T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Placebo-Controlled Phase 3 Study of Oral
`BG-12 for Relapsing Multiple Sclerosis
`Ralf Gold, M.D., Ludwig Kappos, M.D., Douglas L. Arnold, M.D.,
`Amit Bar-Or, M.D., Gavin Giovannoni, M.D., Krzysztof Selmaj, M.D.,
`Carlo Tornatore, M.D., Marianne T. Sweetser, M.D., Ph.D., Minhua Yang, M.S.,
`Sarah I. Sheikh, M.D., and Katherine T. Dawson, M.D.,
`for the DEFINE Study Investigators*
`
`ABS TR ACT
`
`Background
`BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective
`properties in preclinical experiments and to result in significant reductions in disease
`activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study
`involving patients with relapsing–remitting multiple sclerosis.
`Methods
`We conducted a randomized, double-blind, placebo-controlled phase 3 study involv-
`ing patients with relapsing–remitting multiple sclerosis. Patients were randomly
`assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of
`240 mg three times daily, or placebo. The primary end point was the proportion of
`patients who had a relapse by 2 years. Other end points included the annualized
`relapse rate, the time to confirmed progression of disability, and findings on MRI.
`Results
`The estimated proportion of patients who had a relapse was significantly lower in the
`two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26%
`with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The
`annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in
`the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, represent-
`ing relative reductions of 53% and 48% with the two BG-12 regimens, respectively
`(P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated
`proportion of patients with confirmed progression of disability was 16% in the twice-
`daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo
`group, with significant relative risk reductions of 38% with BG-12 twice daily
`(P = 0.005) and 34% with BG-12 thrice daily (P = 0.01). BG-12 also significantly re-
`duced the number of gadolinium-enhancing lesions and of new or enlarging T2-
`weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen
`with placebo). Adverse events associated with BG-12 included flushing and gastro-
`intestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as
`decreased lymphocyte counts and elevated liver aminotransferase levels.
`Conclusions
`In patients with relapsing–remitting multiple sclerosis, both BG-12 regimens, as
`compared with placebo, significantly reduced the proportion of patients who had a
`relapse, the annualized relapse rate, the rate of disability progression, and the number
`of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number,
`NCT00420212.)
`
`From the Department of Neurology, St.
`Josef-Hospital/Ruhr-University Bochum,
`Bochum, Germany (R.G.); the Depart-
`ments of Neurology and Biomedicine,
`University Hospital Basel, Basel, Switzer-
`land (L.K.); NeuroRx Research (D.L.A.) and
`Montreal Neurological Institute and Hos-
`pital, McGill University (D.L.A., A.B.-O.)
`— both in Montreal; Queen Mary Univer-
`sity of London, Blizard Institute of Cell
`and Molecular Science, Barts and the
`London School of Medicine and Dentistry,
`London (G.G.); Medical University of Lodz,
`Lodz, Poland (K.S.); Georgetown Univer-
`sity Hospital, Washington, DC (C.T.); and
`Biogen Idec, Weston, MA (M.T.S., M.Y.,
`S.I.S., K.T.D.). Address reprint requests to
`Dr. Gold at the Department of Neurology,
`St. Josef-Hospital/Ruhr-University Bochum,
`Gudrunstr. 56, D-44791 Bochum, Germa-
`ny, or at ralf.gold@ruhr-uni-bochum.de.
`
`* The Determination of the Efficacy and
`Safety of Oral Fumarate in Relapsing–
`Remitting MS (DEFINE) study investi-
`gators are listed in the Supplementary
`Appendix, available at NEJM.org.
`
`This article was updated on November 21,
`2012, at NEJM.org.
`
`N Engl J Med 2012;367:1098-107.
`DOI: 10.1056/NEJMoa1114287
`Copyright © 2012 Massachusetts Medical Society.
`
`1098
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 001
`
`

`

`Oral BG-12 for Relapsing Multiple Sclerosis
`
`Oral BG-12 (dimethyl fumarate) is
`
`being investigated for the treatment of
`multiple sclerosis. Inflammation and oxi-
`dative stress are central pathologic factors in
`multiple sclerosis.1,2 Immune cell activation and
`infiltration into the central nervous system are
`thought to result in widespread cellular damage,
`potentially owing to the dysregulated production
`and release of reactive oxygen and nitrogen species,
`such as hydrogen peroxide and peroxynitrite, and
`proinflammatory stimuli.3 This combination of
`toxic factors ultimately results in demyelination
`and neurodegeneration, causing disease activity
`and progression of disability.
