Articles
`
`Lancet 2008; 372: 1463–72
`See Comment page 1447
`*Members listed at end of paper
`University Hospital Basel,
`Basel, Switzerland
`(Prof L Kappos MD); University
`Clinic Bochum at St Josef
`Hospital, Bochum, Germany
`(Prof R Gold MD); Institute of
`Neurology, University College
`London, London, UK
`(Prof D H Miller MD,
`D G MacManus MSc,
`K Schmierer PhD, T A Yousry MD);
`General Teaching Hospital,
`Prague, Czech Republic
`(E Havrdova MD); City Hospital
`of Cologne, Cologne, Germany
`(V Limmroth MD); VU Medical
`Centre, Amsterdam, the
`Netherlands
`(Prof C H Polman MD); Biogen
`Idec, Cambridge, MA, USA
`(M Yang MS, K T Dawson MD,
`A W Sandrock MD,
`G N O’Neill MB); University of
`Istanbul, Istanbul, Turkey
`(Prof M Eraksoy MD); Motol
`Hospital, Charles University,
`second Medical School, Prague,
`Czech Republic
`(E Meluzinova MD); and
`Masaryk University, Brno,
`Czech Republic (I Rektor MD)
`Correspondence to:
`Prof Ludwig Kappos, University
`Hospital Basel, Neurology and
`Department of Biomedicine,
`Petersgraben 4, CH 4031, Basel,
`Switzerland
`lkappos@uhbs.ch
`
`Effi cacy and safety of oral fumarate in patients with
`relapsing-remitting multiple sclerosis: a multicentre,
`randomised, double-blind, placebo-controlled phase IIb study
`
`Ludwig Kappos, Ralf Gold, David H Miller, David G MacManus, Eva Havrdova, Volker Limmroth, Chris H Polman, Klaus Schmierer, Tarek A Yousry,
`Minhua Yang, Mefk ûre Eraksoy, Eva Meluzinova, Ivan Rektor, Katherine T Dawson, Alfred W Sandrock, Gilmore N O’Neill, for the BG-12 Phase IIb
`Study Investigators*
`
`Summary
`Background Oral fumarate (BG00012) might have dual anti-infl ammatory and neuroprotective eff ects. Our aim was to
`assess the effi cacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis.
`
`Methods 257 patients, aged 18–55 years, with relapsing-remitting multiple sclerosis were randomly assigned to
`receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or
`placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with
`placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium
`enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative
`number of new GdE lesions (weeks 4–24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at
`week 24, and annualised relapse rate. Analysis was done on the effi cacy-evaluable population. Safety and tolerability
`were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701.
`
`Findings Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE
`lesions from week 12 to 24 compared with placebo (1·4 vs 4·5, p<0·0001). It also reduced number of new or enlarging
`T2-hyperintense (p=0·0006) and new T1-hypointense (p=0·014) lesions compared with placebo. BG00012 reduced
`annualised relapse rate by 32% (0·44 vs 0·65 for placebo; p=0·272). Adverse events more common in patients given
`BG00012 than in those given placebo included abdominal pain, fl ushing, and hot fl ush. Dose-related adverse events
`in patients on BG00012 were headache, fatigue, and feeling hot.
`
`Interpretation The anti-infl ammatory eff ects and favourable safety profi le of BG00012 warrant further long-term
`phase III studies in large patient groups.
`
`Funding Biogen Idec, Inc.
`
`Introduction
`BG00012, an oral formulation of dimethyl fumarate,
`might have novel and complex eff ects on the pathobiology
`of multiple sclerosis. Preclinical experiments have shown
`that dimethyl fumarate and its primary metabolite
`monomethyl fumarate can activate the nuclear-factor-
`E2-related factor-2 (Nrf2) transcriptional pathway,1 which
`controls phase-2 detoxifying enzyme gene expression, and
`is crucial for oxidative stress response and immune
`homoeostasis.2 4 Activation of the Nrf2 pathway defends
`against oxidative-stress-induced neuronal death,5 8 protects
`the blood–brain barrier,9 and supports maintenance of
`myelin integrity10 in the CNS. Dimethyl fumarate induces
`expression of phase-2 detoxifi cation enzymes in astroglial
`and microglial cells.11 It also inhibits expression of
`cytokines and adhesion molecules implicated in the
`infl ammatory response in vitro.11 13 These data suggest that
`BG00012 could have dual neuroprotective and anti-
`infl ammatory eff ects.
