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`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Original Research Paper
`
`Long-term effects of delayed-release dimethyl
`fumarate in multiple sclerosis: Interim analysis
`of ENDORSE, a randomized extension study
`
`Ralf Gold, Douglas L Arnold, Amit Bar-Or, Michael Hutchinson, Ludwig Kappos,
`Eva Havrdova, David G MacManus, Tarek A Yousry, Carlo Pozzilli, Krysztof Selmaj,
`Marianne T Sweetser, Ray Zhang, Minhua Yang, James Potts, Mark Novas, David H Miller,
`Nuwan C Kurukulasuriya, Robert J Fox and Theodore J Phillips
`
`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 glat-
`iramer 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 leukoen-
`cephalopathy 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 treat-
`ment benefit and an acceptable safety profile with DMF.
`
`Keywords: Relapsing–remitting multiple sclerosis, delayed-release dimethyl fumarate (DMF), Expanded
`Disability Status Scale, ENDORSE, DEFINE
`
`Date received: 16 December 2015; revised: 21 March 2016; accepted: 30 March 2016
`
`Introduction
`Delayed-release dimethyl fumarate (DMF) is an oral
`treatment for patients with relapsing–remitting multi-
`ple sclerosis (RRMS).1,2 In two 2-year pivotal phase 3
`trials (DEFINE and CONFIRM) in patients with
`RRMS, DMF significantly reduced clinical and mag-
`netic resonance imaging (MRI) activity and demon-
`strated an acceptable safety profile.3,4 ENDORSE is
`an ongoing 12-year extension of DEFINE/CONFIRM
`designed to evaluate the long-term efficacy and safety
`of DMF. We report a 5-year interim analysis (2 years
`DEFINE/CONFIRM; 3 years ENDORSE) of clinical
`
`Multiple Sclerosis Journal
`
`2017, Vol. 23(2) 253 –265
`
`DOI: 10.1177/
`1352458516649037
`
`© The Author(s), 2016.
`
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Correspondence to:
`R Gold
`Department of Neurology,
`St. Josef Hospital, Ruhr
`University Bochum,
`Gudrunstr 56, Bochum
`44791, Germany.
`ralf.gold@rub.de
`
`Ralf Gold
`Department of Neurology,
`St. Josef Hospital, Ruhr
`University Bochum, Bochum,
`Germany
`
`Douglas L Arnold
`NeuroRx Research, Montreal,
`QC, Canada/Montreal
`Neurological Institute,
`McGill University, Montreal,
`QC, Canada
`
`Amit Bar-Or
`Montreal Neurological
`Institute, McGill University,
`Montreal, QC, Canada
`
`Michael Hutchinson
`St. Vincent’s University
`Hospital, Dublin, Ireland
`
`Ludwig Kappos
`Department of Neurology,
`University Hospital of Basel,
`Basel, Switzerland
`
`Eva Havrdova
`Department of Neurology,
`First Faculty of Medicine,
`Charles University in Prague,
`Prague, Czech Republic
`
`David G MacManus
`Tarek A Yousry
`David H Miller
`NMR Research Unit, Queen
`Square Multiple Sclerosis
`Centre, University College
`London (UCL) Institute of
`Neurology, London, UK
`
`Carlo Pozzilli
`Department of Neurology
`and Psychiatry, Sapienza
`University of Rome, Rome,
`Italy
`
`Krysztof Selmaj
`Medical University of Lodz,
`Lodz, Poland
`
`and MRI outcomes and safety from ENDORSE. This
`report focuses on data for DMF 240 mg twice daily
`(BID; the approved dosage); however, data for all
`treatment groups are presented in figures or tables.
`
`Methods
`
`Patients and study design
`In DEFINE/CONFIRM, eligible patients were of age
`18–55 years, had a diagnosis of RRMS,5 an Expanded
`
`Marianne T Sweetser
`Mark Novas
`Biogen, Cambridge, MA,
`USA
`
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`253
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`Biogen Exhibit 2189
`Mylan v. Biogen
`IPR 2018-01403
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`Multiple Sclerosis Journal 23(2)
`
`Rly thg
`MIIIIJIII Yang
`Jamel Pottl
`Nuwnn C Kurukuluuriyl
`Biogen, Cambridge, MA,
`USA
`Robert J Fox
`Cleveland Clinic, Mellen
`Center for Multiple Sclerosis
`Treatment and Research,
`Cleveland, OH, USA
`Theodore J Phillips
`Baylor Institute for
`Immunoloy Research,
`Multiple Sclerosis Ploy-am,
`Dallas, TX, USA
`
`DEFINEICON FIRM
`
`ENDORSE
`
`Randomized.