`BG-12 has been shown to have beneficial ef-
`fects in preclinical models of neuroinflammation,
`neurodegeneration, and toxic oxidative stress,
`which appear to be mediated predominately
`through activation of the nuclear 1 factor (ery-
`throid-derived 2)–like 2 (Nrf2) antioxidant re-
`sponse pathway, the primary cellular defense
`against the cytotoxic effects of oxidative stress.1,4
`BG-12 may also play a role in modulating immune-
`cell responses by shifting dendritic-cell differentia-
`tion,5 suppressing proinflammatory-cytokine pro-
`duction, or directly inhibiting proinflammatory
`pathways.6
`In a randomized, placebo-controlled, 24-week,
`phase 2 study involving patients with relapsing–
`remitting multiple sclerosis,7 BG-12, as compared
`with placebo, significantly reduced the number of
`new gadolinium-enhancing lesions, new or en-
`larging hyperintense lesions on T2-weighted im-
`ages, and new hypointense lesions on T1-weighted
`images. Here, we report the results of the Deter-
`mination of the Efficacy and Safety of Oral Fuma-
`rate in Relapsing–Remitting MS (DEFINE) study,
`in which two dose regimens of BG-12 were com-
`pared with placebo.
`
`Methods
`
`Study Oversight
`We conducted a randomized, double-blind, pla-
`cebo-controlled, 2-year phase 3 study of BG-12 in
`patients with relapsing–remitting multiple sclero-
`sis. Members of the advisory committee and the
`data and safety monitoring committee (see the
`Study Oversight section in the Supplementary Ap-
`pendix, available with the full text of this article
`at NEJM.org) collaborated with the sponsor, Biogen
`Idec, to develop the protocol and monitor the on-
`going study.
`
`Data were collected by the investigators and
`were analyzed by the sponsor. The investigators
`and sponsor agreed to maintain data confiden-
`tiality during the study. All the authors had
`early access to the data, participated in person
`in the data analysis and interpretation, and vouch
`for the accuracy and completeness of the data
`and the statistical analysis and for the fidelity
`of the study to the protocol. The first draft of
`the manuscript was written by the first author
`and the senior author representing the spon-
`sor, with support from medical writers from
`Infusion Communications, who were funded
`by the sponsor. All the authors participated in
`writing subsequent drafts of the manuscript and
`made the decision to submit it for publication.
`The protocol, including the statistical analysis
`plan, is available at NEJM.org; the study was
`conducted and reported as described in the pro-
`tocol.
`
`Patients
`Key eligibility criteria included an age of 18 to
`55 years, a diagnosis of relapsing–remitting
`multiple sclerosis as defined according to the
`McDonald criteria,8,9 a baseline score of 0 to 5.0
`on the Expanded Disability Status Scale (EDSS,
`which ranges from 0 to 10, with higher scores
`indicating greater disability),10 and disease activ-
`ity as evidenced by at least one clinically docu-
`mented relapse within 12 months before random-
`ization or a brain magnetic resonance imaging
`(MRI) scan, obtained within 6 weeks before ran-
`domization, that showed at least one gadolinium-
`enhancing lesion. Key exclusion criteria were
`progressive forms of multiple sclerosis,9 another
`major disease that would preclude participation
`in a clinical trial, abnormal results on prespeci-
`fied laboratory tests, or recent exposure to con-
`traindicated medications (Table S1 in the Supple-
`mentary Appendix).
`All patients were fully informed of approved
`therapies for multiple sclerosis as an alternative to
`participation in a placebo-controlled trial and pro-
`vided written informed consent; we also obtained
`reconsent from patients after a confirmed relapse
`or progression of disability (after discussion of
`treatment options as detailed below). The study
`was approved by central and local ethics commit-
`tees and was conducted in accordance with the
`International Conference on Harmonization
`Guidelines for Good Clinical Practice11 and the
`Declaration of Helsinki.12
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1099
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 002
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Study Design
`Patients at 198 sites in 28 countries were ran-
`domly assigned, in a 1:1:1 ratio, to receive, in a
`double-blind fashion, BG-12 at a dose of 240 mg
`twice daily, BG-12 at a dose of 240 mg three
`times daily, or placebo (Fig. S1 in the Supplemen-
`tary Appendix). Randomization was performed
`centrally and was stratified according to site.