`An oral formulation of fumaric acid (Fumaderm, Biogen
`Idec Gmbh, Ismaning, Germany) showed eff ectiveness in
`patients with chronic plaque psoriasis, a disorder associated
`
`with immune dysfunction.14 In a pilot study in patients
`with relapsing-remitting multiple sclerosis, this form-
`ulation also reduced the number and volume of gadolinium
`enhancing (GdE) lesions on brain MRI scans compared
`with baseline.15 On the basis of these preliminary fi ndings,
`we have tested the effi cacy and safety of three doses of
`BG00012 versus placebo in a multicentre, randomised,
`double-blind, placebo-controlled, dose-ranging, phase IIb
`study
`in patients with relapsing-remitting multiple
`sclerosis.
`
`Methods
`Patients
`257 patients were recruited from 43 centres in the Czech
`Republic, Germany, Hungary, Netherlands, Poland,
`Russia, Sweden, Switzerland, Turkey, and UK, between
`Nov 24, 2004, and March 31, 2005. Participants were aged
`18–55 years with a diagnosis of relapsing-remitting
`multiple sclerosis by McDonald criteria,16 a baseline
`Expanded Disability Status Scale (EDSS) score between 0
`and 5,17 and either at least one relapse within 12 months of
`randomisation and a previous cranial MRI scan showing
`
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`
`1463
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`Articles
`
`lesions consistent with multiple sclerosis, or GdE lesions
`on MRI scans done within 6 weeks of randomisation.
`Women with child-bearing potential had to use appro-
`priate birth control, and were excluded from the study if
`they were pregnant or breastfeeding. Patients were ex-
`cluded if they had progressive forms of multiple sclerosis
`or serious medical disorders, either concurrently (ie, HIV
`or hepatitis) or by history (ie, malignant disease or
`anaphy lactic reactions, drug or alcohol abuse within
`2 years of randomisation, or a relapse of multiple sclerosis
`within 50 days of randomisation, or no stabilisation from
`a previous relapse at the time of randomisation, or both).
`Patients were excluded if they had been previously treated
`with fumaric acid, FAG-201, BG00012, cladribine, T-cell
`or T-cell-receptor vaccination, total lymphoid irradiation,
`or
`thera peutic monoclonal antibodies apart
`from
`natalizumab. Patients were also excluded if they received
`mitoxantrone or cyclophosphamide within 1 year;
`cyclosporine, azathio prine, methotrexate, natalizumab,
`intravenous immuno globulin, plasmapheresis, or other
`investigational drugs within 6 months; glatiramer acetate
`or interferon beta within 3 months; or corticosteroid (oral
`or intravenous), 4-amino pyridine, or related products
`within 30 days of randomisation.
`
`Study design and outcome measures
`This randomised, double-blind, placebo-controlled, parallel-
`group, dose-ranging study was a 24-week, blinded, placebo-
`controlled treatment period (part 1), followed by 24 weeks
`for dose-blinded safety assessment (part 2) (fi gure 1). Re-
`cruit ment started Nov 24, 2004, and the trial ended May 22,
`2006. During the fi rst 24 weeks, patients were randomly
`assigned to receive oral BG00012 120 mg once daily, 120 mg
`or 240 mg three times daily, or placebo. During the
`following 24 weeks, patients who received BG00012 in the
`fi rst 24 weeks were maintained on the same BG00012 dose,
`and patients who received placebo in the fi rst 24 weeks
`were given BG00012 240 mg three times daily. Patients
`who were randomly assigned to BG00012 240 mg three
`times daily received 120 mg three times daily for the fi rst
`week and 240 mg three times daily from week 2.
`
`Blinded placebo-controlled
`treatment period (part 1)
`
`Dose-blinded safety extension
`period (part 2)
`
`Screening
`
`Placebo
`
`BG00012 240 mg three times daily
`
`Randomisation
`(1:1:1:1)
`
`BG00012 120 mg once daily (120 mg per day)
`
`BG00012 120 mg three times daily (360 mg per day)
`
`BG00012 240 mg three times daily (720 mg per day)
`
`24 weeks
`
`24 weeks
`
`Figure 1: Study design
`
`1464
`
`BG00012 and placebo were administered as enteric-
`coated microtablets in gelatin capsules, which had
`identical appearance and taste. Daily medication was given
`in blister packs of six tablets, with diff erent numbers of
`tablets containing placebo or the active drug to preserve
`the blinding. In the extension phase, all patients received
`a new set of medication. During both study periods,
`reduction to one capsule three times daily for 1 month was
`allowed for patients unable to tolerate higher doses.
`Moreover, dosing inter ruptions were needed for elevated
`liver or renal function tests, or decreased white blood cell
`counts. After dose interruption, patients were examined
`every 2 weeks and allowed to resume dosing when
`laboratory values returned to normal. Patients with
`abnormal values for more than 4 consecutive weeks
`permanently discontinued the study drug.
`The study protocol was approved by independent ethics
`committees, and the study was done in accordance with
`the Declaration of Helsinki, International Conference of
`Harmonisation and Good Clinical Practice guidelines,
`and local regulations. Enrolled patients provided written
`informed consent.