`double-bllnd, placebo-controlled
`parent studies
`
`Phase 1 of randomlzed. dose-blind
`extenslon study
`
`(reference comparator) DMFa 240 mg TID PO
`
`DMF‘ 240 mg TID PO
`
`P80 BID PO
`
`GA 20 mg 00 SC
`
`DMFa 240 mg BID P0
`
`DMF“ 240 mg TID PO
`
`PBOIBID
`
`PBOITID
`
`
`
`Figure 1. Design of ENDORSE extension study (phase 1).
`BID: twice daily; DMF: dimetlryl fiimarabe; GA: glatiramer acetate; PBO: placebo; PO: by mouth; QD: once daily; SC: subcutaneous;
`TID: thrice daily.
`IDMF: delayed-release DMF.
`
`Disability Status Scale (EDSS)6 score of 0—5.0, and
`>1 relapse within lyear before randomization or >1
`gadolinium-enhanced (Gd+) lesion 0—6 weeks before
`randomization. Key exclusion criteria
`included
`relapse or corticosteroid treatment within 50 days
`before randomization or prior treatment with glati-
`ramer acetate (GA) within 3 months before randomi-
`zation (DEFINE) or at any time (CONFIRIVI). Patients
`were randomized to DMF 240 mg BID or thrice daily
`(TID) or placebo (PBO; 1:121 in DEFINE) or daily
`GA 20 mg (1:1:1:1 in CONFIRM) for 96 weeks},4
`
`ENDORSE enrolled eligible patients who completed
`DEFINE/CONFIRM, excluding those who experi-
`enced significant changes in medical history, with-
`drew consent; discontinued study treatment; or if
`alanine transaminase (ALT), aspartate aminotrans—
`ferase (AST), or gamma-glutamyl
`transpeptidase
`increased to >3 times the upper limit of normal
`(ULN). The final
`(week 96) visit of DEFINE/
`CONFIRM served as the baseline for ENDORSE;
`patients were followed every 4weeks for 24weeks
`and every 12weeks thereafter for up to 12 years.
`
`ENDORSE enables up to 14years of follow-up
`(2years DEFINE/CONFIRM+12—year
`extension;
`Figure 1). Originally designed as a multicenter, rand-
`omized, dose-blind, dose-comparison study, patients
`who received DMF 240 mg BID or TID in either par-
`ent study remained on the same dosage in ENDORSE.
`Patients who received PBO or GA were randomized
`
`1:1 to DMF 240mg BID or TID. Afier initiation of
`ENDORSE, DMF was approved for RRMS in several
`countries at 240mg BID. A protocol amendment
`(approved March 2014) outlines a second, open-label
`phase (beyond year 5), in which all participants receiv-
`ing DMF 240 mg TID are switched to BID dosing.
`
`Eflicacy assessments
`The primary efiicacy endpoint was the proportion of
`patients relapsed at 2years (DEFINE) and annualized
`relapse rate (ARR) at 2years (CONFIRM). Additional
`endpoints included time to 12-week sustained disabil-
`ity progression and number of new Tl hypointense
`lesions (Tl ), new or enlarging T2 hyperintense lesions
`(T2), and Gd+ lesions at 2years. Relapse (confirmed
`by an Independent Neurologic Evaluation Committee)
`was defined as new or recurrent neurologic symptoms
`lasting 224 hours, accompanied by new objective
`neurologic findings.
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`R Gold, DL Arnold et al.
`
`Secondary objectives of ENDORSE include assess-
`ment of long-term ARR, proportion of patients
`relapsed, disability progression (measured every
`6 months by EDSS), and MRI assessments of brain
`lesions. Patients at sites with validated MRI capabil-
`ity were eligible to participate in the MRI portion of
`DEFINE/CONFIRM and could continue in the MRI
`cohort at the same ENDORSE site.3,4 MRI scans
`were performed yearly for each patient by the same
`reading center as that of the parent study. MRI end-
`points included number of T1, T2, and Gd+ lesions
`and percentage of patients free of these lesions.
`Normalized brain volume was determined at base-
`line of DEFINE/CONFIRM and ENDORSE, and
`percent brain volume change (PBVC) was calculated
`automatically for each post-baseline MRI visit rela-
`tive to baseline.
`
`Safety assessments
`The primary objective of ENDORSE was evaluation
`of long-term safety of DMF in patients with RRMS.