`To maintain concealment of the study-group
`assignments, each study center used separate ex-
`amining and treating neurologists (all of whom
`remained unaware of the assignments through-
`out the trial). The examining neurologists con-
`ducted neurologic assessments, including assess-
`ment of the EDSS score, whereas the treating
`neurologists were responsible for all aspects of
`patient care, including the treatment of relapses
`and other disease symptoms. To ensure that the
`study-group assignments would not be revealed,
`patients were instructed to take the assigned
`study drug at least 4 hours before study visits, in
`case patients in the BG-12 groups had a side ef-
`fect of flushing.
`All patients were eligible to switch to an alter-
`native therapy for multiple sclerosis if they had
`completed 48 weeks of the study treatment and
`had had one or more confirmed relapses after
`24 weeks; patients could switch at any time if
`they had confirmed progression of disability.
`
`Study Procedures and End Points
`Study visits were scheduled every 4 weeks for safe-
`ty assessments, including the monitoring of lab-
`oratory values; for dispensing of the study drug;
`and for assessment of adherence to the study drug.
`During clinic visits every 12 weeks, standardized
`neurologic assessments, including assessment of
`the EDSS score, were performed by physicians
`who were certified either by in-person training or
`through an online program (www.Neurostatus
`.net). MRI scans were obtained at screening and
`at weeks 24, 48, and 96 in a subgroup of patients
`at sites with full MRI capabilities. All scans were
`evaluated in a blinded manner at a central reading
`facility (NeuroRx Research). Unscheduled visits
`were conducted as needed to evaluate suspected
`relapses.
`The primary end point was the proportion of
`patients who had a relapse by 2 years. Protocol-
`defined relapses were new or recurrent neurologic
`symptoms, not associated with fever or infection,
`that lasted for at least 24 hours and that were ac-
`companied by new objective neurologic findings
`
`according to the examining neurologist’s evalua-
`tion. All protocol-defined relapses were evaluated
`by an independent neurologic evaluation commit-
`tee (see the Study Oversight section in the Supple-
`mentary Appendix), whose members reviewed a
`standardized set of blinded clinical records
`(which did not include MRI data) from the treating
`and examining neurologists.
`Secondary end points at 2 years included the
`number of gadolinium-enhancing lesions and of
`new or enlarging hyperintense lesions on T2-
`weighted images, the annualized relapse rate (the
`total number of relapses divided by the number
`of patient-years in the study, excluding data ob-
`tained after patients switched to alternative mul-
`tiple sclerosis medications), and the time to
`progression of disability. Disability progression
`was defined as at least a 1.0-point increase on the
`EDSS in patients with a baseline score of 1.0 or
`higher or at least a 1.5-point increase in patients
`with a baseline score of 0, with the increased
`score sustained for at least 12 weeks.
`
`Statistical Analysis
`All efficacy analyses were performed on data from
`the intention-to-treat population, which included
`all patients who underwent randomization and
`who received at least one dose of the study drug.
`All statistical tests were two-sided, with an over-
`all type I error rate of 0.05. Sensitivity analyses
`were performed on the primary end point.
`On the basis of data from another clinical
`trial in which an active drug was compared with
`placebo in patients with multiple sclerosis,13 we
`estimated that 48.0% of patients receiving pla-
`cebo and 33.6% of patients receiving BG-12
`would have at least one relapse during the study.
`Using a chi-square test with a two-sided alpha
`level of 0.05, and assuming an estimated drop-
`out rate of 23%, we estimated that we would
`need to enroll 337 patients in each group for the
`study to have 90% power to detect the 30% re-
`duction in the percentage of patients with a re-
`lapse in each BG-12 group as compared with the
`placebo group. The primary end point was ana-
`lyzed with the use of a Cox proportional-hazards
`model, adjusted for baseline EDSS score, age,
`region, and number of relapses in the year be-
`fore study entry. The estimated proportion of
`patients with a relapse was derived with the use
`of the Kaplan–Meier product-limit method, which
`was based on the time-to-first-relapse survival
`distribution.
