The new england
`journal of medicine
`
`established in 1812
`
`september 20, 2012
`
`vol 367 no 12
`
`Placebo-Controlled Phase 3 Study of Oral BG-12
`or Glatiramer in Multiple Sclerosis
`Robert J. Fox, M.D., David H. Miller, M.D., J. Theodore Phillips, M.D., Ph.D., Michael Hutchinson, F.R.C.P.,
`Eva Havrdova, M.D., Mariko Kita, M.D., Minhua Yang, M.S., Kartik Raghupathi, M.S., Mark Novas, M.D.,
`Marianne T. Sweetser, M.D., Ph.D., Vissia Viglietta, M.D., Ph.D., and Katherine T. Dawson, M.D.,
`for the CONFIRM Study Investigators*
`
`A BS TR AC T
`
`BACKGROUND
`BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing–
`remitting multiple sclerosis, which is commonly treated with parenteral agents (in-
`terferon or glatiramer acetate).
`METHODS
`In this phase 3, randomized study, we investigated the efficacy and safety of oral
`BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in
`patients with relapsing–remitting multiple sclerosis. An active agent, glatiramer ac-
`etate, was also included as a reference comparator. The primary end point was the
`annualized relapse rate over a period of 2 years. The study was not designed to test
`the superiority or noninferiority of BG-12 versus glatiramer acetate.
`RESULTS
`At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12
`(0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo
`(0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%,
`P<0.001; glatiramer acetate, 29%, P = 0.01). Reductions in disability progression with
`twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%,
`24%, and 7%, respectively) were not significant. As compared with placebo, twice-
`daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the
`numbers of new or enlarging T2-weighted hyperintense lesions (all P<0.001) and new
`T1-weighted hypointense lesions (P<0.001, P<0.001, and P = 0.002, respectively). In post
`hoc comparisons of BG-12 versus glatiramer acetate, differences were not signifi-
`cant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging
`T2-weighted hyperintense lesions (both BG-12 doses), and new T1-weighted hypoin-
`tense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse
`events occurring at a higher incidence with an active treatment than with placebo
`included flushing and gastrointestinal events (with BG-12) and injection-related
`events (with glatiramer acetate). There were no malignant neoplasms or opportu-
`nistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
`CONCLUSIONS
`In patients with relapsing–remitting multiple sclerosis, BG-12 (at both doses) and
`glatiramer acetate significantly reduced relapse rates and improved neuroradiologic
`outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov
`number, NCT00451451.)
`
`From the Mellen Center for Multiple Scle-
`rosis Treatment and Research, Cleveland
`Clinic, Cleveland (R.J.F.); Nuclear Mag-
`netic Resonance Research Unit, Depart-
`ment of Neuroinflammation, University
`College London Institute of Neurology,
`London (D.H.M.); Multiple Sclerosis Pro-
`gram, Baylor Institute for Immunology
`Research, Dallas (J.T.P.); St. Vincent’s Uni-
`versity Hospital, Elm Park, Donnybrook,
`Dublin (M.H.); the Department of Neu-
`rology, First Faculty of Medicine, Charles
`University in Prague, Prague, Czech Re-
`public (E.H.); Virginia Mason Medical
`Center, Seattle (M.K.); and Biogen Idec,
`Weston, MA (M.Y., K.R., M.N., M.T.S., V.V.,
`K.T.D.). Address reprint requests to Dr.
`Fox at the Mellen Center for Multiple Scle-
`rosis Treatment and Research, Cleveland
`Clinic, 9500 Euclid Ave., U-10, Cleveland,
`OH 44195, or at foxr@ccf.org.
`
`*The members of the Comparator and an
`Oral Fumarate in Relapsing–Remitting
`Multiple Sclerosis (CONFIRM) study
`group are listed in the Supplementary
`Appendix, available at NEJM.org.
`
`This article was updated on October 2,
`2012, at NEJM.org.
`
`N Engl J Med 2012;367:1087-97.
`DOI: 10.1056/NEJMoa1206328
`Copyright © 2012 Massachusetts Medical Society.
