Articles
`
`Published Online
`January 20, 2006
`DOI:10.1016/S1474-4422(06)
`70327-1
`*Study group investigators are
`listed at end of report
`Neuroimaging Research Unit
`(M Filippi MD) and Department
`of Neurology (M Filippi,
`GComi MD), Institute of
`Experimental Neurology and
`University Ospedale San
`Raffaele, Milan, Italy; and
`Department of Neurology,
`University of Texas Health
`Science Center at Houston,
`Houston, TX, USA
`(JSWolinskyMD)
`Correspondence to:
`DrMassimoFilippi,
`Neuroimaging Research Unit,
`Scientific Institute and University
`Ospedale San Raffaele,
`viaOlgettina 60, 20132 Milan,
`Italy
`filippi.massimo@hsr.it
`
`Effects of oral glatiramer acetate on clinical and MRI-
`monitored disease activity in patients with relapsing
`multiple sclerosis: a multicentre, double-blind, randomised,
`placebo-controlled study
`
`Massimo Filippi, Jerry S Wolinsky, Giancarlo Comi, the CORAL Study Group*
`Summary
`Background Parenterally administered glatiramer acetate reduces the frequency of relapses and the formation of
`active brain lesions seen with MRI in multiple sclerosis. This study assessed whether two doses of glatiramer acetate
`given orally could improve clinical and MRI measures of inflammation and neurodegeneration in a large cohort of
`patients with relapsing-remitting multiple sclerosis.
`
`Methods 1912 patients with relapsing-remitting multiple sclerosis were screened and 1651 were randomised to
`receive 50 mg or 5 mg of glatiramer acetate or placebo by daily oral administration over 14 months. The intention-to-
`treat cohort consisted of 1644 patients who took at least one dose of study medication (50 mg glatiramer acetate
`[n=543], 5 mg glatiramer acetate [n=553], placebo [n=548]). After baseline investigation, clinical assessments were
`done every 2 months and MRI was obtained for all patients at baseline and at study exit. Additionally, MRI was
`undertaken every 2 months for a cohort of 486 patients. The primary outcome was the total number of confirmed
`relapses observed during the study period. Several prespecified clinical and MRI secondary and tertiary outcomes
`assessed treatment efficacy on inflammation and neurodegeneration due to multiple sclerosis.
`
`Findings The cumulative number of confirmed relapses did not differ between the two active treatment groups and
`the placebo group. Relative to placebo, the rate ratio for the 50 mg glatiramer acetate treated group was 0·92 (95% CI
`0·77–1·08, p=0·30) and for the 5 mg glatiramer acetate treated group was 0·98 (0·83–1·15, p=0·76). No drug effect
`was seen for any of the secondary and tertiary endpoints. The study drug was safe and well tolerated.
`
`1–7
`
`Interpretation 5 mg and 50 mg glatiramer acetate administered orally on a daily basis do not affect relapse rate or
`other clinical and MRI parameters of disease activity and burden in patients with relapsing-remitting multiple
`sclerosis. Treatment with oral formulations of glatiramer acetate at the doses tested cannot be recommended.
`Introduction
`is a specific multiple sclerosis
`Glatiramer acetate
`immunomodulator, which when injected subcutaneously
`each day reduces the frequency of relapses and the
`formation of active brain lesions as seen with MRI.
`Treatment can also slow the development of MRI-
`measured brain atrophy and the evolution of MRI active
`lesions
`into permanently damaged black holes.5,7
`Although the exact mechanism of action of glatiramer
`acetate in multiple sclerosis is not known, emerging data
`suggest that the drug mainly induces specific regulatory
`T cells of the T-helper 2 and T-helper 3 type, which are
`8–10 These cells then
`formed close to the site of injection.
`circulate to the CNS where they are reactivated by myelin
`basic protein and other myelin antigens and secrete
`protective anti-inflammatory
`cytokines,
`such as
`interleukin 4, 5, and 6, transforming growth factor, and
`brain-derived growth factor, near the site of the multiple
`sclerosis lesions.11 This bystander suppression is probably
`the basis of the effects of glatiramer acetate on clinical and
`MRI measures of inflammation and neurodegeneration.
`All currently approved drugs for multiple sclerosis
`are administered parenterally. However,
`long-term
`
`treatment with injected drugs is not without problems.