`
`1100
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 003
`
`

`

`Oral BG-12 for Relapsing Multiple Sclerosis
`
`For secondary end points, the analyses were
`conducted in the following ranked order: an
`analysis of the number of new or newly enlarg-
`ing hyperintense lesions on T2-weighted images,
`with the use of a negative binomial model; an
`analysis of the number of gadolinium-enhancing
`lesions, with the use of an ordinal logistic-
`regression model; an analysis of the annualized
`relapse rate, with the use of a negative binomial
`regression model; and an analysis of the time to
`progression of disability that was sustained for
`12 weeks, with the use of a Cox proportional-
`hazards model. The analytic models included ad-
`justments for region and baseline characteristics,
`including EDSS score, age, relapse rate, and num-
`ber or volume of baseline lesions, as appropriate.
`A sequential (closed) testing procedure was
`used to control the overall type I error rate due to
`multiple comparisons. Formal testing of the com-
`parison of twice-daily BG-12 with placebo was
`undertaken only if the comparison of thrice-
`daily BG-12 with placebo was significant (P≤0.05).
`Analysis of secondary end points, according to
`the ranked order, followed an additional se-
`quential testing procedure such that if statisti-
`cal significance was not achieved for an end
`point, all lower-ranking end points were also
`considered to be nonsignificant.
`Among patients who switched to an alterna-
`tive therapy for multiple sclerosis, all the data
`before the switch were used for the analysis of
`the clinical end points. For the analyses of MRI
`end points in these patients, the data before the
`switch were used and then data after the rescue
`therapy was initiated were imputed with the use
`of a constant rate assumption.
`Safety analyses were summarized with the use
`of descriptive statistics for all patients who re-
`ceived at least one dose of the study drug. Among
`patients who switched to alternative medications,
`data collected after the switch were excluded
`from the safety analyses.
`
`R esults
`
`Patients
`A total of 1237 patients underwent randomiza-
`tion, of whom 1234 received at least one dose of
`the study drug (intention-to-treat population).
`The baseline demographic and disease character-
`istics were generally well balanced across the
`study groups (Table 1). Patients were 18 to 56 years
`of age and had received a diagnosis of multiple
`
`sclerosis between 0 and 32 years before study en-
`try. Approximately 40% of the patients had previ-
`ously received approved therapies for relapsing–
`remitting multiple sclerosis (Table 1). A total of
`540 patients were included in the subgroup of
`patients who underwent MRI. The baseline de-
`mographic and disease characteristics of patients
`in the MRI cohort were similar to those of pa-
`tients who were not in the MRI cohort and to
`those of the overall study population (Table S2 in
`the Supplementary Appendix).
`A total of 952 patients (77%) completed the
`study (78% in the placebo group and 77% in
`each of the BG-12 groups) (Fig. S2 in the Supple-
`mentary Appendix). The rate of discontinuation
`of the study drug was similar in the three
`groups (35% in the placebo group and 31% in
`each of the BG-12 groups), as was the rate of
`withdrawal from the study (22% in the placebo
`group and 23% in each of the BG-12 groups)
`(Table S3 and Fig. S2 in the Supplementary Ap-
`pendix). The percentage of patients who switched
`to an approved therapy for multiple sclerosis was
`low (13% in the placebo group, 6% in the twice-
`daily BG-12 group, and 5% in the thrice-daily
`BG-12 group). The mean duration of participa-
`tion in the study was 83.9 weeks and was similar
`among the three groups.
`
`Efficacy
`Relapses
`The proportion of patients who had at least one
`relapse of multiple sclerosis by 2 years was sig-
`nificantly reduced with each BG-12 regimen as
`compared with placebo. On the basis of Kaplan–
`Meier estimates, 27% of the patients in the twice-
`daily BG-12 group and 26% in the thrice-daily
`BG-12 group, as compared with 46% in the pla-
`cebo group, had a relapse at 2 years (P<0.001 for
`both comparisons) (Table 2 and Fig. 1A). The
`hazard ratio for the risk of relapse with BG-12
`treatment as compared with placebo during the
`2-year period was 0.51 for the twice-daily group
`(95% confidence interval [CI], 0.40 to 0.66) and
`0.50 for the thrice-daily group (95% CI, 0.39 to
`0.65) (P<0.001 for both comparisons), correspond-
`ing to a 49% and 50% reduction, respectively, in
`the risk of relapse. Each BG-12 regimen, as com-
`pared with placebo, prolonged the time to a first
`relapse (time to relapse in the 25th percentile of
`patients, 38 weeks in the placebo group, as com-
`pared with 87 weeks and 91 weeks in the twice-
`daily and thrice-daily BG-12 groups, respective-
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1101
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 004
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 1. Baseline Characteristics of the Intention-to-Treat Population.*
`
`Characteristic
`
`Age — yr
`
`Female sex — no. (%)
`
`Weight — kg
`
`Race — no. (%)†
`
`White
`
`Asian
`
`Black
`
`Other or unknown
`
`Previous use of approved medication for multiple sclerosis
`— no. (%)‡
`
`Time since diagnosis — yr
`
`Relapses in previous 12 mo — no.