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1087
`
`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. 1039, p. 001
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Multiple sclerosis is a chronic de-
`
`myelinating and neurodegenerative dis-
`ease of the central nervous system, which
`is commonly treated with parenteral agents (in-
`terferon beta and glatiramer acetate). Oxidative
`stress and proinflammatory stimuli are important
`pathologic factors in multiple sclerosis.1-3 Experi-
`mental data suggest that BG-12, an oral formula-
`tion of dimethyl fumarate, has antiinflammatory
`and cytoprotective properties that are mediated
`through activation of the nuclear factor (erythroid-
`derived 2)–like 2 transcriptional pathway, among
`others.3-6
`Here, we report the results of the Comparator
`and an Oral Fumarate in Relapsing–Remitting
`Multiple Sclerosis (CONFIRM) trial, a randomized,
`multicenter, double-blind, 2-year study evaluat-
`ing the efficacy and safety of BG-12, at a dose of
`240 mg two or three times per day, versus placebo
`in patients with relapsing–remitting multiple
`sclerosis. A rater-blinded, active agent approved for
`relapsing–remitting multiple sclerosis (subcutane-
`ous glatiramer acetate at a dose of 20 mg per day)
`was also included as a reference comparator, to
`allow a relative benefit–risk assessment of BG-12
`through comparison of the active-treatment groups
`with the placebo group.
`
`Me thods
`
`STUDY OVERSIGHT
`The study was approved by central and local ethics
`committees and conducted in accordance with
`the International Conference on Harmonization
`Guidelines for Good Clinical Practice7 and the
`Declaration of Helsinki.8 An advisory committee
`participated in study design and oversight of study
`conduct, a data and safety monitoring committee
`reviewed all pertinent benefit–risk data, and an
`independent neurologic evaluation committee,
`whose members were unaware of the study-group
`assignments, provided confirmation of relapses
`of multiple sclerosis (see the Supplementary Ap-
`pendix, available with the full text of this article
`at NEJM.org). Data were gathered by the investi-
`gators and were analyzed by the sponsor (Biogen
`Idec), and data remained confidential during the
`study. All the authors were involved in all stages
`of manuscript development and vouch for the
`completeness and accuracy of the data. The first
`draft was cowritten by the first and last authors
`(the latter is a representative of the sponsor),
`
`with assistance from a medical-communications
`agency paid by the sponsor. The study was con-
`ducted in accordance with the study protocol,
`which is available at NEJM.org.
`
`PATIENTS
`Key eligibility criteria were a diagnosis of relaps-
`ing–remitting multiple sclerosis (McDonald cri-
`teria9), an age of 18 to 55 years, a score of 0 to 5 on
`the Expanded Disability Status Scale (EDSS, which
`ranges from 0 to 10, with higher scores indicating
`greater disability),10 and at least one clinically doc-
`umented relapse in the previous 12 months or at
`least one gadolinium-enhancing lesion 0 to 6 weeks
`before randomization. Key exclusion criteria were
`progressive forms of multiple sclerosis,11 other
`clinically significant illness, prespecified laborato-
`ry abnormalities, and prior exposure to glatiramer
`acetate or contraindicated medications (see the
`Supplementary Appendix for additional details).
`Patients were informed of approved therapies12
`for multiple sclerosis, and they provided written
`informed consent. Reconsent was required after
`a confirmed relapse or confirmed disability pro-
`gression.
`
`STUDY DESIGN
`Patients at 200 sites in 28 countries were random-
`ly assigned in a 1:1:1:1 ratio to receive oral pla-
`cebo, BG-12 at a dose of 240 mg two times daily,
`BG-12 at a dose of 240 mg three times daily, or
`subcutaneous daily injections of 20 mg of gla tir-
`a mer acetate for 96 weeks (Fig. S1 in the Supple-
`mentary Appendix). Patients receiving gla tir a mer
`acetate were aware of their treatment assignment.
`All study management and site personnel, investi-
`gators, and patients were unaware of assignment
`to the BG-12 and placebo groups; examining neu-
`rologists, technicians at the magnetic resonance
`imaging (MRI) reading center, and members of
`the independent neurologic evaluation committee
`were unaware of all study-group assignments. Each
`site used separate examining and treating neurol-
`ogists, thereby maintaining rater blinding for all
`study groups, including the group that received
`gla tir a mer acetate. To ensure that the assignments
`to the BG-12 and placebo groups would not be
`revealed, patients in those groups were instructed
`not to take the study medication within 4 hours
`before each study visit, since a flushing reaction
`is known to be more common with BG-12.13 Pa-
`tients could switch to an alternative medication
`
`1088
`
`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. 1039, p. 002
`
`

`

`Oral BG-12 in Multiple Sclerosis
`
`for multiple sclerosis if they had two confirmed
`relapses and had completed 48 weeks of study
`treatment or if they had confirmed disability pro-
`gression (see the Supplementary Appendix).
`
`STUDY PROCEDURES AND END POINTS
`Standardized neurologic assessments, including an
`EDSS assessment, were performed every 12 weeks
`and at the time of suspected relapse (evaluated
`during unscheduled visits). MRI scans were ob-
`tained in a subset of patients at sites with MRI
`capabilities, at screening and at weeks 24, 48, and
`96, and were evaluated in a blinded manner at a
`central MRI reading center.