`These include patient discomfort and the occurrence of
`adverse events associated with frequent injections, such
`as local injection site reactions. These issues, through
`reduction of patient compliance, probably negatively
`affect patients’ use of all available drugs. Thus, there is a
`strong rationale for assessment of whether drugs that
`are known to be effective when given parenterally also
`exert positive effects on clinical and MRI measures of
`disease activity when given orally. With a double-blind,
`randomised, placebo-controlled
`trial we aimed
`to
`ascertain the effect of two doses of oral glatiramer
`acetate on clinical and MRI measures of inflammation
`and neurodegeneration in a large cohort of patients with
`relapsing-remitting multiple sclerosis.
`Methods
`Patients
`1912 patients were screened, after giving written
`informed consent, at 158 participating clinical centres
`worldwide. Of these, a total of 1651 patients with
`clinically definite relapsing-remitting multiple sclerosis
`were
`randomly assigned enteric-coated
`tablets
`
`http://neurology.thelancet.com Published online January 20, 2006 DOI:10.1016/S1474-4422(06)70327-1
`
`1
`
`Page 1 of 8
`
`YEDA EXHIBIT NO. 2018
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Articles
`
`containing 50 mg or 5 mg of glatiramer acetate (Teva
`Pharmaceuticals) or placebo by daily oral administration.
`One patient received a randomisation number through
`mistaken use of the interactive voice response system
`and six participants never received study medication.
`This left an intention-to-treat cohort of 1644 randomised
`participants who took at least one dose of study
`medication (50 mg glatiramer acetate [n=543], 5 mg
`glatiramer acetate [n=553], placebo [n=548]). The first
`patient was enrolled on March 13, 2000, and the last on
`Sept 3, 2000. The last date of follow-up was Nov 26, 2001.
`Each participant was required to have clinically definite
`multiple sclerosis,12 a disease duration from onset of at
`least 6 months, and a relapsing-remitting course, to be
`age 18–50 years, have an inclusive expanded disability
`status scale (EDSS) score 13 at baseline of 0·0–5·0, and
`have had at least one documented relapse in the year
`before study entry. All participants were relapse free and
`had not used steroids for at least 30 days before screening
`or before randomisation. Men and women were asked to
`use birth control when appropriate. Prior use of
`glatiramer acetate, oral myelin, cladribine, and total body
`irradiation or total lymphoid irradiation were not allowed.
`The use of immunosuppressive drugs in the 12 months
`before study entry, or the use of interferons, intravenous
`immunoglobulins, more than 30 consecutive days of
`chronic steroid treatment, or participation in clinical
`studies of experimental drugs in the 6 months before
`study entry were not allowed. Patients were excluded if
`they had life-threatening or unstable clinically significant
`disease, were pregnant or lactating, had major current
`gastrointestinal disorders, used medication that could
`cause major gastrointestinal disturbances, or had
`medical or psychiatric conditions that could affect their
`ability to give informed consent. Participants were also
`excluded for known sensitivity to gadolinium chelates or
`an inability to undergo MRI. The study was approved by
`local ethics committees.
`
`Procedures
`The study was a double-blind, placebo-controlled,
`randomised trial lasting 56 weeks. For trial purposes a
`month was defined as 4 weeks or 21–35 days. Eligible
`patients
`underwent
`physical and
`neurological
`examination
`including assessment with EDSS,
`ambulation
`index,
`timed 25
`foot walk, electro-
`cardiogram, chest radiography, and laboratory studies.
`The coordinating centre reviewed the results of the
`screening assessments and,
`if all
`inclusion and
`exclusion criteria were satisfied, gave approval for
`patient enrolment. Eligible patients returned within
`28 days of screening, again gave written informed
`consent, had an interval history taken, underwent repeat
`neurological examination and laboratory testing, and
`had a brain MRI scan with administration of gadolinium
`chelates. They were then randomly assigned to a group
`and received their first dose of study medication under
`
`observation. Study drug was provided as 50 mg
`glatiramer acetate with matching 5 mg placebo, 5 mg
`glatiramer acetate with matching 50 mg placebo, or as
`50 mg and 5 mg matching placebo tablets formulated for
`enteric release. The randomisation list, stratified by
`study centres, was computer generated by the Teva
`Pharmaceuticals Statistics and Data Management
`Department. Equal allocation of the three treatment
`groups was used. Eligible participants were assigned a
`study number by an automated
`interactive voice
`response system (ClinPhone, Princeton, NJ, USA).