`
`EDSS score at baseline — no. (%)§
`
`0
`
`1.0 or 1.5
`
`2.0 or 2.5
`
`3.0 or 3.5
`
`4.0 or 4.5
`
`5.0
`
`Placebo
`(N = 408)
`
`38.5±9.1
`
`306 (75)
`
`71.1±17.0
`
`318 (78)
`
`42 (10)
`
`8 (2)
`
`40 (10)
`
`172 (42)
`
`5.8±5.8
`
`1.3±0.7
`
`21 (5)
`
`105 (26)
`
`112 (27)
`
`97 (24)
`
`56 (14)
`
`16 (4)
`
`Twice-Daily BG-12
`(N = 410)
`
`Thrice-Daily BG-12
`(N = 416)
`
`38.1±9.1
`
`296 (72)
`
`70.7±18.5
`
`321 (78)
`
`38 (9)
`
`8 (2)
`
`43 (10)
`
`162 (40)
`
`5.6±5.4
`
`1.3±0.7
`
`29 (7)
`
`109 (27)
`
`116 (28)
`
`82 (20)
`
`56 (14)
`
`16 (4)
`
`38.8±8.8
`
`306 (74)
`
`71.3±16.9
`
`330 (79)
`
`36 (9)
`
`10 (2)
`
`40 (10)
`
`168 (40)
`
`5.1±5.3
`
`1.3±0.6
`
`24 (6)
`
`104 (25)
`
`146 (35)
`
`85 (20)
`
`42 (10)
`
`14 (3)
`
`Mean score on EDSS
`
`2.48±1.24
`
`2.40±1.29
`
`2.36±1.19
`
`MRI findings¶
`Gadolinium-enhancing T1-weighted lesions — no.
`Hyperintense T2-weighted lesions
`Mean no.
`
`<9 — no. of patients
`
`≥9 — no. of patients
`
`1.6±3.4
`
`1.2±3.3
`
`1.2±4.1
`
`49.2±38.6
`
`47.6±34.7
`
`55.8±44.3
`
`12
`
`168
`
`9
`
`167
`
`14
`
`170
`
`* Plus–minus values are means ±SD. The intention-to-treat population included all patients who underwent randomization
`and received at least one dose of the study drug. All the baseline characteristics were well balanced among the study
`groups (nominal P>0.05).
`† Race was self-reported.
`‡ Approved medications for multiple sclerosis include interferon beta-1a (used in 27% of all randomly assigned patients),
`glatiramer acetate (15%), interferon beta-1b (14%), and natalizumab (3%). Patients may have received more than one
`prior medication for multiple sclerosis. Patients may also have received other, nonapproved therapies for multiple scle-
`rosis. (The percentage of patients receiving any medication for multiple sclerosis before study entry was 54 to 56%
`across treatment groups.)
`§ Scores on the Expanded Disability Status Scale (EDSS) range from 0 to 10, with higher scores indicating a greater degree
`of disability. The baseline score was higher than 5.0 in one patient in each group, and the score was unknown for one
`patient in the twice-daily BG-12 group.
`¶ Magnetic resonance imaging (MRI) was performed in 180 patients in the placebo group, 176 in the twice-daily BG-12
`group, and 184 in the thrice-daily BG-12 group.