`
`Study procedures and endpoints
`To prevent unblinding of treatment assignment, separate
`study personnel were assigned to treat patients and to
`assess drug effi cacy. A treating neurologist was responsible
`for routine neurological care, assessing and treating adverse
`events, and analysing laboratory test results. Neurologists
`not otherwise involved in the care of study participants
`assessed patients at scheduled and unscheduled relapse
`examinations. These examining neurologists were trained
`and certifi ed in EDSS examination after attending special
`training courses, viewing a DVD-ROM,18 and successfully
`passing a multiple choice test.
`Patients attended clinics every 4 weeks during both study
`periods. Patients were instructed not to take their
`medication within 4 h before clinic visits because of the
`possibility for study unblinding due to fl ushing. Brain
`MRI scans were done at baseline and at weeks 4, 8, 12, 16,
`20, and 24. Participating imaging sites were equipped with
`MRI systems operating at 1·0 or 1·5 Tesla. For all patients,
`46 contiguous 3-mm-thick axial images of the brain were
`acquired with a dual echo fast (turbo) spin echo (FSE)
`sequence (repetition time [TR] 2500–3300 ms, echo
`time 1 [TE1] 10–40 ms, echo time 2 [TE2] 80–100 ms) to
`provide proton density and T2-weighted images. Further-
`more, a conventional spin echo sequence (TR 500–700 ms,
`TE 10–20 ms) was undertaken before and after injection of
`gadolinium-based contrast medium to provide T1-weighted
`images in the corresponding spatial location to the FSE
`scans. We used a fi eld of view of 250 mm together with a
`reconstructed image matrix of 256×256, resulting in an
`in-plane spatial resolution of 0·97×0·97 for all images.
`All scans were analysed from hard-copy fi lm by
`two trained observers (KS and DGM) under the
`supervision of an experienced neuroradiologist (TAY) at a
`
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`
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`Articles
`
`309 patients assessed for eligibility
`
`257 patients enrolled and randomly
` assigned to study groups in
` placebo-controlled treatment
` period (part 1)
`
`65 assigned to receive placebo
`
`64 assigned to receive
` BG00012 120 mg once daily
`
`64 assigned to receive
` BG00012 120 mg three times daily
`
`64 assigned to receive
` BG00012 240 mg three times daily
`
`1 did not receive
` BG00012
`
`6 withdrew from study
`3 voluntary withdrawal
`1 lack of tolerance
`1 non-compliance
` 1 lost to follow-up
`
`6 discontinued
` placebo but
` completed
` follow-up
`
`4 withdrew from study
`1 adverse event
`1 lack of tolerance
`1 voluntary withdrawal
`1 non-compliance
`
`6 discontinued
` BG00012 but
` completed
` follow-up
`
`5 withdrew from study
`2 adverse events
`2 voluntary withdrawal
`1 lack of tolerance
`
`8 discontinued
` BG00012 but
` completed
` follow-up
`
`6 withdrew from study
`4 adverse events
`1 lack of tolerance
`1 voluntary withdrawal
`
`10 discontinued
` BG00012 but
` completed
` follow-up
`
`59 completed part 1
`
`60 completed part 1
`
`59 completed part 1
`
`57 completed part 1
`
`225 patients enrolled in dose-blinded
` safety-extension phase (part 2)
`
`59 transitioned from placebo to BG00012
` 240 mg three times daily
`
`58 continued BG00012
` 120 mg once daily
`
`56 continued BG00012
` 120 mg three times daily
`
`52 continued BG00012
` 240 mg three times daily
`
`3 withdrew from study
`3 adverse events
`
`6 discontinued
` BG00012 but
` completed
` follow-up
`
`2 withdrew from study
`2 voluntary withdrawals
`
`2 discontinued
` BG00012 but
` completed
` follow-up
`
`1 withdrew from study
`1 voluntary withdrawal
`
`3 discontinued
` BG00012 but
` completed
` follow-up
`
`0 withdrew from study
`
`1 discontinued
` BG00012 but
` completed
` follow-up
`
`56 completed part 2
`
`56 completed part 2
`
`55 completed part 2
`
`52 completed part 2
`
`Figure 2: Trial profi le
`
`central reading centre. New GdE lesions, compared with
`the previous scan, were identifi ed and marked every
`month on postcontrast T1-weighted sequences. For new
`or enlarging T2 lesions, the week-24 scan was compared
`with the baseline (week-0) scan. The proton-density
`weighted scan was marked, although the second echo, a
`more heavily T2-weighted sequence, was also reviewed to
`confi rm the presence of a new lesion. Enlarging T2
`lesions were defi ned as those that appeared larger on two
`contiguous slices or showed at least twice the diameter
`compared with the baseline scan. New T1-hypointense
`black-hole lesions were identifi ed and marked on the
`unenhanced T1-weighted scans at week 24 compared with
`the baseline scans.