`At each study site a
`treating neurologist was
`responsible for the overall medical management of the
`patient, including safety monitoring. An examining
`neurologist was
`responsible
`for all scheduled
`neurological examinations and exacerbation follow-ups.
`All patients had neurological assessments every
`2 months (56±7 days); additional assessments were
`undertaken for symptoms suggestive of a relapse. MRI
`was done for all patients at 56 weeks and for a cohort of
`486 individuals seen at 41 of the sites every 2 months.
`Safety assessments
`that
`included vital signs,
`haematology, and biochemical tests were done at all
`regularly scheduled clinical visits. All personnel involved
`in the study were unaware of the treatment allocation.
`Both the treating neurologist and the patient were
`informed of the importance of not discussing safety
`issues with the examining neurologist.
`A relapse was defined as the appearance of one or more
`new neurological symptoms or the reappearance of
`one or more previously experienced neurological
`symptoms.4,14 Patients were instructed to telephone their
`local centre immediately if they perceived that they might
`be experiencing a relapse. A visit was arranged within
`7 days of notification. Neurological deterioration had to
`last at least 48 h and be preceded by a relatively stable or
`improving neurological state in the prior 30 days. An
`event was counted as a relapse only when the patient’s
`symptoms were accompanied by objective changes in the
`neurological examination corresponding to an increase
`of at least 0·5 points on the EDSS, or one grade in the
`score of two or more functional systems or two grades in
`one functional system. Deterioration associated with
`fever or infections that can cause transient, secondary
`impairment of neurological function in patients with
`multiple sclerosis was not regarded as a relapse. Change
`in bowel, bladder, or cognitive function alone was not
`accepted as a relapse. The trial principal investigator (GC)
`reviewed all exacerbation
`reports
`to check
`their
`consistency with this relapse definition. Relapses could
`be treated with a standard dose of 1·0 g intravenous
`methylprednisolone for 3 consecutive days.
`The primary outcome was the total number of relapses
`observed for the intention-to-treat population during the
`56 weeks of study treatment. Secondary outcome
`measures consisted of the number of relapses treated
`with corticosteroids, the area under the curve for the
`
`2
`
`http://neurology.thelancet.com Published online January 20, 2006 DOI:10.1016/S1474-4422(06)70327-1
`
`Page 2 of 8
`
`YEDA EXHIBIT NO. 2018
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Articles
`
`change in EDSS from baseline, the number and volume
`of enhancing lesions, the number of new lesions on
`T2-weighted images, and the number of new enhancing
`lesions in a subcohort of participants undergoing more
`frequent MRI monitoring. Tertiary outcomes included
`the change in EDSS from entry to 56 weeks, the timed
`25 foot walk, ambulation index, proportion of patients
`who were relapse free, time to first relapse, proportion of
`patients who were relapse free by trimester on study,
`time to the second relapse, number of relapses requiring
`hospitalisation, brain atrophy, and the number and
`volume of hypointense
`lesions on T1-weighted
`enhanced scans.
`Before any clinical site could enrol study participants
`they were required to image a volunteer patient with
`clinically definite multiple sclerosis
`twice with
`repositioning according to a strict study imaging
`protocol using imagers with minimum field strength of
`1·0 Tesla. These
`test
`images were sent
`to
`the
`neuroimaging research unit in Milan as film and
`electronic data for review to ensure that the site could
`perform high-quality imaging; 158 MRI sites were
`approved. Conventional or fast spin echo sequences (TR
`2200–2800, TE 15–50/80–120, 3 mm slice thickness and
`44 contiguous axial slices) were used to obtain proton
`density and T2-weighted images. T1-weighted images
`(TR 600–650, TE 10–20, 3 mm slice thickness and
`44 axial slices) were obtained 5 min after the injection of
`0·1 mmol/kg of gadolinium chelates. A series of axial,
`coronal, and sagittal images was obtained to create an
`axial
`reference scan
`for
`the subsequent careful
`repositioning of each patient at the follow-up session.
`Image quality was reviewed centrally according to
`predetermined criteria.