`Adverse events (AEs) and concomitant medications
`were monitored and recorded continuously. Laboratory
`assessments were performed on a schedule: blood
`chemistry and urinalysis at baseline, every 4 weeks
`until week 24, and every 12 weeks thereafter and
`hematological parameters at baseline and every
`12 weeks for up to 12 years. On initiation of the
`amended protocol, the frequency of some study proce-
`dures was decreased to every 24 weeks; however,
`patients continued visits every 12 weeks for drug dis-
`pensing and vital signs assessment.
`
`Patients who completed or discontinued DMF and
`had a lymphocyte count less than the lower limit of
`normal (LLN) were followed at least every 12 weeks
`until lymphocyte counts recovered or until 48 weeks
`after
`the
`last dose (whichever came sooner).
`Unscheduled relapse assessment was performed as
`necessary.
`
`Statistical analysis
`This 5-year interim analysis (data cutoff date: 14 May
`2014) included patients who received ⩾1 dose of
`DMF in ENDORSE. Results are summarized through-
`out DEFINE/CONFIRM (years 1–2) and ENDORSE
`(years 3–5). Data are presented according to treatment
`received in the parent or extension study: continuing
`DMF (BID/BID and TID/TID) and new to DMF
`(PBO/BID, PBO/TID, GA/BID, and GA/TID). To
`increase sample size in the brain atrophy analysis,
`DMF BID/TID dosing was pooled from the groups
`new to DMF.
`
`A Poisson or negative binomial regression model was
`used to analyze ARR. The proportion of patients
`relapsed or with progression was estimated based on
`the Kaplan–Meier product limit method. Disability
`progression was defined as ⩾1.0-point increase in
`EDSS from baseline EDSS = 1.0 sustained for
`24 weeks or ⩾1.5-point increase in EDSS from base-
`line EDSS = 0 sustained for 24 weeks. Numbers of T1
`and T2 lesions were analyzed by negative binomial
`regression model, adjusted for region and lesion vol-
`ume at DEFINE/CONFIRM baseline. Number of
`Gd+ lesions was analyzed by logit regression.
`
`Comparisons of brain atrophy between BID/BID and
`PBO/DMF and GA/DMF were based on the analysis
`of covariance of ranked data, adjusted for DEFINE/
`CONFIRM or ENDORSE baseline number of Gd+
`lesions and T2 lesion volume.
`
`No sample size was calculated for ENDORSE; num-
`ber of eligible patients was determined by the number
`of DEFINE/CONFIRM participants.
`
`Safety parameters were tabulated according to the
`treatment received during parent study or extension
`phase 1, continuing DMF (BID/BID and TID/TID) and
`new to DMF (PBO/BID, PBO/TID, GA/BID, and GA/
`TID), and summarized using descriptive statistics.
`
`Standard protocol approvals, registrations, and
`patient consents
`The study was approved by central and local ethics
`committees and conducted
`in accordance with
`International Conference on Harmonization Guidelines
`for Good Clinical Practice and the Declaration of
`Helsinki. All patients provided written informed
`consent.
`
`Results
`Efficacy data are described below for the DMF BID
`dosage and reported for DMF TID in tables or figures;
`safety data for both dosages are summarized below.
`
`Patients
`Of 2651 patients randomized and dosed in DEFINE/
`CONFIRM, 2079 completed these studies and 1736
`were enrolled and dosed in ENDORSE (intention-
`to-treat (ITT) population): BID/BID, n = 501; TID/
`TID, n = 502; PBO/BID, n = 249; PBO/TID, n = 248;
`GA/BID, n = 118; and GA/TID, n = 118. As of
`14 May 2014, total follow-up for this 5-year interim
`analysis was 4981 patient-years. Follow-up of patients
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`Multiple Sclerosis Journal 23(2)
`
`continuing and new to DMF was 3058 and 1923
`patient-years, respectively. For BID/BID patients
`remaining on study (n = 364), minimum follow-up
`was ~5 years. Among patients new to DMF BID in
`ENDORSE, minimum follow-up for those remaining
`on study (n = 163) was ~3 years (Supplementary Table
`e-1). Of
`the DEFINE/CONFIRM MRI cohort
`(n = 1221), 746 were treated in ENDORSE: 363
`received DMF BID and 383 DMF TID. Patient dis-
`position is presented in Figure 2. Baseline demo-
`graphic and disease characteristics at the start of
`DEFINE/CONFIRM were generally well balanced
`across treatment groups and were similar between the
`ENDORSE ITT population (Table 1) and MRI cohort
`(Supplementary Table e-2).