`EDSS scores were assessed at baseline and at weeks 12,
`24, 36, and 48. Patients were monitored for relapses at all
`clinic visits, and suspected relapses were assessed on
`
`unscheduled visits. The treating neurologist was contacted
`within 48 h of symptom onset, and the assessment was
`done within 72 h; EDSS scores were reviewed during
`unscheduled visits. Relapses were defi ned as new or
`recurrent neurological symptoms lasting for 24 h or
`longer, not associated with fever or infection, and
`accompanied by new objective neurological fi ndings on
`examination. At the neurologists’ discretion, patients with
`relapses were treated per protocol with intravenous
`methyl prednisolone 1000 mg per day for 3 or 5 days.
`Haematology, blood chemistry, and urinalysis were
`done every 4 weeks. Electrocardiographs were done at
`screening and at weeks 12, 24, 36, and 48. All adverse
`events were documented throughout the study, regardless
`of severity or relation to study drug. Patients discontinuing
`BG00012 during the fi rst or the second part of the study
`were encouraged to remain in the study until week 24
`
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`
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`
`
`
`Plaubo. N=65
`BG00012 120 mg
`3600012 120 mg
`3600012 240 mg
`
`once daily, N=64
`thrutirnasdily, N=64 three times daily, N=63
`34—8 (10-2)
`36-3 (9-5]
`37-3 (9-1)
`42 (6696)
`44 (69%)
`42 (67%)
`62 (9796)
`64 (100%)
`60 (95%)
`7 (4-0-11-5)
`5 (30-90)
`6 (40-120)
`
`35-6 (8-2)
`36 (55%)
`64 (98%)
`6 (40—110)
`
`Age (years)
`Sex (ferrule)
`Ethnic orig'n (white)
`Median time since symptom omet (year) (IQR)
`Median number ofrelapses
`Previous lyear
`Previous 3%
`(-1355 score
`NumberodeElsions
`o
`1
`2
`3
`24
`Mean
`
`1
`2
`267 (1.23)
`
`38 (58%)
`10 (15%)
`10 (159i)
`3 (5%)
`4 (6%)
`1-6 (6-6)
`
`1
`2
`2.52 (1.11)
`
`30 (47%)
`19 (3096)
`3 (5%)
`3 (5%)
`9 (14%)
`1-4 (2‘1)
`
`1
`2
`2-51 (1.02)
`
`30 (47%)
`7 (11%)
`m (16%)
`3 (5%)
`14(22%)
`25 (4-2]?
`
`1
`3
`237 (1.33)
`
`41(65%)
`10 (15%)
`4(69s)
`2 (3%)
`6 (1056)
`1-3 (3-4)
`
`Data are n (96) or man (50), uniessoduwlse stated EDSS=Expandui Disabllty Status Sale. GdE=9adolh|um enhancing. lQRdmmrtlle range. 'htentlon-m—treat
`powhtlmjpoofivempiadm; p=not slgilfiram versus 9600012 120 mgonoe rial}; p=0m9versus 8600012 240 mgthrmthisdaliy basedon ioglt regression.
`
`Tahiti: Dcnognphics and baseline clinic] clinch-”stirs“
`
`
`
`
`
`or 48, respectively, and to continue protocol-scheduled
`assessments.
`
`The primary endpoint was the total number of new GdE
`lesions over four scans atweeks 12, 16, 20, and 24 (calculated
`as the sum ofthe scans): this time was selected on the basis
`ofan apparent latency to clinical effect from the pilot study
`of multiple sclerosis.“ Secondary MRI endpoints included
`the cumulative number of new GdE lesions from week 4
`
`to 24, and the numbers ofnew or enlarging T2-hyperintense
`lesions and new Tl-hyperintense lesions at week 24. The
`efficacy of BG00012 on relapses and disability progression,
`and its safety and tolerability, were also assessed.
`
`Statistical analysis
`Mean and variability estimates to calculate sample size
`were derived from summary data from placebo-treated
`patients with relapsing-remitting multiple sclerosis in
`other clinical studies (mean=8 - 6, SD=12 - 7).” The standard
`deviation for the group treated with the active compound
`was
`calculated by assuming a negative binomial
`distribution of the number of MRI lesions on the basis of
`
`the mean in the calculation. A sample size of 65 patients
`per group had 80% power to detect a treatment effect of
`55% reduction or more on the total number of new GdE
`lesions, when comparing the mean of the placebo group
`with that of the two groups treated with the two highest
`doses of active drug combined. This
`sample size
`calculation assumed that the total lesion number was
`
`from four consecutive scans and was based on a two-group
`Satterthwaite t test of equal means and unequal variances.