`The primary efficacy end point was the annu-
`alized relapse rate at 2 years, based on protocol-
`defined relapses (new or recurrent neurologic
`symptoms not associated with fever or infection,
`lasting at least 24 hours, accompanied by new
`objective neurologic findings, and separated from
`the onset of other confirmed relapses by at least
`30 days) that were confirmed by the independent
`neurologic evaluation committee. Secondary ef-
`ficacy end points included the number of new or
`enlarging hyperintense lesions on T2-weighted
`images, the number of new hypointense lesions on
`T1-weighted images, the proportion of patients
`with a relapse, and the time to disability progres-
`sion, each at 2 years. Disability progression was
`defined as an increase in the EDSS score of at
`least 1.0 point in patients with a baseline score of
`1.0 or more or an increase of at least 1.5 points
`in patients with a baseline score of 0, confirmed
`at least 12 weeks later. Tertiary end points in-
`cluded a comparison of the relative benefits and
`risks of BG-12 or gla tir a mer acetate versus placebo
`and the number of gadolinium-enhancing lesions
`at 2 years (see the Supplementary Appendix).
`
`STATISTICAL ANALYSIS
`We estimated that a sample of 308 patients per
`group would provide approximately 84% power at
`a two-sided significance level of 0.05 to detect a
`25% relative reduction in the 2-year annualized
`relapse rate, with the assumption of an annual-
`ized relapse rate of 0.61 in the placebo group. A
`sequential (closed) testing procedure was used to
`control for overall type I error due to multiple
`comparisons (see the Supplementary Appendix).
`Primary and secondary end points were ana-
`lyzed in the intention-to-treat (ITT) population
`(all randomly assigned patients who received
`
`study treatment) and in the MRI cohort (patients
`in the ITT population for whom any postbase-
`line MRI data were available), with the use of
`two-sided statistical tests at a significance level
`of 0.05.
`The annualized relapse rate (total number of
`relapses divided by patient-years in the study, ex-
`cluding data obtained after patients switched to
`alternative multiple sclerosis medications) was an-
`alyzed with the use of a negative binomial re-
`gression model adjusted for baseline EDSS score,
`age, region (regions were defined on the basis of
`not only geography but also the type of health care
`system and access to health care in each coun-
`try), and number of relapses in the 12 months
`before study entry. Four sensitivity analyses were
`performed (see the Supplementary Appendix).
`Negative binomial regression was used for
`analysis of the total number of new or enlarging
`hyperintense lesions on T2-weighted images and
`the total number of new hypointense lesions on
`T1-weighted images at 2 years. A Cox proportional-
`hazards model was used for analysis of the pro-
`portion of patients with clinical relapse and the
`time to disability progression. Models were ad-
`justed for region, EDSS score, age, relapse rate,
`and volume of lesions, as appropriate.
`In general, analyses of primary and secondary
`end points were based on all observed data before
`patients switched to alternative multiple sclerosis
`medications, with analyses of MRI end points
`additionally based on missing data imputed with
`the use of a constant-rate assumption. The study
`was not designed to test the superiority or non-
`inferiority of BG-12 versus gla tir a mer acetate.
`Safety was analyzed with the use of descriptive
`statistics for the safety population (all patients who
`received at least one dose of the study medication),
`excluding data obtained after patients switched to
`alternative multiple sclerosis medications.