`Identification of enhancing
`lesions, high-signal intensity lesions on T2-weighted
`images, and hypointense
`lesions on T1-weighted
`enhanced images was done by consensus of two
`experienced observers. Trained
`technicians
`then
`outlined
`the
`lesions using a semi-automated
`segmentation technique based on local thresholding,
`with reference to the marked hardcopies.15 Brain atrophy
`was measured as previously described.16
`
`Statistical analysis
`The power of the trial was calculated on the basis of a
`simulation study by use of an SAS random number
`generator with assumptions that a patient on placebo
`would have a relapse rate of  i and be randomly selected
`from an exponential distribution with =  i/n
`representing
`the use of
`the negative binomial
`distribution with r=1. The expected annual placebo
`relapse rate ( ) for the study was 0·90. The simulation
`study was adjusted for two interim analyses according to
`Lan and DeMet’s correction for type I error, leaving final
`analysis at an alpha level of 0·0428 for the power
`estimation. Adjustment
`for
`two contrasts (5 mg
`glatiramer acetate vs placebo and 50 mg glatiramer
`
`acetate vs placebo), testing according to Hochberg’s
`modification to Bonferroni’s method, based on two-
`tailed
`tests, was also
`taken
`into account. Power
`assessment suggested that for a projected treatment
`effect of 30% or more for the 50 mg glatiramer acetate
`cohort and of 10% or more for the 5 mg glatiramer
`acetate group, a 56 week study enrolling 1275 patients
`would provide 91% power.
`The main statistical analysis was based on the outcome
`of two contrasts (5 mg glatiramer acetate vs placebo and
`50 mg vs placebo) derived from the baseline-adjusted,
`exposure-weighted, quasi-likelihood
`(over-dispersed)
`poisson regression (SAS Proc GENMOD version 9.1.3).
`This model was predefined for the analysis of the
`primary endpoint, reflecting our previous experience
`with relapse count data with a variance larger than the
`mean rate.4 Baseline EDSS score, number of relapses in
`the previous year, age, and sex were predefined in the
`statistical analysis plan as covariates and thus were
`included in the analysis model. Study centres were
`pooled into countries that were also included in the
`model as prespecified in the statistical analysis plan. The
`country-by-treatment interaction term was tested, at
`alpha level of 0·10, with the –2 log likelihood ratio test.
`Since
`the
`interaction
`term was not statistically
`significant (p 0·10), it was not included in the model.
`
`Role of the funding source
`The study was fully sponsored by Teva Pharmaceutical
`Industries. Study design, conduct, and analysis were run
`
`1912 patients screened
`
`1651 enrolled
`
`261 ineligible
`
`7 excluded
` 6 did not receive study drug
` 1 randomised in error
`
`1644 randomised
`
`543 assigned 50 mg oral
` glatiramer acetate
`
`553 assigned 5 mg oral
` glatiramer acetate
`
`548 assigned placebo
`
`37 withdrew
` prematurely
` 4 had an adverse
` experience
` 2 lost to follow-up
` 24 withdrawn by
` patient or
` investigator
` 4 were pregnant
` 3 other
`
`41 withdrew
` prematurely
` 2 had an adverse
` experience
` 2 lost to follow-up
` 26 withdrawn by
` patient or
` investigator
` 1 was pregnant
` 10 other
`
`42 withdrew
` prematurely
` 6 had an adverse
` experience
` 1 died
` 8 lost to follow-up
` 19 withdrawn by
` patient or
` investigator
` 4 were pregnant
` 4 other
`
`506 completed the study
`
`512 completed the study
`
`506 completed the study
`
`Figure 1:Trial profile
`
`http://neurology.thelancet.com Published online January 20, 2006 DOI:10.1016/S1474-4422(06)70327-1
`
`3
`
`Page 3 of 8
`
`YEDA EXHIBIT NO. 2018
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Articles
`
` years
`
` duration,
` 2-year
` 1-year
`
` index
`
`Age,
`Women
`Disease
`Prior
`Prior
`EDSS
`Ambulation
` steroid
`Past
` interferon-beta
`Past
` with
`Patients
` of
`Number
`Enhancing lesion volume, mm3
`T2 lesion volume, mL
`T1
`Central
`
` hypointense
` brain
`
`50 mg glatiramer acetate
`36·8
` (75%)412
`
`406
`
`5 mg glatiramer acetate Placebo
` (7·3)36·1
` (75%)401
`
` years
` relapse
` relapse
`
`7·9
`
` rate
` rate
`
`2·3
`
` (1·1)2·2
`0·8
`
` (1·1)2·3
` (0·8)0·8
`
`
`1·5
`
` use
`
` use
` enhancement
` enhancing
`
`328
`
`49
`
`
`
` lesions
`
`285
`13·5 (13·0)
` lesion
` volume,
`
` (1073)329
`15·1 (15·5)
` volume,
` mL
`
`258
` at
`
` (807)294
`14·6 (14·4)
` mL
`306
`
`Data are mean (SD) or number (%).