`Additionally, we assumed an alpha value of 0-05 with no
`adjustment for multiple comparisons. The calculation was
`done with Nquery (version 5.0)
`statistical
`software
`(Statistical Solutions, Saugus, MA. USA).
`
`MRI endpoints were analysed with the non-parametric
`Wilcorron rank sum test. Annualised relapse rate was
`analysed with a Poisson regression model adjusted for
`the number of relapses in the 12 months before study
`entry, and proportion of relapse-free patients was analysed
`with Fisher exact test. No formal statistics were done on
`
`the
`EDSS scores. MRI analyses are reported for
`efficacy-evaluable population (ie, patients who had no
`missing MRI data). MRI scans must have been done
`before or at least 24 days after steroid treatment. Clinical
`efficacy analyses are reported for the intention-to-treat
`population, defined as all patients who were randomised
`and received at least one dose of drug. All statistical tests
`were two-sided, with an alpha value of0 - 05; no adjustment
`(type I error rate) for multiple comparisons was made.
`The safety population included all patients who received
`at least one 3600012 dose. Differences in adverse-event
`
`reporting between all BG00012 groups combined versus
`placebo group were calculated with the Fisher exact test.
`
`Role of the funding source
`The employees of Biogen Idec Inc listed as authors
`participated with the other authors in the study design
`and statistical analysis ofthe data. These authors reviewed
`and approved the manuscript. The corresponding author
`had full access to all study data and had final responsibility
`for submission of the publication.
`
`Results
`
`257 patients were randomly assigned to receive BG00012
`120 mg once daily, or 120 mg or 240 mg three times daily,
`or placebo. One patient, who was randomly assigned to
`the highest dose of BGOOOIZ, withdrew before receiving
`the drug (figure 2). Patients were well-matched for
`
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`
`Sawai (IPR2019-00789), EX. 1048, p. 004
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`Articles
`
`5
`
`'p<00001vsplacebo
`
`TotalnunbevodeEiesions
`
`W
`
`2
`
`figmuzwmg
`“mums My
`”Spud”
`
`'
`
`3600112
`3600312
`Placdm 360G312
`120 mg once 120 mg three 240 mg three
`daill
`times daiy
`times daily
`Tmtment group
`
`
`
`
`
`demographic and baseline disease characteristics (table 1).
`The mean number ofbaseline GdE lesions was higher for
`the BG00012 120 mg three times daily group than for all
`other treatment groups (table 1).
`During the first 24 weeks, more patients receiving
`3600012 120 mg and 240 mg three times daily
`discontinued study drug than patients receiving BG00012
`120 mg once daily or placebo (figure 2). Overall,
`21 of 256 patients who received the drug withdrew from
`the first part of the study. An additional ten patients who
`completed the first part of the study did not enter in the
`second part. During the second 24 weeks, more patients
`changing from placebo to BGOOOIZ 240 mg three times
`daily prematurely discontinued study drug than patients
`maintaining their original treatment. Overall, six patients
`withdrew from this part of the study. 235 patients
`completed their study visits during the first 24 weeks
`and 219 completed the second 24 weeks.
`Patients receiving BG00012 240 mg three times daily
`26% of those receiving placebo. Furthermore, the mean
`had fewer total new GdE lesions (69% reduction) at
`number of Tl-hypointense lesions after 24 weeks of
`weeks 12, 16, 20, and 24 combined compared with those
`treatment was lower (53% reduction) in the BG00012
`receiving placebo (1-4 vs 4-5, p<0-0001)
`(figure 3).
`Similarly, a sensitivity analysis of the intention-to-treat
`240 mg three times daily dose group compared with the
`placebo group. No significant differences were seen
`population on this endpoint showed that patients receiving
`between the lower BGOOOIZ dose groups (ie, 120 mg once
`this dose ofBGOOOlZ had fewer new GdE lesions compared
`daily and 120 mg three times daily) and the placebo group
`with those receiving placebo (1-3 vs 4-8, p<0-0001).
`on any ofthe MRI endpoints assessed.
`Although treatment with BG00012 led to fewer total new
`During the first part ofthe study, the annualised relapse
`GdE lesions in patients receiving 120 mg once daily (3 - 3)
`rate for patients who received BG00012 240 mg three
`and three times daily (3-1)
`than placebo (4- 5),
`these
`treatment group differences were not significant.
`times daily decreased by 32% (table 2). The proportion of
`relapse-free patients was close between the two groups. A
`From week 4 to 24, patients receiving BG00012 240 mg
`similar percentage of patients in every treatment group
`three times daily had fewer cumulative new GdE lesions
`was treated with intravenous methylprednisolone per
`(44% reduction) than those receiving placebo (table 2).