`
`Efficacy
`Relapses. Cumulative ARR for ENDORSE BID/BID
`patients during years 0–5 was 0.163 (95% confidence
`interval (95% CI): 0.140, 0.190; Figure 3(a) presents
`ARRs by yearly interval), and the estimated propor-
`tion relapsed at 5 years was 40.1% (95% CI: 35.9%,
`44.7%; Figure 3(b)).
`
`Cumulative ARR for ENDORSE PBO/BID patients
`during years 0–5 was 0.240 (95% CI: 0.196, 0.296).
`Improvements were generally observed following the
`switch from PBO to DMF after year 2 (Figure 3(a)).
`The estimated proportion of PBO/BID patients
`relapsed at 5 years was 51.5% (95% CI: 45.2%,
`58.1%; Figure 3(b)).
`
`Cumulative ARR for ENDORSE GA/BID patients
`during years 0–5 was 0.199 (95% CI: 0.148, 0.269;
`Figure 3(a) presents data by yearly interval), and the
`estimated proportion relapsed at 5 years was 42.1%
`(95% CI: 33.5%, 52.0%; Figure 3(b)).
`
`Disability progression. An estimated 18.6% (95% CI:
`15.3%, 22.4%) of ENDORSE BID/BID patients had
`confirmed 24-week EDSS progression after 5 years
`(Figure 3(c)). For PBO/BID patients, the estimated
`proportion with disability progression after 5 years
`was 21.1% (95% CI: 16.2%, 27.1%; Figure 3(c)); for
`GA/BID patients, the corresponding proportion was
`25.7% (95% CI: 18.4%, 35.2%; Figure 3(c)).
`
`MRI outcomes
`Patients continuing DMF in ENDORSE. Among
`ENDORSE BID/BID patients, 73% and 63% were free
`of T1 and T2 lesions, respectively, during years 4–5;
`88% were free of Gd+ lesions (year 5 scan). For BID/
`BID patients, adjusted mean number of T1 and T2
`lesions during years 4–5 was 0.5 (95% CI: 0.3, 0.7)
`
`and 1.2 (95% CI: 0.8, 1.8), respectively (Figure 4(a)
`and (b)); mean (±standard error (SE)) number of Gd+
`lesions at year 5 was 0.2 ± 0.05 (Figure 4(c)).
`
`in ENDORSE. Of
`to DMF
`Patients new
`ENDORSE PBO/BID patients, 85% and 68% were free
`of T1 and T2 lesions, respectively, during years 4–5;
`82% were free of Gd+ lesions (year 5 scan). For PBO/
`BID patients, adjusted mean number of T1 and T2
`hyperintense lesions during years 4–5 was 0.2 (95%
`CI: 0.1, 0.5) and 0.8 (95% CI: 0.4, 1.5), respectively
`(Figure 4(a) and (b)); mean (±SE) number of Gd+
`lesions at year 5 was 0.2 ± 0.06 (Figure 4(c)).
`
`Of ENDORSE GA/BID patients, 64% and 62% were
`free of T1 and T2 lesions, respectively, during years
`4–5 and 86% were free of Gd+ lesions (year 5 scan).
`For GA/BID patients, adjusted mean number of T1
`and T2 lesions during years 4–5 was 0.7 (95% CI: 0.3,
`1.7) and 1.6 (95% CI: 0.7, 3.8), respectively, and
`mean (±SE) number of Gd+ lesions at year 5 was
`0.6 ± 0.48.
`
`Brain atrophy. At year 2 of DEFINE/CONFIRM,
`among patients in ENDORSE, adjusted PBVC from
`baseline was significantly lower with DMF BID ver-
`sus PBO (p = 0.0070); in post hoc exploratory analy-
`ses, significantly lower PBVC was observed versus
`GA (p = 0.0035; Table 2). Adjusted PBVC relative to
`ENDORSE baseline at years 3, 4, and 5 was not sig-
`nificantly different in BID/BID patients compared
`with the PBO/DMF or GA/DMF groups (Table 2).