`
`Table 1: Baseline characteristics of the intention-to-treat cohort
`
` (1·2)
`
`actually enrolled. The increase in the number of patients
`enrolled was not driven by any statistical consideration,
` (8·0)36·6
` (7·7)
`but reflected the fast recruitment rate (all patients were
` (73%)
`enrolled in 6 months) and the enthusiasm of the site
` (6·1)7·4
` (6·2)7·7
` (6·2)
`investigators for an oral treatment for multiple sclerosis.
`2·1
` (1·1)2·2
` (1·2)2·2
` (0·7)1·5
` (0·7)1·5
` (0·8)
`15 of the study sites enrolled 18 or more patients. The
` (1·2)
`baseline demographics of the intention-to-treat cohort
` (0·8)0·8
` (0·9)
`are provided in table 1. 120 patients withdrew from the
` (60%)330
` (60%)323
` (59%)
`study prematurely (69 based on
`the patient’s or
` (9%)39
` (7%)49
` (9%)
` (49%)270
` (51%)251
` (47%)
`investigator’s decision, 12 related to adverse events, 12
` baseline
`2·03
` (5·23)2·56
` (5·86)2·24
`lost to follow-up, nine because of pregnancy, one death
` (871)
`from pneumococcal meningitis, and 17 for other
`reasons). Median exposure to the study drug and time in
`2·06
` (3·50)2·33
` (4·43)2·25
` (3·65)
` (34)304
` (24)305
` (25)
`the study were closely similar for all three treatment
`groups (data not shown).
`The total number of confirmed relapses did not differ
`between the two active treatment groups and the
`placebo-treated patients (figure 2). The mean numbers
`of relapses were 0·54, 0·60, and 0·61 for the 50 mg
`glatiramer acetate, 5 mg glatiramer acetate, and placebo
`groups, respectively. The median values were 0 for all
`study groups. The rate ratio for the groups treated with
`50 mg glatiramer acetate, relative to placebo, was 0·92
`(95% CI 0·77–1·08, p=0·30) and for the 5 mg glatiramer
`acetate group, relative to placebo, was 0·98 (0·83–1·15,
`p=0·76). Post-study power reassessment accounting for
`the number of patients entered and the observed relapse
`rate remained at 91% for a 30% treatment effect and was
`43% for a 15% treatment effect. The number and
`proportions of patients who were relapse free, as well as
`the entire relapse distributions did not differ between
`treatment groups (figure 3). There was no difference in
`the time to first confirmed relapse (data not shown). The
`number of unconfirmed relapses was similar between
`the three cohorts (0·74, 0·75, and 0·78 for 50 mg
`glatiramer acetate, 5 mg glatiramer acetate, and placebo
`groups, respectively). The mean change in EDSS from
`baseline to termination visit was similar between the
`treatment groups (–0·03, 0·00, and 0·04, respectively).
`Ambulation index changed little over the course of the
`trial for the treatment groups (0·07, 0·04, 0·08). There
`were no differences for any other secondary or tertiary
`clinical outcome (data not shown).