`protocol for relapses (11:11 [17%] in the placebo group:
`BG00012 240 mg also reduced the mean number of new
`n=9 [14%] in the BG00012 120 mg once daily group; n=11
`or enlarging T2-hyperintense lesions (48% reduction)
`[17%] in the BG00012 120 mg three times daily group;
`during the first 24 weeks compared with placebo. During
`and n=6 [10%] in the BG00012 240 mg three times daily
`this period, no new T2 lesions developed in 63% of
`
`
`group). During the second part of the study,patients receiving this dose of BG00012 compared with the
`
`Figle 3: Munmhl ru mhar adeE lesions from sun! at weeks 11, 16, 20,
`and 24 combined
`Vertical bars-SE.
`
`MRl’!
`Numberofnew GdElesions (weels 12-24)
`Mean
`Median (DQR)
`p value vs placebo
`Number ofnew GdE lesions (weels 4—24)
`Mean
`Median (iQR)
`p value vs placebo
`MmberofnedeEles‘onspei-patientperscan
`(weeks 12-24]
`Mean
`Median (iQR)
`p valuei
`
`PIMo"
`
`54
`4-5 (7-4]
`20 (0-5-0)
`
`53
`66 (11-4)
`3-0 (0—7-0)
`
`54
`
`3600012 120 rrg
`onn daily
`
`8600012 120 mg
`til mtimudaily
`
`M00012 240 mg
`Him-timer daily
`
`59
`3-3 (5-1)
`10 (0-40)
`0-266
`55
`6-2 (89)
`3-0 (0-7-0)
`0-943
`59
`
`56
`3-1 (5-9)
`170 (0-3-5)
`0-068
`54
`6-7 (10-9)
`2-0 (0-7-0)
`0801
`56
`
`54
`1-4 (3-8)
`00 (0—1-0)
`<0-0001
`52
`3-7 (11-2)
`0-0 (0—3-0]
`0-002
`54
`
`1-13 (1.84)
`o-so (0—1-25)
`
`0-83 (1.29)
`0.25 (0—1-00)
`0-266
`
`0-78 (1-48)
`025 (0-0-88)
`0-068
`
`035 (094)
`o-oo (mo-25)
`<0-0001
`(Continues on nut: page)
`
`
`
`
`wwwthelancetcom Vol 371 October 25, 2008
`
`1467
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`Sawai (IPR2019-00789), EX. 1048, p. 005
`
`Sawai (IPR2019-00789), Ex. 1048, p. 005
`
`

`

`Articles
`
`Plaoobo"
`
`
`
`BG00012 120 mg
`once daily
`
`NOOOIZ 110 mg
`throatimudaily
`
`8600012 240 mg
`three times hily
`
`(Continued from previms page)
`Numberofnew orenlarging D-hyperintense lesions
`(week 24)
`o
`1
`2
`3
`24
`Mean
`Median (IQR)
`p value vs placebo
`Numberofnele—hypointense lesions (week 24)
`0
`1
`2
`3
`24
`Mean
`Median (lQR)
`)1 value vs placebo
`Clinials
`Weeks 0—24
`Annualised relapse rate (95% on
`)1 value vs placebo
`Rehpsefne
`p value vs placebo”
`Weeks 25-48
`Annualised relapse rate (95% G)1I
`Rehpse—fne
`Weeks 0—48
`Annualised relapse rate (95% (1)1
`Rehrse-free
`
`54
`
`59
`
`56
`
`54
`
`14 (26%)
`10 (19%)
`8 (15%)
`1 (2%)
`21 (39%)
`42 (5-4)
`2-0 (00-60)
`-
`S4
`25 (46%)
`9 (17%)
`7 (13%)
`3 (6%)
`10 (19%)
`1-7 (2-5)
`1-0 (0-2-0)
`
`16 (27%)
`6 (10%)
`10 (17%)
`7 (12%)
`20 (34%)
`3-8 (4-7)
`2-0 [0-0-5-0)
`0-965
`59
`26 (44%)
`15 (25%)
`7 (12%)
`5 (8%)
`6 (10%)
`1-3 [1-8)
`1-0 (0-2-0)
`0-732
`
`15 (27%)
`11 (20%)
`8 (14%)
`2 (4%)
`20 (36%)
`4-1 (5-7)
`2-0 (00-45)
`0-839
`56
`21 (38%)
`17 (30%)
`a (14%)
`1 (2%)
`9 (16%)
`1-5 (2-0)
`1-0 (0-20)
`0-836
`
`65
`0-65 (0-43-1-01)
`-
`49 (75%)
`~
`59
`0-26 (0-30-53)
`52 (75%)
`59
`0-41 (0-26-0-64)
`40(6896)
`
`64
`0-42 (0-24—0-71)
`0-196
`53 (83%)
`0-387
`58
`0-24 (0-11—0-50)
`50 (86%)
`58
`0-29 (0-17-0-50)
`“(76%)
`
`64
`0-78 (052-116)
`0-572
`44 (69%)
`0-437
`S6
`0-47 (0-27—0-82)
`43 07%)
`56
`0-60 (041-088)
`32 (9%)
`
`34 (63%)
`6 (11%)
`o (0%)
`2 (4%)
`12 (22%)
`2-2 (5-4)
`0-0 (00-30)
`0-0006
`S4
`35 (65%)
`11 (20%)
`4 (7%)
`3 (6%)
`1 (2%)
`0-8 (2-0)
`0-0 (0-1-0)
`0-014
`