`Annualized rate of adjusted mean PBVC calculated
`throughout 5 years of follow-up was −0.32 per year
`(95% CI: −0.37, −0.27)) in BID/BID patients, compa-
`rable with that of healthy volunteers.7
`
`Safety. The overall incidence of AEs, serious AEs
`(SAEs), and discontinuations due to AEs (Supple-
`mentary Table e-3) was similar among the treatment
`groups who continued DMF from DEFINE/CONFIRM
`and those new to DMF; however, a higher proportion
`of patients new to DMF discontinued due to AEs,
`largely from flushing and gastrointestinal (GI) events
`that tend to occur early in DMF therapy.3,4,8 The most
`common individual AEs and SAEs are summarized in
`Table 3. Multiple sclerosis (MS) relapse and naso-
`pharyngitis were most common in patients continuing
`DMF. Flushing and GI-related events were more
`common among patients new to DMF, with inci-
`dences highest during the first year of ENDORSE
`(Supplementary Figure e-1) and generally consistent
`with those of DMF-treated patients in the parent stud-
`ies, wherein incidences were highest during the first
`month and decreased substantially thereafter.3,4,8
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`R Gold, DL Arnold et al.
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`aSome additional patients (n = 68 across treatment groups) completed ENDORSE at year 2, prior to the protocol amendment extending the study duration.
`AE: adverse event; BID: twice daily; DMF: dimethyl fumarate; GA: glatiramer acetate; MS: multiple sclerosis; PBO: placebo; TID: thrice daily.
`Figure 2. Patient disposition.
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`Multiple Sclerosis Journal 23(2)
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`Table 1. Baseline demographics of the ITT population in ENDORSE and at start of DEFINE and CONFIRM.
`
`Characteristica
`
`Continued DMFb
`
`New to DMF
`
`Start of ENDORSE
` Age (years)
` Age < 40 years, n (%)
` Female, n (%)
` White, n (%)
` Weight (kg), mean (SD)
` Time since first MS symptoms (years)
` Time since diagnosis of MS (years)
` Alternative RRMS treatment in prior study,d
`
`n (%)
`Start of DEFINE and CONFIRM
` Relapses in prior year
` EDSS score
`
`BID/BID
`(n = 501)
`
`TID/TID
`(n = 502)c
`
`PBO/BID
`(n = 249)
`
`PBO/TID
`(n = 248)
`
`GA/BID
`(n = 118)
`
`GA/TID
`(n = 118)
`
`39.7 (9.1)
`237 (47)
`352 (70)
`403 (80)
`70.6 (17.8)
`10.0 (6.5)
`6.9 (5.0)
`13 (3)
`
`40.0 (9.1)
`233 (46)
`354 (71)
`413 (82)
`71.8 (17.0)
`9.3 (6.1)
`6.4 (4.9)
`10 (2)
`
`39.9 (8.8)
`119 (48)
`178 (71)
`202 (81)
`70.8 (16.6)
`10.1 (6.7)
`6.8 (5.3)
`24 (10)
`
`40.5 (9.4)
`114 (46)
`166 (67)
`198 (80)
`73.8 (16.9)
`9.5 (6.2)
`7.0 (5.4)
`13 (5)
`
`38.2 (8.5)
`68 (58)
`86 (73)
`98 (83)
`73.4 (21.5)
`9.0 (5.8)
`6.2 (5.0)
`8 (7)
`
`39.5 (9.5)
`56 (47)
`76 (64)
`103 (87)
`72.0 (17.9)
`9.2 (6.3)
`6.3 (4.8)
`6 (5)
`
`1.3 (0.7)
`2.5 (1.3)
`
`1.3 (0.7)
`2.4 (1.1)
`
`1.3 (0.8)
`2.5 (1.1)
`
`1.4 (0.8)
`2.5 (1.2)
`
`1.3 (0.6)
`2.6 (1.2)
`
`1.4 (0.6)
`2.7 (1.2)
`
`BID: twice daily; DMF: dimethyl fumarate; EDSS: Expanded Disability Status Scale; GA: glatiramer acetate; ITT: intention-to-treat; MS: multiple sclerosis;
`PBO: placebo; RRMS: relapsing–remitting multiple sclerosis; SD: standard deviation; TID: thrice daily.
`aValues are mean (SD) unless otherwise stated.
`bDMF: delayed-release DMF.
`c One patient randomized to DMF TID took GA throughout the CONFIRM study. This patient was counted in the TID/TID group of the ITT population and in
`the GA/TID group of the safety population in ENDORSE.
`dInterferon β-1a.
`
`Although the study was not designed to assess the
`duration of each GI or flushing episode in a precise
`manner, AE duration was summarized based on the
`investigator-reported onset and resolution dates.
