan;21(1):57-66.
doi: 10.1177/1352458514537013. Epub 2014 Jul 2.

Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS)

Ralf Gold  1 , Gavin Giovannoni  2 , J Theodore Phillips  3 , Robert J Fox  4 , Annie Zhang  5 , Leslie Meltzer  5 , Nuwan C Kurukulasuriya  5
Affiliations

Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS)

Ralf Gold et al. Mult Scler. 2015 Jan.

Abstract

Background: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.

Objective: To evaluate delayed-release DMF in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.

Methods: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.

Results: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.

Conclusion: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

Keywords: Delayed-release dimethyl fumarate; efficacy; multiple sclerosis; newly diagnosed; safety.

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Conflict of interest statement

Conflicts of interest: RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience.

GG: honoraria from Abbvie, Bayer HealthCare, Biogen Idec, Canbex, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen Idec, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co-chief editor of MS and Related Disorders.

JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, Teva, and Xenoport; research support from Roche.

RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen Idec and Novartis; research grant funding from Novartis.

AZ, LM, NCK: employees of Biogen Idec, Inc.

Figures

Figure 1.
Figure 1.
Patient disposition: newly diagnosed population. The ITT population for the integrated analysis comprised 2301 patients, of whom 678 were newly diagnosed (332 from DEFINE and 346 from CONFIRM) and treated with placebo (n = 223), delayed-release DMF BID (n = 221), or delayed-release DMF TID (n = 234). The deaths in the delayed-release DMF TID group were due to a motor vehicle accident and complications of an MS relapse. Abbreviations: BID, twice daily; TID, three times daily.
Figure 2.
Figure 2.
ARR at 2 years in the newly diagnosed population. ARR was calculated using a negative binomial regression model adjusted for baseline EDSS score (≤2.0 vs. >2.0), baseline age (<40 vs. ≥40), study, region, and number of relapses in the year prior to study entry. The error bars indicate 95% confidence intervals. Abbreviations: ARR, annualized relapse rate; BID, twice daily; CI, confidence interval; TID, three times daily. §p < 0.0001 vs. placebo.
Figure 3.
Figure 3.
Proportion of patients relapsed and time to 12-week confirmed disability progression at 2 years in the newly diagnosed population. (a) Estimated proportion of patients relapsed at week 96 was derived using Kaplan–Meier analysis. Hazard ratios, 95% CI, and p values were based on a stratified Cox proportional hazards model with study as the stratifying variable, adjusted for baseline EDSS score (≤2.0 vs. >2.0), baseline age (<40 vs. ≥40), region, and number of relapses in the year prior to study entry. (b) Estimated proportion of patients with disability progression at Week 96 was derived using Kaplan–Meier analysis. Hazard ratio, 95% CI, and p values were based on a stratified Cox proportional hazards model with study as the stratifying variable, adjusted for baseline EDSS score (as a continuous variable), baseline age (<40 vs. ≥40), and region. Abbreviations: BID, twice daily; CI, confidence interval; DR-DMF, delayed-release dimethyl fumarate; TID, three times daily. aNumber of patients at risk 5 days prior to the week 96 visit.
Figure 4.
Figure 4.
MRI endpoints at 2 years in the newly diagnosed population. (a) The number of new or newly enlarging T2-hyperintense lesions was analyzed using negative binomial regression adjusted for study, region, and baseline volume of T2-hyperintense lesions. Error bars indicate 95% CI. (b) The odds of having more Gd+ lesions were analyzed using ordinal logistic regression adjusted for study, region, and baseline number of Gd+ lesions. Percentages are the reduction in odds of having more Gd+ lesion activity, compared with placebo. (c) The number of new non-enhancing T1-hypointense lesions was analyzed using negative binomial regression adjusted for study, region, and baseline volume of T1-hypointense lesions. Error bars indicate 95% CI. Abbreviations: BID, twice daily; CI, confidence interval; Gd+, gadolinium-enhancing; TID, three times daily. §p < 0.0001 vs. placebo
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