`63
`044 [026-076)
`0-272
`51 (81%)
`0-524
`52
`0-16 (0-07—0-41)
`48 (92%)
`52
`028 (016-050)
`40 (77%)
`
`Dataare numbers (96) orman (SD), unlss hilatedothuwlse. GdE=grlolhlum allandng. "31:ka range'Pbcebo-traml paflerlstranslflonedmm2 240 mg
`momflydukgmdsfiw.Tmbmmmmmmfivmmmduflngmmhmmofm GdEleslonspev san, m2
`splubo MMlmmmm-ourpopumm mnfovvnelszs—wmdwaeks 0-48wevefmmthe Immoarpoplabndmumdrhm period.
`11mm Poison ngiesdon, aflmdfornmbuofmhpseslmhellnmflshefommdyenuy.mummmmmummng-wp
`lorelved Bcoomzfovtpmwweeks. IlmsedeisherexacttestPathmnhovfldrdmfiomdiesndywmexpeflendnganhpemoorfldued notmhavevehsu‘l.
`
`Talcz: MRI and clinical endpoint
`
`
`
`annualised relapse rate for patients who received placebo
`changing to BG00012 240 mg three times daily, BG00012
`120 mg once daily, BG00012 120 mg three times daily, or
`BG00012 240 mg three times daily was reduced by 60%,
`43%, 40%, and 64% compared with annualised relapse
`rates during the first part of the study.
`During the first part ofthe study, 75% ofpatients treated
`with placebo and 88% of all patients receiving BG00012
`reported at least one adverse event (n=55 [86%] of those
`treated with BGOOOIZ 120 mg once daily; n=S9 [92%] of
`those treated with BG00012 120 mg three times daily, and
`n=55 [87%] of those treated with BG00012 240 mg
`three times daily). The most common adverse events
`included flushing, multiple
`sclerosis
`relapse, and
`
`headache (table 3). Adverse events significantly more
`common in patients receiving BG00012 240 mg three
`times daily than in those receiving placebo included
`upper abdominal pain (p=0-029), abdominal pain
`(p=0-013), hot flush (p=0-013), and flushing (p<0-0001).
`However. the frequency offlushing events decreased with
`increasing BG00012 doses. In general, flushing started
`within 30 min of drug administration and subsided
`within 90 min. Gastrointestinal adverse events were
`
`reported by 25% of patients on placebo, 30% of those on
`BG00012 120 mg once daily, 39% on BG00012 120 mg
`three times daily, and 41% on BG00012 240 mg three
`times daily. The most common gastrointestinal events
`were nausea. diarrhoea, and upper abdominal pain
`
`1468
`
`wwwjhelancetcom Vol 372 omh-rzs, 2008
`
`Sawai (IPR2019-00789), EX. 1048, p. 006
`
`Sawai (IPR2019-00789), Ex. 1048, p. 006
`
`

`

`
`
`Articles
`
`See Onllneforwdatable
`
`SuOnllneforwdrfigue
`
`(table 3). The severity of these gastrointestinal events was
`mild to moderate except for one severe event each in the
`placebo, BG00012 120 mg once daily, and BG00012 120 mg
`three times daily groups, and four events in the BG00012
`240 mg three times daily group. Adverse events with
`BG00012 doserehted patterns were headache, fatigue,
`and feeling hot.
`Infections were reported in similar
`proportions of BG00012 and placebo patients (34% in
`both groups). Only one serious infection, an incident of
`pelvic inflammatory disease in a patient
`receiving
`BG00012 120 mg three times daily, was reported. This
`patient responded well to standard medical management.
`Serious adverse events were reported in 12% of pau'ents
`on placebo and 9% ofthose on BG00012. The only serious
`adverse event to occur in more than one patient was
`multiple sclerosis relapse (table 3).