`There were no apparent differences in the duration of
`flushing or GI-related AEs across the treatment
`groups based on the available investigator-reported
`data. Overall, the median (25%, 75% percentile) dura-
`tion of flushing and related symptoms (n = 689 events
`out of 466 patients who had any events) was 80 days
`(7, 716 days), and the median duration of GI-related
`events (n = 1011 events out of 523 patients who had
`any events) was 12 days (4, 71 days).
`
`The incidence of individual AEs leading to treatment
`discontinuation was ⩽1%–4% (Supplementary Table
`e-4). Of patients new to DMF, AEs leading to treat-
`ment discontinuation were generally related to flush-
`ing and GI tolerability; the majority of discontinuations
`occurred during the first 6 months of treatment
`(Supplementary Table e-3), consistent with observa-
`tions in DEFINE/CONFIRM.3,4
`
`The most commonly reported ENDORSE SAE was
`MS relapse, with other SAEs occurring in ⩽5 patients
`in any treatment group (Table 3). Incidence of serious
`
`infections was ⩽4%
`treatment group
`in any
`(Supplementary Table e-3). A total of 27 malignancies
`occurred in 18 patients continuing DMF and 8 new to
`DMF; overall incidence of malignancies was 2% for
`patients who continued DMF (Supplementary Table
`e-5). No increased risk of malignancy was observed
`among DMF-treated patients compared with cancer
`rates reported for the general MS population (4%
`summary estimate (95% CI: 3%, 6%)).9
`
`Hematological findings in ENDORSE were consist-
`ent with those from DEFINE/CONFIRM. Patients
`new to DMF had decreases in mean white blood cell
`(WBC) and lymphocyte counts, whereas these values
`remained stable with no further overall decrease in
`patients continuing DMF. The incidence of lympho-
`cyte counts <0.5 × 109/L was 7%–8% of the patients
`continuing DMF and 6%–9% of those new to DMF.
`There was no overall increased risk of serious oppor-
`tunistic infections; however, subsequent to the data
`cutoff for this report, a fatal case of progressive mul-
`tifocal leukoencephalopathy (PML) in a patient
`treated with DMF 240 mg TID was reported in the set-
`ting of severe, prolonged lymphopenia (~290–580
`cells/mL3 over 3.5 years); full details of this case are
`reported separately.10
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`

`I o-1yoummy-mnemE-woounm
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`BID/BID
`
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`Figure 3. (a) ARR by yearly interval, (b) time to first relapse, and (0) 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 regession, adjusted for baseline EDSS score ($2.0 vs >2.0),
`baseline age (<40 vs >40years), region, and number of relapses in the lyear 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: Bipanded Disability Status Scale; GA: glatiramer
`acetate; l'I'T: intention-tomcat; MS: multiple sclerosis; PBO: placebo; TED: thrice daily.
`
`journals.sagepub.cothome/msj
`
`Page 7 of 13
`
`259
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`

`

`Multiple Sclerosis Journal 23(2)
`
`l 0-1 youmyouomEFINE-MCONFIRM)
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`
`Figure 4. (a) Number of new or enlarging T2 hyperintense lesions by yearly interval, (b) number of new nonenhancing
`Tl hypointense lesions by yearly interval, and (0) mean number of Gd-l- lesions by yearly interval: DEFINE, CONFIRM,
`and ENDORSE analysis (MRI cohort).
`BID: twice daily; CI: confidence interval; GA: glatiramer acetate; Gd+: gadolinimn-enhanced; MRI: magnetic resonance image; P30:
`placebo; TID: thrice daily.
`
`Hepatic AEs or SAEs occurred in $3% or <1% of the
`patients, respectively,
`in any treatment group. Few
`patients ($3%) continuing DMF had ALT or AST
`levels 23 X ULN, and no case fulfilled Hy’s law crite-
`ria for drug-induced liver injury. The incidence of
`transaminase elevations in ENDORSE is consistent
`
`with observations in DEFINE/CONFIRM, wherein
`incidences were similar between the DMF- and PEG-
`
`treated groupsfir4
`
`In DEFINE/CONFIRM, 19% of the patients receiv-
`ing DMF BID and 18% of the PBO—treated patients
`
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`

`

`R Gold, DL Arnold et al.
`
`Table 2. Percent brain volume change.
