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Randomized Controlled Trial
. 2017 Feb;23(2):253-265.
doi: 10.1177/1352458516649037. Epub 2016 Jul 11.

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

Ralf Gold  1 , Douglas L Arnold  2 , Amit Bar-Or  3 , Michael Hutchinson  4 , Ludwig Kappos  5 , Eva Havrdova  6 , David G MacManus  7 , Tarek A Yousry  7 , Carlo Pozzilli  8 , Krysztof Selmaj  9 , Marianne T Sweetser  10 , Ray Zhang  10 , Minhua Yang  10 , James Potts  10 , Mark Novas  10 , David H Miller  7 , Nuwan C Kurukulasuriya  10 , Robert J Fox  11 , Theodore J Phillips  12
Affiliations
Randomized Controlled Trial

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

Ralf Gold et al. Mult Scler. 2017 Feb.

Abstract

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM.

Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE).

Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID.

Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia.

Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

Keywords: DEFINE; ENDORSE; Expanded Disability Status Scale; Relapsing–remitting multiple sclerosis; delayed-release dimethyl fumarate (DMF).

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Gold has received consultant fees and grant or research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, and Teva Neuroscience and compensation from Sage (editor fees). Dr Arnold has received revenue from Acorda Therapeutics, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Mitsubishi, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi-Aventis, Teva, and NeuroRx Research and research support from Novartis and Biogen. Dr Bar-Or has received honoraria or research support from Biogen, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, Medimmune, Merck Serono, Novartis, Ono Pharmacia, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience. Dr Hutchinson has received honoraria from Bayer Schering, Biogen, Merck Serono, and Novartis and editorial fees from the Multiple Sclerosis Journal. Dr Kappos’ employer (University Hospital, Basel) has received steering committee or advisory board or consultant fees for Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees for Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; educational support from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen, Merck, Novartis, Roche, Swiss MS Society, Swiss National Research Foundation, European Union, and Roche Research Foundations. Dr Havrdova has received honoraria from Acetlion, Bayer, Biogen, Genzyme, Merck Serono, Novartis, Sanofi, Teva, Receptos, and Roche and support from Czech Ministry of Education, research project PRVOUK-P26/LF1/4. Mr. MacManus has received research grants from Apitope, Biogen, GlaxoSmithKline, Novartis, Richmond Pharma, and Schering AG. Dr Yousry has received research support from Biogen, GlaxoSmithKline, Novartis, and Schering AG; honoraria from Biogen, Bayer Schering, and Novartis. Dr Pozzilli has received consultant fees from Actelion, Biogen, Genzyme, Merck Serono, Novartis, and Teva Neuroscience and grant or research support from Biogen, Merck Serono, Novartis, and Teva Neuroscience. Dr Selmaj has received consultant fees from Genzyme, Novartis, Ono, Roche, Synthon, and Teva and fees for noncontinuing medical education (CME) services from Biogen. Dr Miller has received honoraria for advisory committee and/or consultancy advice in MS studies from Biogen, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe, and Bayer Schering Pharma and compensation for performing central MRI analysis of MS trials from GlaxoSmithKline, Biogen, Novartis, and Apitope. Dr Fox has received consultant fees from Allozyne, Avanir, Biogen, Novartis, Questcor, Teva, and XenoPort and grant or research support from Novartis. Drs Zhang, Potts, Sweetser, Novas and Kurukulasuriya and Ms Yang are current or former employees of and hold stock or stock options in Biogen. Dr Phillips has received consultant fees from Acorda, Biogen, EMD Serono, Genzyme, and Sanofi and research support from Roche.

Figures

Figure 1.
Figure 1.
Design of ENDORSE extension study (phase 1). BID: twice daily; DMF: dimethyl fumarate; GA: glatiramer acetate; PBO: placebo; PO: by mouth; QD: once daily; SC: subcutaneous; TID: thrice daily. aDMF: delayed-release DMF.
Figure 2.
Figure 2.
Patient disposition. AE: adverse event; BID: twice daily; DMF: dimethyl fumarate; GA: glatiramer acetate; MS: multiple sclerosis; PBO: placebo; TID: thrice daily. aSome additional patients (n = 68 across treatment groups) completed ENDORSE at year 2, prior to the protocol amendment extending the study duration.
Figure 3.
Figure 3.
(a) ARR by yearly interval, (b) time to first relapse, and (c) time to disability progression by EDSS (24-week confirmation): DEFINE, CONFIRM, and ENDORSE integrated analysis (ENDORSE ITT population). (a) Adjusted ARR and 95% CI based on negative binomial regression, adjusted for baseline EDSS score (⩽2.0 vs >2.0), baseline age (<40 vs ⩾40 years), region, and number of relapses in the 1 year prior to entry into DEFINE or CONFIRM. Data after patients switched to alternative MS medications during the period are excluded. (b) Only objective relapses are included in the Kaplan–Meier estimate analysis; patients who did not experience a relapse prior to switching to alternative MS medications or withdrawal from study are censored at the time of switch or withdrawal. (c) Patients were censored if they withdrew from study or switched to alternative MS medication without a progression. ARR: annualized relapse rate; BID: twice daily; CI: confidence interval; EDSS: Expanded Disability Status Scale; GA: glatiramer acetate; ITT: intention-to-treat; MS: multiple sclerosis; PBO: placebo; TID: thrice daily.
Figure 4.
Figure 4.
(a) Number of new or enlarging T2 hyperintense lesions by yearly interval, (b) number of new nonenhancing T1 hypointense lesions by yearly interval, and (c) mean number of Gd+ lesions by yearly interval: DEFINE, CONFIRM, and ENDORSE analysis (MRI cohort). BID: twice daily; CI: confidence interval; GA: glatiramer acetate; Gd+: gadolinium-enhanced; MRI: magnetic resonance image; PBO: placebo; TID: thrice daily.
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