`
`ly). Sensitivity analyses, performed with the use
`of logistic regression, in which patients who dis-
`continued the study drug or withdrew from the
`study without having had a relapse were consid-
`ered to have had a relapse if the reason for dis-
`continuation or withdrawal was suggestive of a
`
`lack of efficacy, showed that BG-12 treatment
`also reduced the proportion of patients who had
`a relapse by 2 years (odds ratio for relapse, 0.42
`with twice-daily BG-12 and 0.41 with thrice-daily
`BG-12; P<0.001 for both comparisons). An addi-
`tional sensitivity analysis that included all proto-
`
`1102
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 005
`
`

`

`Oral BG-12 for Relapsing Multiple Sclerosis
`
`Table 2. Clinical and MRI End Points during the 96-Week Study.*
`
`End Point
`
`Patients with relapse at 2 yr — %†
`
`Hazard ratio vs. placebo (95% CI)
`
`Odds ratio vs. placebo (95% CI)§
`
`Time to first relapse, 25th percentile — wk¶
`
`Annualized relapse rate at 2 yr
`
`Adjusted relapse rate (95% CI)‖
`
`Rate ratio vs. placebo (95% CI)
`
`Confirmed progression of disability at 2 yr
`
`Patients with progression sustained for 12 wk — %†
`
`Hazard ratio vs. placebo (95% CI)
`
`MRI assessments
`New or newly enlarging T2-weighted lesions at 2 yr
`as compared with baseline
`
`Placebo
`(N = 408)
`
`Twice-Daily BG-12
`(N = 410)
`
`Thrice-Daily BG-12
`(N = 416)
`
`46
`
`—
`
`—
`
`38
`
`27
`
`26
`
`0.51 (0.40–0.66)‡
`
`0.50 (0.39–0.65)‡
`
`0.42 (0.31–0.57)‡
`
`0.41 (0.30–0.56)‡
`
`87
`
`91
`
`0.36 (0.30–0.44)
`
`0.17 (0.14–0.21)
`
`0.19 (0.15–0.23)
`
`—
`
`27
`
`0.47 (0.37–0.61)‡
`
`0.52 (0.40–0.67)‡
`
`16**
`
`18
`
`0.62 (0.44–0.87)††
`
`0.66 (0.48–0.92)‡‡
`
`Adjusted mean no. of lesions (95% CI)
`
`17.0 (12.9–22.4)
`
`2.6 (2.0–3.5)
`
`4.4 (3.2–5.9)
`
`Ratio of adjusted mean no. of lesions in treat-
`ment group to adjusted mean no. in placebo
`group (95% CI)
`Gadolinium-enhancing T1-weighted lesions at 2 yr
`Mean no.
`
`Odds ratio vs. placebo (95% CI)
`
`0.15 (0.10–0.23)‡
`
`0.26 (0.17–0.38)‡
`
`1.8±4.2
`
`—
`
`0.1±0.6
`
`0.5±1.7
`
`0.10 (0.05–0.22)‡
`
`0.27 (0.15–0.46)‡
`
`* Plus–minus values are means ±SD. Clinical results are derived from the 1234 patients in the intention-to-treat popu-
`lation; MRI results are derived from the 469 patients in the MRI cohort with postbaseline data (165 in the placebo
`group, 152 in the twice-daily BG-12 group, and 152 in the thrice-daily BG-12 group). CI denotes confidence interval.
`† The proportion of patients was estimated by Kaplan–Meier analysis.
`‡ P<0.001.
`In this sensitivity analysis based on logistic regression, patients who discontinued the study drug or withdrew from
`§
`the study without having had a confirmed relapse as assessed by the independent neurologic evaluation committee
`were considered to have had a relapse if the reason for discontinuation or withdrawal was suggestive of relapse or
`lack of efficacy; otherwise, they were considered not to have had a relapse.
`¶ The 25th percentile of time to first relapse was the time at which the estimated proportion of patients who had a re-
`lapse was at least 25%.
`‖ The annualized relapse rate included only relapses that were confirmed by the independent neurologic evaluation
`committee.
`** Data were available for 409 patients in this group.
`†† P = 0.005.
`‡‡ P = 0.01.
`
`col-defined relapses, regardless of whether they
`were confirmed by the independent neurologic
`evaluation committee, showed results that were
`consistent with those of the primary analysis
`(Fig. S3 in the Supplementary Appendix).
`The annualized relapse rate at 2 years was
`0.17 in the twice-daily BG-12 group and 0.19 in
`the thrice-daily BG-12 group, as compared with
`0.36 in the placebo group, representing relative
`reductions with BG-12 of 53% and 48%, respec-
`tively (P<0.001 for both comparisons) (Fig. S4 in
`the Supplementary Appendix).