`Baseline MRI data were available and adequate for
`analysis of 1590 patients; 1429 patients had adequate
`termination imaging. Paired imaging data were available
`for analysis for 1397 patients, or 85% of the intention-to-
`treat cohort. The mean number of distinct
`enhancements identified on MRI at study exit did not
`differ between the treatment groups (table 2). The rate
`ratio indicated no benefit for 50 mg glatiramer acetate
`treatment over that of placebo for both the intention-
`to-treat analysis and for the cohort of patients with active
`scans at baseline (rate ratio=1·1, 95% CI 0·9–1·35
`and 1·03, 0·81–1·32, respectively). No significant
`differences emerged for any of the other MRI disease
`measures for the entire cohort with both baseline and
`
`under the supervision of an ad-hoc steering committee,
`made up of independent clinicians and scientists. An
`independent data safety monitoring committee was
`responsible for monitoring safety, the two interim
`analyses, and overseeing the overall progress and
`integrity of the study. The present manuscript was
`drafted and finalised independently of the sponsor. The
`funding source had no role in study design, data
`analysis, data interpretation, or writing of the report. The
`corresponding author had full access to all the data in
`the study and had final responsibility for the decision to
`submit for publication.
`Results
`A total of 1644 patients were included in the intention-
`to-treat cohort (figure 1). The study was planned to enrol
`1275 patients—ie, much fewer than those who were
`
`450
`
`Placebo
`5 mg glatiramer acetate
`50 mg glatiramer acetate
`
`0·7
`
`0·6
`
`0·5
`
`0·4
`
`0·3
`
`0·2
`
`0·1
`
`Cumulative mean number of relapses
`
`0
`
`0
`
`50
`
`100
`
`150
`
`200
`250
`Days in study
`
`300
`
`350
`
`400
`
`Figure 2: Mean cumulative number of confirmed relapses during the 56-week trial duration, displayed as a
`function of the number of days the patients in each group were in the study
`
`4
`
`http://neurology.thelancet.com Published online January 20, 2006 DOI:10.1016/S1474-4422(06)70327-1
`
`Page 4 of 8
`
`YEDA EXHIBIT NO. 2018
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Articles
`
`Placebo
`5 mg glatiramer acetate
`50 mg glatiramer acetate
`
`0
`
`1
`
`2
`
`3
`Number of relapses
`
`4
`
`5
`
`6
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Patients
`
`Figure 3: Total number relapses during the trial, by treatment group
`
`Disappointingly, the present double-blind, placebo-
`controlled, randomised, phase III trial of two doses of
`glatiramer acetate formulated as enteric-coated tablets
`yielded overall negative results for both clinical and MRI
`measures of multiple-sclerosis-related disease activity
`and irreversible tissue damage. Taking into account the
`sensitivity of the outcome measures used and the
`number of patients treated in the present trial, the lack
`of an effect seems to be a credible result. There are
`several possible explanations for such a result. First, trial
`primary outcome measure power calculations were
`based on an expected frequency of relapse that was
`
`50 mg glatiramer acetate 5 mg glatiramer acetate Placebo
` number
`1·78
` (4·06)1·82
` enhancement
`206
` (44%)200
` (1175·2)–97·9
` (759·3)–89·4
`
`
`
` lesion
`Enhancing
` with
`Patients
`Change in enhancing lesion volume, mm3 –12·6
`New
` T2
` lesions
`792·4
`Change in T2 lesion volume, mm3
`New
` T1
` hypointense
`Change
` in
` brain
`
` (3205·2)772·7
`
`6·5
`
` lesions
`
` (10·6)7·9
` (3639·8)782·22
`
` (4320·7)
`
`1·6
`
` volume,
`
` mL
`
`–7·5
`
`Data are mean (SD) or number (%).
`
`Table 2: MRI findings at termination or change from baseline in the intention-to-treat cohort
`
`Any
`Cardiovascular
`Gastrointestinal
`Endocrine
`Haematic
`Metabolic
`Musculoskeletal
`Nervous
`Respiratory
`Skin
`Special
`Urogenital
`
` adverse
`
`50 mg glatiramer acetate 5 mg glatiramer acetate Placebo
` event
`456
` (84%)462
`
` system
` system
` system
` and
` and
`
` system
`
`
`
` system
` system
`
` senses
` system
`
`61
`182
`
`5
`
` lymphatic
` nutritional
`94
`198
`136
`81
`75
`123
`
` (11%)53
` (34%)175
` (1%)3
` system
` disorders
` (17%)97
` (37%)211
` (25%)128
` (15%)88
` (14%)69
` (23%)127
`
` (10%)63
` (32%)173
` (1%)5
`
`15
`40
`
` (18%)97
` (38%)203
` (23%)126
` (16%)91
` (13%)70
` (23%)119
`
`Table 3: Number of adverse events, by body systems and treatment groups
`
`termination imaging (table 2), or for the subcohort of
`subjects who underwent bimonthly imaging (data not
`shown).