`During the first 24 weeks, the flequency of adverse
`events that led to drug discontinuation increased slightly
`with increasing doses of BGO(X)12 (8% of patients on
`BG00012 120 mg once daily, 11% of those on BG00012
`120 mg three times daily, and 13% of those on BG00012
`240 mg three times daily). Adverse events resulting in drug
`discontinuation included flushing (one patient on BG(X)012
`120 mg three times daily and one on BG00012 240 mg
`three times daily),
`increased alanine aminotransferase
`concentration (one patient on BG00012 120 mg once daily
`and one on BG00012 120 mg three times daily), nausea
`(two patients on BG00012 240 mg three times daily), and
`vomiting (two patients on BGOOOIZ 240 mg three times
`
`daily). Diarrhoea was the only event that led to withdrawal
`of more than one patient from the first part of the study
`(two patients on BG00012 120 mg once daily). Only one
`BG00012-treated patient (120 mg once daily) withdrew
`because of non-compliance.
`The profile of adverse events during the second part of
`the study was broadly similar to that of the first part. and
`no new safety issues were apparent in patients changing
`from placebo to BG00012 24-0 mg (webtable). In addition
`to nasopharyngitis, the most common infections during
`the second part of the study included influenza (4%),
`upper respiratory tract infection (4%), and pharyngitis
`(4%). These events were reported in similar numbers of
`patients in every treatment group. For patients receiving
`BG00012 during both study periods, adverse events such
`as flushing, headache, nausea, upper abdominal pain,
`and pruritus took place more frequently during the first
`24 weeks than during the second 24weeks. In all BG00012
`groups, the frequency of flushing decreased from 66%
`(n=127) events during month 1 to 5% (n=9) during
`month 6, and the frequency of gastrointestinal events
`decreased from 52% (n=l32) during month 1 to 4%
`(n=10) during month 6 (webfigure).
`Fewer patients who received BGOOOIZ during the entire
`study withdrew from the second part of the study than
`those changing from placebo to BG00012 240 mg three
`times daily (2% vs 5%). All withdrawals in patients on
`BGOOOIZ during the entire study were voluntary and in
`those changing from placebo to BG00012 240 mg three
`
`Flushing
`Multiple sclerosis relapse
`Headache
`Nasopharyngitis
`those:
`Diarrhoea
`Pruritus
`Upperabdorninal pain
`Hotflush
`Abdominal pain
`Serious adverse events
`Multiple Ilerosis relapm
`Abdominal pain
`lower imb fracture
`Multiple sclerosis
`Pelvic inflammatory dima:
`Phlebitis
`Urinary retention
`Utaine leiomyoma
`Vertigo
`
`Plan-ho, ”=65
`
`6 (9%)
`16 (25%)
`7 (11%)
`10 (15%)
`5 (8%)
`3 (5%)
`5 (8%)
`2 (3%)
`0 (0%)
`0 (0%)
`
`5 (8%)
`0 (0%)
`1 (2%)
`0 (0%)
`0 (0%)
`0 (0%)
`0 (0%)
`1 (2%)
`1 (2%)
`
`NOOOIZ 120 mg
`one-daily, N=64
`34 (53%)
`11 (17%)
`s (8%)
`7 (11%)
`1 (2%)
`6 (9%)
`6 (9%)
`5 (8%)
`5 (8%)
`2 (3%)
`
`3600011 total.
`3600012 240 mg
`3600012 no rrlg
`three times daily, N=64 thmtimuchily, N=63 N=191
`31 (48%)
`25 (40%)
`90 (47%)1
`20 (31%)
`12 (19%)
`43 (23%)
`11 (17%)
`13 (21%)
`29 (15%)
`6 (9%)
`7 (11%)
`20 (10%)
`9 (14%)
`1o (16%)
`20 (10%)
`5 (8%)
`7 (11%)
`18 (9%)
`s (8%)
`6 (10%)
`17 (9%)
`4 (6%)
`9 (14%)
`18 (9%)
`1 (2%)
`6 (10%)
`12 (6%):
`2 (3%)
`6 (10%)
`10 (5%)
`
`3 (5%)
`0 (0%)
`0 (0%)
`1 (2%)
`0 (0%)
`0 (0%)
`0 (0%)
`0 (0%)
`o (0%)
`
`6 (9%)
`o (0%)
`0 (0%)
`0 (0%)
`1 (2%)
`1 (2%)
`0 (0%)
`0 (0%)
`0 (0%)
`
`s (8%)
`1 (2%)
`o (0%)
`o (0%)
`o (0%)
`o (0%)
`1 (2%)
`o (0%)
`o (0%)
`
`14 0%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`
`Data at! numbers (95). ‘Reponed In 101607 mofpatlents h anytratmerlt group, regardlessofstudy drug. 1300001, dl 9600012 group comblndvusus placebo.
`1p=00125. al 3600012 groups (onbhdversusflacebo.
`
`1'ch 3: Advent lvmb in the placebo-controlled t