`
`R esults
`
`PATIENTS
`Of 1430 randomly assigned patients, 1417 were
`included in the ITT population (Fig. S2 in the Sup-
`plementary Appendix). Baseline demographic and
`disease characteristics were similar among the
`four study groups (Table 1) and between the MRI
`cohort (681 patients) (Table S1 in the Supplemen-
`tary Appendix) and non-MRI cohort (736 pa-
`tients). Approximately 29% of patients had re-
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1089
`
`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. 1039, p. 003
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 1. Baseline Demographic and Disease Characteristics (ITT Population).*
`
`Characteristic
`
`Age — yr
`
`Female sex — no. (%)
`
`Weight — kg
`
`Race — no. (%)‡
`
`White
`
`Asian
`
`Black
`
`Other or unknown
`
`Time since diagnosis — yr
`
`Any prior approved DMT — no. (%)§
`
`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
`
`Mean score on EDSS¶
`
`Placebo
`(N = 363)
`
`36.9±9.2
`
`251 (69)
`
`72.6±16.9
`
`305 (84)
`
`28 (8)
`
`9 (2)
`
`21 (6)
`
`4.8±5.0
`
`111 (31)
`
`1.4±0.8
`
`13 (4)
`
`78 (21)
`
`111 (31)
`
`98 (27)
`
`50 (14)
`
`13 (4)
`
`2.6±1.2
`
`Twice-Daily BG-12
`(N = 359)
`
`Thrice-Daily BG-12
`(N = 345)†
`
`Glatiramer Acetate
`(N = 350)†
`
`37.8±9.4
`
`245 (68)
`
`71.9±17.9
`
`37.8±9.4
`
`250 (72)
`
`72.5±17.8
`
`36.7±9.1
`
`247 (71)
`
`71.4±19.1
`
`304 (85)
`
`28 (8)
`
`2 (<1)
`
`25 (7)
`
`4.9±5.1
`
`101 (28)
`
`1.3±0.6
`
`15 (4)
`
`85 (24)
`
`94 (26)
`
`105 (29)
`
`47 (13)
`
`12 (3)
`
`2.6±1.2
`
`292 (85)
`
`290 (83)
`
`26 (8)
`
`5 (1)
`
`22 (6)
`
`4.6±5.2
`
`100 (29)
`
`1.4±0.7
`
`15 (4)
`
`84 (24)
`
`94 (27)
`
`99 (29)
`
`42 (12)
`
`11 (3)
`
`2.5±1.2
`
`25 (7)
`
`11(3)
`
`24 (7)
`
`4.4±4.7
`
`103 (29)
`
`1.4±0.6
`
`18 (5)
`
`77 (22)
`
`96 (27)
`
`99 (28)
`
`46 (13)
`
`14 (4)
`
`2.6±1.2
`
`* All baseline characteristics were well balanced among the study groups (nominal P>0.05). Plus–minus values are means
`±SD. DMT denotes disease-modifying therapy, EDSS Expanded Disability Status Scale, and ITT intention to treat.
`† One patient randomly assigned to the thrice-daily BG-12 group took glatiramer acetate throughout the study. This pa-
`tient was counted in the thrice-daily BG-12 group of the ITT population and in the glatiramer acetate group of the safety
`population.
`‡ Race was self-reported.
`§ Prior exposure to interferon beta-1a (in 21% of the ITT population), interferon beta-1b (11%), natalizumab (1%), and
`glatiramer acetate (<1%) was balanced across groups; one patient was randomly assigned to glatiramer acetate who
`had previously been exposed to the drug. Patients may have received more than one prior multiple sclerosis medica-
`tion. Patients may also have received other, nonapproved therapies for multiple sclerosis (the proportion of patients
` receiving any multiple sclerosis medication before the study was 40 to 41% across study groups).
`¶ Scores on the EDSS range from 0 to 10, with higher scores indicating a greater degree of disability. One patient in the
`twice-daily BG-12 group had a baseline score higher than 5.0.
`
`ceived an approved disease-modifying therapy
`before study entry.
`Study completion rates were similar across
`study groups (overall rate in the ITT population,
`80%), with a mean time in the study of 86.1,
`84.4, 84.1, and 88.5 weeks in the placebo, twice-
`daily BG-12, thrice-daily BG-12, and gla tir a mer
`acetate groups, respectively. The rate of study-
`drug discontinuation was higher in the placebo
`group than in the other groups (36% vs. 30% in
`the twice-daily BG-12 group, 28% in the thrice-
`daily BG-12 group, and 25% in the gla tir a mer
`acetate group) (Table S2 in the Supplementary
`Appendix), as was the proportion of patients who
`
`switched to alternative multiple sclerosis medica-
`tions (11% vs. 7%, 8%, and 6%, respectively).
`
`EFFICACY
`Clinical End Points
`The frequency of relapses of multiple sclerosis was
`significantly reduced by twice-daily and thrice-
`daily BG-12, with an adjusted annualized relapse
`rate at 2 years (primary end point) of 0.22 and
`0.20, respectively, representing reductions relative
`to placebo (annualized relapse rate, 0.40) of 44%
`and 51% (P<0.001 for both comparisons). Gla tir-
`a mer acetate also reduced the annualized relapse
`rate (0.29; relative reduction, 29% vs. placebo;
`
`1090
`
`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. 1039, p. 004
`
`

`

`Oral BG-12 in Multiple Sclerosis
`
`P = 0.01) (Fig. 1A and Table 2). Similar results were
`obtained in four sensitivity analyses that used
`different definitions of relapse or that included
`data after patients switched to alternative medi-
`cations, findings that show the robustness of the
`results for the primary end point (Fig. S3 in the
`Supplementary Appendix).