`
`Disability
`As compared with placebo, BG-12 reduced the
`risk of confirmed progression of disability that
`was sustained for 12 weeks by 38% over the 2-year
`study period in the twice-daily BG-12 group
`(hazard ratio, 0.62; 95% CI, 0.44 to 0.87; P = 0.005)
`and by 34% in the thrice-daily BG-12 group (haz-
`ard ratio, 0.66; 95% CI, 0.48 to 0.92; P = 0.01),
`(Table 2 and Fig. 1B). The estimated proportion
`of patients with progression of disability was
`27% with placebo, 16% with twice-daily BG-12,
`and 18% with thrice-daily BG-12.
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1103
`
`The New England Journal of Medicine
`
` For personal use only No other uses without permission
`
` Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1038, p. 006
`
`

`

`The NEW ENGLAND JOURNAL anEDICINE
`
`
`
`A
`
`100
`90
`30
`
`70
`so
`
`50
`40
`
`3°
`
`§
`‘0‘
`0'
`8-
`1!o:
`
`f
`:
`E
`‘8
`&
`
`Hazard ratio vs. placebo (95% Cl)
`Twice-daily BG-12: 0.51 (0.40—0.66); P<0.001
`Thrice-daily 36-12: 0.50 (0.39—0.65); P<0.001
`Estimated proportion with relapse at 2 yr
`Twicedaily 36-12: 27%
`Thrice—daily BG-lZ: 26%
`Placebo: 46%
`
`Placebo
`
`d ‘ BG 12
`i
`Tw1ce— ally
`~
`
`
`
`Thrice-daily 36-12
`
`60
`
`72
`
`84
`
`96
`
`0
`
`12
`
`24
`
`36
`
`48
`
`Weeks on Study
`
`356
`353
`346
`
`321
`324
`322
`
`282
`303
`301
`
`243
`286
`286
`
`224
`267
`270
`
`205
`255
`251
`
`190
`243
`244
`
`115
`154
`166
`
`No. at Rlslt
`408
`Placebo
`Twice-daily BG-12 410
`Thrice-daily 36-12 416
`
`B
`
`100
`90
`
`80
`
`70
`60
`
`.—
`é
`8
`7i
`a
`o
`g
`
`Hazard ratio vs. placebo (95% Cl)
`Twice-daily 35-12: 0.62 (0.44—0.87); P-0.005
`Thrice-daily 36-12: 0.66 (0.48—0.92); p-o.o13
`Estimated proportion with disability progression at 2yr
`Twice<daily 36-12: 16%
`Thrice—daily BG-12: 18%
`Placebo: 27%
`
`Thrice-daily 36-12
`
`I a
`
`E f
`
`9 so
`40
`30
`20
`
`Flgure 1. Kaplan-Meier Plot of Primary and Secondary
`Clinical Outcomes.
`
`Panel A shows the time to the first relapse that was
`confirmed by the independent neurologic evaluation
`committee and the proportion of patients with a con-
`firmed relapse among patients in the group that received
`86-12 twice daily, the group that received 86-12 thrice
`daily, and the placebo group. The Pvalues and hazard
`ratios for a relapse with 86-12 as compared with place-
`bo were calculated with the use of a Cox proportional-
`hazards model, adjusted for baseline score (52.0 vs.
`>2.0) on the Expanded Disability Status Scale (EDSS,
`which ranges from 0 to 10, with higher scores indicat-
`ing greater disability), age at baseline (<40 years vs.
`240 years), region, and the number of relapses in the
`year before study entry. The estimated proportion of
`patients with a relapse at 2 years is a Kaplan—Meier es-
`timate. Panel B shows the time to confirmed progres-
`sion ofdisability in each ofthe three groups. The Pval-
`ues and hazard ratios for progression with 86-12 as
`compared with placebo were calculated with the use of
`a Cox proportional-hazards model, adjusted for baseline
`score on the EDSS, age at baseline, and region. The es-
`timated proportion of patients with confirmed progres-
`
`sion ofdisease at 2 years is a Kaplan—Meier estimate.
`
`group were free from gadolinium-enhancing le-
`sions on MRI at 2 years (93% in the twice-daily
`BG-12 group and 86% in the thrice-daily BG-12
`group vs. 62% in the placebo group) (Table S4 in
`the Supplementary Appendix).