`
`ENDORSE MRI cohort of DEFINE and CONFIRM
`
`
`
`Year 1
` N
` Mean (SD)
` Median
` p-value vs BID/BIDb
`Year 2
` n
` Mean (SD)
` Median
` p-value vs BID/BIDb
`
`DMFa BID
`
`PBO
`
`GA
`
`197
`−0.42 (0.747)
`−0.34
`−
`
`189
`−0.83 (0.962)
`−0.68
`−
`
`179
`−0.39 (0.684)
`−0.33
`0.8961
`
`158
`−0.94 (0.906)
`−0.81
`0.0070
`
`88
`−0.62 (0.704)
`−0.71
`0.0464
`
`79
`−1.15 (0.784)
`−1.09
`0.0035
`
`ENDORSE MRI cohort assessed from ENDORSE baseline
`
`
`
`BID/BID
`
`PBO/DMFa
`
`GA/DMFa
`
`Year 3 (year 1 of ENDORSE)
` n
` Mean (SD)
` Median
` p-value vs BID/BIDc
`Year 4 (year 2 of ENDORSE)
` n
` Mean (SD)
` Median
` p-value vs BID/BIDc
`Year 5 (year 3 of ENDORSE)
` n
` Mean (SD)
` Median
` p-value vs BID/BIDc
`
`163
`−0.45 (0.669)
`−0.35
`−
`
`148
`−0.61 (0.809)
`−0.61
`−
`
`129
`−0.85 (0.958)
`−0.86
`−
`
`127
`−0.52 (0.708)
`−0.41
`0.6955
`
`120
`−0.85 (0.981)
`−0.68
`0.2189
`
`103
`−1.19 (1.252)
`−0.96
`0.1678
`
`78
`−0.42 (0.858)
`−0.28
`0.2216
`
`63
`−0.80 (1.008)
`−0.61
`0.6346
`
`57
`−1.07 (1.272)
`−1.00
`0.5001
`
`BID: twice daily; DMF: dimethyl fumarate; GA: glatiramer acetate; Gd+: gadolinium-enhanced; PBO: placebo; SD: standard devia-
`tion; MRI: magnetic resonance image.
`aDelayed-release DMF.
`bBased on rank model, adjusted for DEFINE/CONFIRM baseline Gd+ lesion count and T2 lesion volume.
`cBased on rank model, adjusted for ENDORSE baseline Gd+ lesion count and T2 lesion volume.
`
`experienced renal or urinary AEs. Renal or urinary
`events were reported in 23%, 20%, and 13% of
`ENDORSE BID/BID, PBO/BID, and GA/BID
`patients, respectively. For BID/BID patients, the most
`common renal or urinary AEs (⩾3% occurrence in all
`treatment groups) were proteinuria (7%), microalbu-
`minuria (6%), and hematuria (5%). Renal or urinary
`AEs resulted in discontinuation in ⩽1% of any treat-
`ment group, and serious renal or urinary AEs occurred
`in <1% of any treatment group.
`
`with novel mechanisms of action affords practitioners
`a wider array of options to treat RRMS and increases
`opportunities to individualize therapy for patients
`intolerant of, or suboptimally responsive to, other
`therapies. This is particularly germane to MS, the het-
`erogeneous nature of which contributes to variability
`in therapeutic response.12,13 Additionally, oral agents
`afford convenience of administration. Efficacy must
`always be carefully weighed against risk of AEs, par-
`ticularly throughout longer treatment periods.14–17
`
`Discussion
`DMF is an oral agent indicated for the treatment of
`relapsing forms of MS.11 The availability of agents
`
`In this first phase of ENDORSE, low clinical and
`MRI activity was sustained during 5 years of DMF
`treatment. Patients initially randomized to PBO or
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`Multiple Sclerosis Journal 23(2)
`
`Table 3. Most common AEs (incidence ⩾10% in any treatment group) and serious AEs (incidence ⩾3 patients in any
`treatment group).