`As compared with placebo, twice-daily BG-12,
`thrice-daily BG-12, and gla tir a mer acetate signifi-
`cantly reduced the risk of relapse, by 34% (P = 0.002),
`45% (P<0.001), and 29% (P = 0.01), respectively
`(Table 2). The Kaplan–Meier estimate of the pro-
`portion of patients with a relapse at 2 years was
`41% in the placebo group as compared with 29%,
`24%, and 32% in the twice-daily BG-12, thrice-
`daily BG-12, and gla tir a mer acetate groups, respec-
`tively (Fig. S4 in the Supplementary Appendix).
`Similar findings were observed in sensitivity analy-
`ses (Fig. S5 in the Supplementary Appendix).
`Disability progression was not significantly
`reduced with twice-daily BG-12, thrice-daily BG-
`12, or gla tir a mer acetate, as compared with
`placebo (relative reduction, 21% [P=0.25], 24%
`[P = 0.20], and 7% [P = 0.70], respectively) (Fig.
`1B and Table 2). The Kaplan–Meier estimate of
`the proportion of patients with disability pro-
`gression was 17% in the placebo group as com-
`pared with 13%, 13%, and 16% in the twice-
`daily BG-12, thrice-daily BG-12, and gla tir a mer
`acetate groups, respectively. In a preplanned sen-
`sitivity analysis, 24-week confirmed disability pro-
`gression was not significantly reduced versus pla-
`cebo in the twice-daily BG-12, thrice-daily BG-12,
`and gla tir a mer acetate groups (38% [P = 0.06], 33%
`[P = 0.12], and 13% [P = 0.55], respectively), with an
`estimated proportion of patients with disability
`progression of 13% in the placebo group versus
`8%, 9%, and 11% in the twice-daily BG-12, thrice-
`daily BG-12, and gla tir a mer acetate groups, respec-
`tively (Table S3 in the Supplementary Appendix).
`
`MRI End Points
`As compared with placebo, twice-daily BG-12,
`thrice-daily BG-12, and gla tir a mer acetate signifi-
`cantly reduced the mean number of new or enlarg-
`ing hyperintense lesions on T2-weighted images
`at 2 years, by 71%, 73%, and 54%, respectively
`(P<0.001 for all comparisons) (Table 2, and Fig.
`S6A in the Supplementary Appendix), and re-
`duced the mean number of new hypointense le-
`sions on T1-weighted images, by 57% (P<0.001),
`65% (P<0.001), and 41% (P=0.002), respectively
`
`(Table 2, and Fig. S6B in the Supplementary Ap-
`pendix). The percentage of patients free from new
`or enlarging hyperintense lesions on T2-weighted
`images at 2 years was higher with twice-daily
`BG-12 (27%), thrice-daily BG-12 (31%), or gla tir-
`a mer acetate (24%) than with placebo (12%); cor-
`responding percentages free from new hypoin-
`tense lesions on T1-weighted images were 39%,
`44%, and 34% versus 21%.
`The odds of having more gadolinium-enhanc-
`ing lesions at 2 years was also significantly reduced
`by twice-daily BG-12, thrice-daily BG-12, and gla-
`tir a mer acetate treatment as compared with pla-
`cebo, by 74%, 65%, and 61%, respectively
`(P<0.001 for all comparisons) (Table 2, and Fig.
`S6C in the Supplementary Appendix).
`
`Benefits and Risks of BG-12 versus Gla tir a mer
`Acetate
`In the prespecified comparison of the relative ef-
`ficacy of each active treatment with placebo, the
`estimated treatment effects of both doses of BG-
`12 were numerically similar to or larger than those
`of gla tir a mer acetate across efficacy end points
`(Table 2). In a post hoc direct evaluation of the
`relative benefit of BG-12 versus gla tir a mer acetate,
`estimates and 95% confidence intervals excluded
`unity for some comparisons (Fig. S7 in the Supple-
`mentary Appendix). Nominal P values for com-
`parisons of twice-daily BG-12 and thrice-daily
`BG-12 with gla tir a mer acetate were as follows: an-
`nualized relapse rate, P = 0.10 and P = 0.02, re-
`spectively; new or enlarging hyperintense lesions
`on T2-weighted images, P = 0.007 and P = 0.002;
`new hypointense lesions on T1-weighted images,
`P = 0.08 and P = 0.003; proportion of patients with
`a relapse, P = 0.58 and P = 0.09; and time to dis-
`ability progression, P = 0.44 and P = 0.37.
`
`SAFETY
`The overall incidence of adverse events was simi-
`lar across study groups (87 to 94%) (Table 3).