`Most study patients reported one or more adverse
`events over the course of the study (table 3). The
`proportion of patients in any category of recorded events
`did not differ between the three study groups. The most
`commonly reported events (experienced at least once by
`at least 5% of any treatment cohort) in decreasing order
`of occurrence were infection of any type, headache,
`asthenia,
`pain,
`depression,
`accidental
`injury,
`paraesthesia, nausea, pharyngitis, sleep disorder,
`abdominal pain, arthralgia, back pain, urinary tract
`infection, diarrhoea, sinusitis, influenza syndrome,
`constipation, anxiety, and dyspepsia. Abnormal vital
`signs were infrequently encountered and were equally
`distributed among the study groups. No changes in
`laboratory values were reported in the group data.
`Discussion
`that parenterally
`Previous studies have shown
`administered glatiramer acetate reduces clinical (relapse
`rate)1–4,6 and MRI (formation of active lesions) 4 markers
`of inflammation in patients with relapsing-remitting
`multiple sclerosis. Data from the MRI-monitored trial, 4
`prolonged observation of patients enrolled in the US
`trial,3 and meta-analysis of all existing trials 6 have also
`identified a significant, albeit modest, effect of injected
`glatiramer acetate on MRI (formation of black holes and
`development of brain atrophy) 5,7 markers of irreversible
`tissue loss. On the basis of these findings and on the
`drug’s safety profile, 1–4 glatiramer acetate has become
`one of several approved treatments for relapsing-
`remitting multiple sclerosis; the other being three
`interferon-beta
`preparations,
`natalizumab
`(use
`suspended) and mitoxantrone, which are all given
`parenterally. At present, more than 90 000 patients
`worldwide have been treated with injected glatiramer
`acetate. Because the drug must be subcutaneously
`administered on a daily basis and in view of the fact that
`multiple sclerosis is a lifelong chronic disorder, the
`availability of effective formulations of glatiramer acetate
`for oral administration would represent an important
`advance in the treatment of multiple sclerosis. Orally
`active treatment would decrease patient discomfort and
`avoid any local and systemic injection site reactions
`common to all available treatments. This advance should
`result in increased patient acceptance and compliance
`with
`treatment and, possibly,
`increased
`treatment
`efficacy. Admittedly, this study was undertaken without
`previous phase II trials on oral glatiramer acetate.
`Nevertheless, because such trials already existed for the
`injectable preparation and because these trials are
`mainly done to gain information about drug safety, it
`was felt that such trials would have delayed the
`availability of an oral preparation for the treatment of
`multiple sclerosis.
`
`http://neurology.thelancet.com Published online January 20, 2006 DOI:10.1016/S1474-4422(06)70327-1
`
`5
`
`Page 5 of 8
`
`YEDA EXHIBIT NO. 2018
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Articles
`
`about 30% higher than that actually observed in the
`placebo group. However, as shown by the post-hoc
`power assessment, this is unlikely to have substantially
`affected the outcome of the trial. Second, the oral
`administration by itself might be the reason for the
`absence of treatment efficacy. However, preclinical data
`convincingly showed that glatiramer-acetate specific
`T-helper 2 and T-helper 3 cells isolated from mesenteric
`lymph nodes of mice treated with glatiramer acetate can
`migrate to the target organ and suppress ongoing
`inflammatory reactions
`in an antigen non-specific
`fashion.17 Therefore, a species-specific difference in the
`gut-associated immune response could be a plausible
`explanation of oral glatiramer acetate inefficacy in
`human beings. Third, the 5 mg and 50 mg enteric-
`coated tablets of glatiramer acetate used might not be
`the right doses or formulations for treating multiple
`sclerosis. The doses selected
`for
`this
`trial were
`extrapolated
`from studies
`in experimental allergic
`encephalomyelitis. The results constitute additional
`evidence that experimental allergic encephalomyelitis is
`not an adequate model for multiple sclerosis 18 and call
`for more rigorous dose-finding trials in people affected
`by multiple sclerosis.