`
`Event, n (%)a
`
`Continued DMFb
`
`New to DMFb
`
`BID/BID
`(n = 501)
`
`TID/TID
`(n = 501)
`
`PBO/BID
`(n = 249)
`
`PBO/TID
`(n = 248)
`
`GA/BID
`(n = 118)
`
`GA/TID
`(n = 119)
`
`Any AE
` MS relapse
` Nasopharyngitis
` Flushing
` Urinary tract infection
` Headache
`
` Upper respiratory
`tract infection
` Diarrhea
` Back pain
` Fatigue
` Bronchitis
` Proteinuria
` Abdominal pain upper
` ALT increased
`Any SAE
` MS relapse
` Urinary tract infection
` Breast cancer
` Gastritis
` Fall
` Uterine leiomyoma
` Traffic accident
`
`454 (91)
`149 (30)
`124 (25)
`52 (10)
`93 (19)
`73 (15)
`72 (14)
`
`45 (9)
`48 (10)
`40 (8)
`34 (7)
`36 (7)
`18 (4)
`14 (3)
`109 (22)
`50 (10)
`5 (<1)
`3 (<1)
`2 (<1)
`3 (<1)
` 0
`1 (<1)
`
`459 (92)
`170 (34)
`121 (24)
`64 (13)
`78 (16)
`61 (12)
`66 (13)
`
`38 (8)
`60 (12)
`46 (9)
`49 (10)
`36 (7)
`27 (5)
`21 (4)
`124 (25)
`58 (12)
` 0
`3 (<1)
` 0
`2 (<1)
`1 (<1)
`3 (<1)
`
`237 (95)
`70 (28)
`45 (18)
`76 (31)
`35 (14)
`31 (12)
`32 (13)
`
`39 (16)
`24 (10)
`26 (10)
`19 (8)
`19 (8)
`30 (12)
`17 (7)
`59 (24)
`23 (9)
` 0
` 0
` 0
`1 (<1)
`3 (1)
`1 (<1)
`
`231 (93)
`67 (27)
`45 (18)
`59 (24)
`36 (15)
`27 (11)
`31 (13)
`
`36 (15)
`26 (10)
`24 (10)
`18 (7)
`29 (12)
`29 (12)
`19 (8)
`40 (16)
`19 (8)
`3 (1)
` 0
`3 (1)
` 0
` 0
`1 (<1)
`
`104 (88)
`28 (24)
`18 (15)
`26 (22)
`17 (14)
`12 (10)
`8 (7)
`
`11 (9)
`11 (9)
`5 (4)
`8 (7)
`5 (4)
`10 (8)
`12 (10)
`19 (16)
`8 (7)
`1 (<1)
` 0
` 0
`1 (<1)
` 0
`1 (<1)
`
`101 (85)
`31 (26)
`17 (14)
`25 (21)
`10 (8)
`10 (8)
`9 (8)
`
`12 (10)
`3 (3)
`6 (5)
`5 (4)
`7 (6)
`12 (10)
`8 (7)
`23 (19)
`10 (8)
` 0
`2 (2)
` 0
` 0
` 0
` 0
`
`AE: adverse event; ALT: alanine aminotransferase; BID: twice daily; DMF: dimethyl fumarate; GA: glatiramer acetate; MS: multiple
`sclerosis; PBO: placebo; TID: thrice daily.
`Safety population is based on received treatment.
`a AE incidence represents cumulative incidence throughout the observation period; SAE incidence represents cumulative incidence
`throughout the entire observation period (parent and extension studies).
`bDMF: delayed-release DMF.
`
`GA in DEFINE/CONFIRM demonstrated improve-
`ments after switching to DMF in ENDORSE; how-
`ever, with no control group, the relative impact of
`changes in the natural course of MS in ENDORSE
`cannot be assessed. In addition, as with other long-
`term extension studies,17,18 bias could result because
`not all patients randomized in the parent study were
`enrolled and dosed in ENDORSE.
`
`The recommended dosage for DMF is 240 mg BID.
`Data for 240 mg TID were included to explore the
`general consistency of between-dose effects. In this
`interim analysis, effect sizes with DMF BID and TID
`were broadly similar; however, ENDORSE was not
`powered to analyze dose-dependent differences.
`
`MRI is valuable for diagnosis, prognosis, and assess-
`ment of treatment response in patients with MS.19
`Continued DMF treatment resulted in a low frequency
`
`of new non-enhancing T1 hypointense lesions, new or
`enlarging T2 hyperintense lesions, and Gd+ lesions
`over 5 years. Reduced MRI disease activity was also
`noted in patients who switched to DMF in ENDORSE.
`
`There was a short delay in treatment initiation in
`ENDORSE
`introduced during re-randomization;
`therefore, some patients who switched from PBO or
`GA received DMF later than continuously treated
`patients in the extension (mean treatment gap of
`19 days for continuous BID vs 42–65 days for switch-
`ers (MRI cohort)).
`
`Accelerated loss of brain tissue in MS correlates
`with cognitive impairment and worse EDSS and
`quality of life.20–23 Annual rates of brain volume loss
`in patients treated continuously with DMF were low
`and comparable with rates in healthy volunteers.7
`This analysis suggests a continuous beneficial effect
`
`262
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`Page 10 of 13
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`R Gold, DL Arnold et al.
`
`of DMF on brain atrophy and a higher impact of
`early versus delayed treatment. DMF demon