`Adverse events reported more frequently with
`BG-12 than with placebo included flushing, gas-
`trointestinal events (diarrhea, nausea, and upper
`abdominal pain), upper respiratory tract infec-
`tions, and erythema. For flushing, which includ-
`ed events of flushing and hot flush, the incidence
`was 35% with twice-daily BG-12 and 28% with
`thrice-daily BG-12 versus 6% with placebo and 3%
`with gla tir a mer acetate; for gastrointestinal events,
`the incidence was 36% with twice-daily BG-12
`
`n engl j med 367;12 nejm.org september 20, 2012
`
`1091
`
`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. 1039, p. 005
`
`

`

`
`
`—— Placebo
`— Twice-daily BG-12
`— Thrice-daily BG-12
`—— Glatiramer acetate
`
`90
`
`80
`
`70
`
`60
`
`50
`40
`
`30
`
`20
`
`Twice-daily BG-12 vs. placebo: hazard ratio, 0.79 (95% Cl, 0.52-1.19); P=0.25
`Thrice-daily BG-12 vs. placebo: hazard ratio, 0.76 (95% Cl, 0.50-1.16); P—0.20
`Glatiramer acetate vs. placebo: hazardratio, 0.93 (95% Cl, 0.63-1.37); P—0.70
`
`Twice-daily BG-12: estimated proportion at 2 yr, 139%
`Thrice-daily BG-12: estimated proportion at 2yr, 13%
`Glatiramer acetate: estimated proportion at 2 yr, 16%
`Placebo: estimated proportion at 2 yr, 17%
`
`10 0
`
`Baseline
`
`No.at Risk
`Placebo
`Twice-daily BG-12
`Thrice-daily BG-12
`Glatirameracetate
`
`363
`359
`345
`350
`
`12
`
`339
`323
`309
`326
`
`24
`
`317
`302
`287
`307
`
`36
`
`297
`283
`277
`291
`
`48
`
`Week of Study
`
`273
`270
`269
`279
`
`60
`
`254
`263
`262
`269
`
`72
`
`235
`257
`249
`262
`
`84
`
`228
`249
`238
`249
`
`96
`
`149
`146
`159
`178
`
`ProportionofPatientswithDisabilityProgression(%)
`
`
`are Kaplan—Meierestimates.
`
`Figure 1. Clinical Outcomes at 2 Years in the Intention-to-Treat Population.
`Annualized relapse rates (Panel A) were calculated with the use of a negative binomial regression model, with adjustmentfor baseline
`score (<2.0 vs. >2.0) on the ExpandedDisability Status Scale (EDDS, which ranges from 0 to 10, with higherscores indicating a greater
`degreeof disability), baseline age (<40 years vs. 40 years), region (regions were defined on the basis of not only geography but also the
`type of health care system and accessto health care in each country), and numberof relapses in the 12 months before study entry. Re-
`lapses were confirmed by an independent neurologic evaluation committee. The I bars indicate 95% confidence intervals. Hazard ratios for
`time to disability progression (Panel B) were calculated with the use of a Cox proportional-hazards model, with adjustmentfor baseline
`EDSSscore, baseline age (<40 years vs. >40 years), and region. The estimated proportions ofpatients with disability progression at 2 years
`
`
`1092
`
`N ENGLJ MED 367;12 NEJM.ORG SEPTEMBER 20, 2012
`
`The New England Joumal of Medicine
`For personal use only Noother uses without permission
`Copyright © 2012 Massachusetts Medical Society All nghts reserved
`
`Sawai (IPR2019-00789), Ex. 1039, p. 006
`
`
`
`
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`29% reduction
`P-0.01
`
`51% reduction
`
`
`P<0.001
`
`
`44% reduction
`P<0.001
`
`0.6
`
`0.5
`
`04
`
`03
`
`2
`
`&g
`
`as
`
`oe
`
`A Annualized Relapse Rate
`
`3iN
`= 02
`
`=< ol
`
`3 E
`
`
`
`0.0:
`
`Placebo
`(N=363)
`
`Twice-Daily
`BG-12
`(N=359)
`
`Thrice-Daily
`BG-12
`(N=345)
`
`Glatiramer
`Acetate
`(N=350)
`
`B Timeto 12-Wk Confirmed Disability Progression
`100
`
`Sawai (IPR2019-00789), Ex. 1039, p. 006
`
`

`

`ORAL BG-12 IN MULTIPLE SCLEROSIS
`
`Table 2. Clinical End Points (ITT Population) and MRI End Points (MRI Cohort) during the Study.*
`Placebo
`(N= 363)
`
`End Point
`
`Twice-Daily BG-12 Thrice-Daily BG-12