`The favourable safety profile of both doses of oral
`glatiramer acetate observed in the present study is not
`surprising. Previous experience with 34 patients with
`multiple sclerosis treated orally with 20 mg, 100 mg, and
`300 mg glatiramer acetate in enteric-coated capsules
`daily for 10 days in a double-blind, placebo-controlled,
`randomised phase I trial showed no safety or tolerability
`issues at any of the tested doses (unpublished). The
`favourable safety profile of oral glatiramer acetate is
`consistent with data from previous trials1–4 and post-
`marketing experience of parenterally administered
`glatiramer acetate.
`In conclusion, 5 mg and 50 mg glatiramer acetate
`administered orally on a daily basis did not demonstrate
`an effect on relapse rate or on other clinical and MRI
`parameters of disease activity and burden in a large
`group of patients with relapsing-remitting multiple
`sclerosis. The study drug was safe and well tolerated.
`Authors’ contributions
`MF, JSW, GC, and the Clinical and MRI Steering Committees designed
`the protocol, collected the data, and, together with the Organising
`Committee and the Data Safety Monitoring Committee, coordinated the
`study; the Data Safety Monitoring Committee undertook independent
`outcome assessment; MF, JSW, GC, the Clinical and MRI Steering
`Committees, and the Data Safety Monitoring Committee did the
`statistical analysis; and MF, JSW, GC, and the Clinical and MRI
`Steering Committees wrote and edited the paper.
`Conflicts of interest
`Unless otherwise stated, the trial investigators and members of the
`various study committees were not employed by Teva Pharmaceutical
`Industries and were not holders of equity interest or patent rights. Apart
`from Y Stark, D Ladkani, L Pardo, W Mulchay, E Pieri, R Kreitman,
`M Pantev, M Gurevich, and members of the organising committee and
`employees of Teva Pharmaceutical Industries, all members of the
`Clinical Steering Committee, MRI Steering Committee, and
`academicians on the other committees were reimbursed for their
`
`specific services on a contractual basis by Teva Pharmaceutical
`Industries. M Filippi, J S Wolinsky, and G Comi also received travel
`grants from the company.
`The CORAL study group
`Argentina: Buenos Aires, Instituto Italiano (E Cristiano, L Patrucco,
`M Pietrani, F Ogresta, C Molina, M Franze, E Jaime); Buenos Aires,
`Hospital Ramos Mejia (D O Garcea, F Caceres, F Meli, C Romero,
`R Blessing, L Garofalo); Buenos Aires, Hospital Britanico (A Carra,
`P Onaha, M A Martinez, J Rogondino, M Bianco). Australia: Adelaide,
`Queen Elizabeth Hospital (K Boundy, G Purdie, C Pozza, B Pirgousis);
`Melbourne, Royal Melbourne Hospital (J King, J Joubert, B Tressi,
`P Mitchell, J Sathasivam); Perth, Sir Charles Gardiner Hospital
`(W Carroll, A Kenmode, S Davis, M Fallon, C Harris); Sydney, Royal
`Pince Alfred Hospital (J Pollard, J Spies, G Parker, H Lackey). Austria:
`Innsbruck, Universitaetsklinik (T Berger, F Deisenhammer, E Dilitz,
`S Felber); St Poelten, Krankenhaus der Landeshaptstadt (U Baumhackl,
`C Franta, J Retzl, E Salomonowitz); Vienna, Donauspital im SMZ-Ost
`(W Kristoferitsch, G Wimmer, R Grass, M Schlederer, M Urban).
`Belgium: Brussels, University Clinic St Luc (C J M Sindic, S Gaffette,
`G Cosnard, Th P J Duprez, E Ligot, T Munier); Charleroi, Hospital Civil
`de Charleroi (P Seeldrayers, Th Piette, D Baleriaux, P David, Y Dusart,
`C Tragne, Th Metens); Diepenbeek, L Willems Institute (R H J Medaer,
`E Vanrose, Y Palmers, G Gelin, P Baudouin, P Caluwaerts); Edegem,
`University Hospital Antwerp (I Nagels, P Cras, P M Parizel, P Deferme,
`K Swerts); Melsbroek, National MS Center (D ‘Hooghe, G Wilms).
`Canada: Calgary, Foothills Hospital MS Center (L Metz, D Patry,
`M Yeong, B Yacyshyn); Greenfield P