`
`SAFETY
`
`Adverse Events
`
`The overall incidence of adverse events was simi-
`lar across the three groups (95 to 96%) (Table 3);
`in the case of most of the patients, the adverse
`events were of mild or moderate severity. Adverse
`events that occurred more frequently in patients
`receiving BG-12 than in patients receiving place-
`bo included flushing, gastrointestinal events (e.g.,
`diarrhea, nausea, upper abdominal pain, abdom-
`inal pain, and vomiting), proteinuria, and pruri-
`tus (Table 3). The incidences offlushing and gas-
`trointestinal events were highest in the first month
`of the study and decreased thereafter (Fig. SS in
`the Supplementary Appendix). Overall, the inci—
`dence of adverse events leading to discontinua-
`tion of the study drug was similar across the
`groups (13% in the placebo group and 16% in each
`of the BG-12 groups), although discontinuations
`due to flushing and overall gastrointestinal events
`occurred more frequently in patients who re-
`ceived BG-12 than in patients who received pla-
`cebo (discontinuation due to flushing, 2% in the
`twice-daily BG—12 group and 1% in the thrice-
`
`
`
`31
`
`'
`
`5 E
`
`10
`0 ‘
`0
`
`Twice-daily 36-12
`,
`
`, ,i—l—Ifi—Ifi—l—I
`12
`24
`36
`48
`60
`72
`84
`96
`
`Weeks on Study
`
`No. at Rlslt
`129
`224
`242
`265
`291
`319
`345
`375
`408
`Placebo
`167
`267
`278
`290
`304
`325
`333
`359
`Twice-daily BG-12 409
`
`
`
`
`
`
`
`
`314 291 276 266325346360Thrice—daily 36-12 416 168
`
`MRI End Points
`
`As compared with placebo, BG-12 reduced the
`number of new or enlarging hyperintense lesions
`on Tz—weighted images at 2 years by 85% with the
`twice-daily regimen and by 74% with the thrice-
`daily regimen (P<0.001 for both comparisons)
`and reduced the odds of an incrmse in the num-
`
`ber of gadolinium-enhancing lesions at 2 years
`by 90% and 73%, respectively (P< 0.001 for both
`comparisons)
`(Table 2). Larger percentages of
`patients in the BG-12 groups than in the placebo
`
`1104
`
`N ENGLJ MED 367;12
`
`rumour.
`
`ssprmarnzo,1012
`
`The New England Journal of Medicine
`For personal use only No other uses Without permission
`Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), EX. 103 8, p. 007
`
`Sawai (IPR2019-00789), Ex. 1038, p. 007
`
`

`

`Oral BG-12 for Relapsing Multiple Sclerosis
`
`Table 3. Adverse and Serious Adverse Events.*
`
`Adverse Event
`
`Any adverse event
`
`Most frequently reported adverse events†
`
`Flushing
`
`Multiple sclerosis relapse
`
`Diarrhea
`
`Nausea
`
`Upper abdominal pain
`
`Proteinuria
`
`Abdominal pain
`
`Pruritus
`
`Vomiting
`
`Adverse events leading to discontinuation
`
`Death‡
`
`Any serious adverse event
`
`Most frequently reported serious adverse events§
`
`Multiple sclerosis relapse
`
`Gastroenteritis
`
`Gastritis
`
`Ovarian cyst
`
`Headache
`
`Pneumonia
`
`Serious infection
`
`Malignant neoplasm
`
`Placebo
`(N = 408)
`
`Twice-Daily BG-12
`(N = 410)
`
`Thrice-Daily BG-12
`(N = 416)
`
`number of patients (percent)
`
`387 (95)
`
`395 (96)
`
`396 (95)
`
`20 (5)
`
`189 (46)
`
`55 (13)
`
`38 (9)
`
`28 (7)
`
`34 (8)
`
`22 (5)
`
`19 (5)
`
`24 (6)
`
`55 (13)
`
`0
`
`86 (21)
`
`60 (15)
`
`0
`
`0
`
`1 (<1)
`
`0
`
`1 (<1)
`
`7 (2)
`
`2 (<1)
`
`154 (38)
`
`111 (27)
`
`132 (32)
`
`114 (27)
`
`62 (15)
`
`53 (13)
`
`40 (10)
`
`38 (9)
`
`46 (11)
`
`42 (10)
`
`40 (10)
`
`65 (16)
`
`1 (<1)
`
`74 (18)
`
`39 (10)
`
`4 (<1)
`
`0
`
`1 (<1)
`
`0
`
`2 (<1)
`
`10 (2)
`
`2 (<1)
`
`78 (19)
`
`54 (13)
`
`52 (12)
`
`50 (12)
`
`37 (9)
`
`34 (8)
`
`30 (7)
`
`68 (16)
`
`1 (<1)