`(N= 359)
`(N=345)
`
`Glatiramer Acetate
`(N=350)
`
`0.39 (0.24-0.65)+
`
`Annualized relapse rate at 2 yr
`Rate (95% Cl)
`Percentage reduction vs. placebo (95% Cl)
`Timetofirst confirmed relapse, 25th percentile— wk]
`Estimated proportionofpatients with a relapseat 2 yr
`Proportion — %4
`Hazardratio vs. placebo (95% Cl)**
`Disability progression at 2 yr
`Estimated proportion ofpatients with progression
`confirmed atleast 12 wk later — %4
`Hazardratio vs. placebo (95% Cl) t+
`New orenlarging T,-weighted hyperintense
`lesions at 2 yrff
`No.ofpatients evaluated
`Adjusted meanno.oflesions (95% Cl)
`Ratio of mean no.oflesionsin active-treatment group
`to mean no.in placebo group (95% Cl)
`New T,-weighted hypointense lesions at2 yr
`No.of patients evaluated
`Adjusted meanno.oflesions (95% Cl)
`Ratio of mean no.oflesionsin active-treatment group
`to mean no.in placebo group (95% Cl)
`Gadolinium-enhancinglesionsat 2 yrf§
`No.of patients evaluated
`No.oflesions
`
`0.40 (0.33-0.49)
`
`30
`
`41
`
`0.22 (0.18-0.28)
`44.0 (26.0-57.7)+
`72
`
`0.20 (0.16-0.25)
`50.5 (33.8-63.1)+
`NA||
`
`0.29 (0.23-0.35)
`28.6 (6.9-45.2)§
`57
`
`29
`
`24
`
`32
`
`0.66 (0.51-0.86)}+
`
`0.55 (0.42-0.73)t
`
`0.71 (0.55-0.92) ++
`
`13
`
`13
`
`16
`
`0.79 (0.52-1.19)
`
`0.76 (0.50-1.16)
`
`0.93 (0.63-1.37)
`
`139
`
`140
`
`140
`
`153
`
`17.4 (13.5-22.4)
`
`5.1 (3.9-6.6)
`0.29 (0.21-0.41)+
`
`4.7 (3.6-6.2)
`0.27 (0.20-0.38)+
`
`8.0 (6.3-10.2)
`0.46 (0.33-0.63)+
`
`139
`
`7.0 (5.3-9.2)
`
`140
`
`140
`
`154
`
`3.0 (2.3-4.0)
`0.43 (0.30-0.61)+
`
`2.4 (1.8-3.2)
`0.35 (0.24-0.49) +
`
`4.1 (3.2-5.3)
`0.59 (0.42-0.82)+
`
`147
`0.5+1.7
`
`144
`0.441.2
`
`161
`0.741.8
`
`Odds ratio vs. placebo (95% Cl)
`
`0.26 (0.15-0.46)+
`
`0.35 (0.20-0.59)+
`
`Plus—minus values are means +SD. Cl denotes confidenceinterval, and NA not available.
`*
`{ Annualized relapse rates were calculated on the basis of negative binomial regression, with adjustment for baseline EDSS score (<2.0 vs.
`>2.0), baseline age (<40 years vs. 240 years), region (regions were defined on the basis of not only geography but also the type of health
`care system and accessto health care in each country), and number ofrelapses in the 12 months before study entry. Relapses were con-
`firmed by an independent neurologic evaluation committee.
`P<0.001.
`P<0.05.
`
`aS Values were calculated with the use of the Kaplan-Meier product-limit method.
`
`The exact estimate was not available because the 25th percentile was greater than 96 weeks.
`** Hazard ratios were calculated with the use of a Cox proportional-hazards model, with adjustmentfor baseline EDSS score (<2.0 vs. >2.0),
`baseline age (<40 years vs. =40 years), region, and numberofrelapses in the 12 months before study entry.
`+t Ps0.01.
`tt Hazard ratios were calculated with the use of a Cox proportional-hazards model, with adjustmentfor baseline EDSS score as a continuous
`variable, region, and baseline age (<40 yearsvs. =40 years).
`i) Patients who were evaluated werepatients in the MRI cohort with postbaseline data. Missing data before the useofalternative multiple
`sclerosis medications and visits after patients switched to alternative multiple sclerosis medications were imputed with the use of a constant-
`rate assumption. Ratios, relative reductions, 95% Cls, and P values were calculated with the use of negative binomial regression for new
`T2-weighted and new T,-weighted lesions and ordinallogistic regression for gadolinium-enhancinglesions, with adjustment for region and
`baseline T,-weighted lesion volume, T,-weighted lesion volume, or numberof gadolinium-enhancing lesions, as appropriate.
`
`and 41% with thrice-daily BG-12 versus 26% with
`placebo and 15% with glatiramer acetate. Flush-
`ing and gastrointestinal events were of mild or
`moderate severity for most patients; the incidence
`of these events was highestin the first month of
`the study, decreasing thereafter (Fig. S8 in the
`
`Supplementary Appendix). Adverse events report-
`ed morefrequently in the glatiramer acetate group
`than in the placebo group wereinjection-related
`events: injection-site pain (placebo, 0%; glatira-
`meracetate, 8%) and injection-site erythema (pla-
`cebo, 0%; glatiramer acetate, 9%).
`
`N ENGLJ MED 367;12 NEJM.ORG SEPTEMBER 20, 2012
`
`1093
`
`The New England Joumal of Medicine
`For personal use only Noother uses without permission
`Copyright © 2012 Massachusetts Medical Society All rights reserved
`
`Sawai (IPR2019-00789), Ex. 1039, p. 007
`
`Sawai (IPR2019-00789), Ex. 1039, p. 007
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 3. Adverse Events (Safety Population).
`
`Event
`
`Any adverse event
`
`Most common adverse events†
`
`Multiple sclerosis relapse
`
`Flushing‡
`
`Nasopharyngitis
`
`Headache
`
`Diarrhea‡
`
`Urinary tract infection
`
`Nausea‡
`
`Upper respiratory tract infection‡
`
`Back pain
`
`Fatigue
`
`Upper abdominal pain‡
`
`Proteinuria
`
`Placebo
`(N = 363)
`
`Twice-Daily BG-12
`(N = 359)
`
`Thrice-Daily BG-12
`(N = 344)*
`
`Glatiramer Acetate
`(N = 351)*
`
`number of patients (percent)
`
`333 (92)
`
`338 (94)
`
`316 (92)
`
`304 (87)
`
`155 (43)
`
`13 (4)
`
`58 (16)
`
`49 (13)
`
`28 (8)
`
`42 (12)
`
`29 (8)
`
`34 (9)
`
`33 (9)
`
`33 (9)
`
`17 (5)
`
`25 (7)
`
`35 (10)
`
`110 (31)
`
`110 (31)
`
`62 (17)
`
`52 (14)
`
`45 (13)
`
`52 (14)
`
`40 (11)
`
`36 (10)
`
`35 (10)
`
`37 (10)
`
`36 (10)
`
`29 (8)
`
`24 (7)
`
`85 (25)
`
`83 (24)
`
`63 (18)
`
`46 (13)
`
`50 (15)
`
`41 (12)
`
`51 (15)
`
`47 (14)
`
`36 (10)
`
`33 (10)
`
`33 (10)
`
`35 (10)
`
`15 (4)
`
`119 (34)
`
`6 (2)
`
`51 (15)
`
`46 (13)
`
`14 (4)
`
`46 (13)
`
`15 (4)
`
`27 (8)
`
`32 (9)
`
`30 (9)
`
`4 (1)
`
`30 (9)
`
`30 (9)
`
`Depression
`
`Adverse events leading to study-drug discontinuation
`
`Death§
`
`Any serious adverse event
`
`Most common serious adverse events¶
`
`Multiple sclerosis relapse
`
`Gastroenteritis
`
`Cellulitis
`
`Abdominal pain
`
`Back pain
`
`Muscle strain
`
`Depression
`
`Spontaneous abortion
`
`Anaphylactic reaction
`
`Convulsion
`
`Pneumonia
`
`38 (10)
`
`1 (<1)
`
`79 (22)
`
`51 (14)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2 (<1)
`
`0
`
`2 (<1)
`
`1 (<1)
`
`44 (12)
`
`0
`
`61 (17)
`
`39 (11)
`
`2 (<1)
`
`2 (<1)
`
`2 (<1)
`
`2 (<1)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`41 (12)
`
`1 (<1)
`
`54 (16)
`
`30 (9)
`
`2 (<1)
`
`1 (<1)
`
`0
`
`0
`
`2 (<1)
`
`1 (<1)
`
`0
`
`0
`
`0
`
`0
`
`35 (10)
`
`1 (<1)
`
`60 (17)
`
`36 (10)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2 (<1)
`
`0
`
`2 (<1)
`
`0
`
`2 (<1)
`
`* One patient randomly assigned to the thrice-daily BG-12 group and included in the BG-12 group of the ITT population took glatiramer ace-
`tate throughout the study and was therefore counted in the glatiramer acetate group of the safety population.
`† These events were reported by at least 10% of patients in any group. The events are listed by decreasing incidence among BG-12–trea