Ziemssen and Gilgun-Sherki BMC Neurology (2015) 15:189
`DOI 10.1186/s12883-015-0448-4
`
`Open Access
`
`R ES EAR CH A R T I C LE
`Sub-analysis of geographical variations in
`the 2-year observational COPTIMIZE trial of
`patients with relapsing–remitting multiple
`sclerosis converting to glatiramer acetate
`Tjalf Ziemssen1* and Yossi Gilgun-Sherki2
`
`Abstract
`Background: Studies suggest that patients with relapsing–remitting multiple sclerosis (RRMS) who fail to benefit from
`a disease-modifying treatment (DMT) may benefit from converting to another DMT class. COPTIMIZE was a 24-month
`observational study designed to assess the disease course of patients converting to glatiramer acetate (GA) 20 mg daily
`from another DMT and the association of disease characteristics and reasons for converting. This sub-analysis was to
`determine if any findings varied by three geographic locations: Latin America (LA), Canada and Western Europe (CWE),
`and Eastern Europe (EE).
`Methods: A total of 668 patients were included (263 LA, 248 CWE, 157 EE) in an analysis of annualized relapse rate (ARR)
`and annualized rate of deterioration (ARD), as well as secondary endpoints including reason for DMT switch and changes
`in disability and fatigue scores. Repeated-measures analysis of variance and log transformation were used to analyze ARR
`and ARD, whereas the Wilcoxon signed rank test was used for secondary endpoints.
`Results: The sub-analysis of treatment outcomes stratified by region showed that Latin American patients had higher
`ARR before conversion to GA compared with patients from the other two areas and subsequently experienced the
`largest reduction in ARR. Latin American patients also had higher baseline rates of comorbidities and relapses with
`incomplete remissions and improved more than those in the other two regions based on measures of fatigue, quality of
`life, depression, and cognition scores. Latin American patients also generally had a better perception of the benefits
`associated with their conversion to GA in terms of efficacy and adverse events.
`Conclusions: These findings indicate that, in RRMS patients, converting to GA is associated with positive treatment
`outcomes regardless of geographic location. However, the reasons for converting and the type and degree of any
`associated benefits appear to vary depending on various factors, including patients’ geographical location.
`Keywords: Multiple sclerosis, RRMS, Glatiramer acetate, Demographics
`
`Background
`Multiple sclerosis (MS) is a chronic relapsing disorder of
`the central nervous system characterized by inflamma-
`tion, multifocal demyelination, and neuronal and axonal
`damage [1]. The majority of MS patients initially present
`with relapsing–remitting MS (RRMS)
`that
`frequently
`
`* Correspondence: tjalf.ziemssen@uniklinikum-dresden.de
`1Center of Clinical Neuroscience, Neurological University Clinic, University
`Clinic Carl Gustav Carus, University of Technology Dresden, Fetscherstraße
`74, D-01307 Dresden, Germany
`Full list of author information is available at the end of the article
`
`develops to a progressive disease course [1]. The preva-
`lence of MS varies according to geographic location from
`10 to 20 per 100,000 in Central and South America to >30
`per 100,000 in northern Europe and North America [2].
`Immunomodulating disease-modifying therapies (DMTs)
`have been shown to improve multiple measures of disease
`activity in RRMS patients, including the annualized relapse
`rate (ARR), proportion of relapse-free individuals, and ac-
`cumulation of T2 lesion burden [3–5]. However, these
`agents are only partially effective in controlling disease pro-
`gression; studies have reported treatment interruption or
`
`© 2015 Ziemssen and Gilgun-Sherki. Open Access This article is distributed under the terms of the Creative Commons
`Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution,
`and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link
`to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication
`waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise
`stated.
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`Ziemssen and Gilgun-Sherki BMC Neurology (2015) 15:189
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`discontinuation because of lack of tolerability, progression
`of disability, or inadequate clinical response [6]. Addition-
`ally, the development of neutralizing antibodies, specifically
`with interferon β products (IFNs) and natalizumab [7], can
`interfere with the biologic response [8].
`Converting to another DMT class represents one treat-
`ment strategy for MS patients with an inadequate re-
`sponse to first-line treatments or intolerant side effects
`[9]. Expert guidance on the specific steps of a conversion
`has been reported [10]; however, the lack of information
`on outcomes in different populations [11] results in lim-
`ited guidance on regional patient considerations.
`The COPTIMIZE study was designed to monitor clin-
`ical outcomes after converting from failing or ineffective
`DMT therapy for RRMS to glatiramer acetate (GA) in a
`prospective way. GA is approved in 57 countries as a
`20 mg daily subcutaneous (s.c.) injection for reducing re-
`lapse frequency in patients with RRMS. It has long-term
`efficacy and safety data, with the longest continuous
`treatment exposure of more than 20 years [12, 13]. The
`primary results of COPTIMIZE, presented elsewhere
`[14], indicate that a conversion to GA is associated with
`positive treatment outcomes and that the benefits vary
`depending on patients’ reasons for changing. The pri-
`mary objective of the present sub-analysis is to deter-
`mine whether benefits associated with converting to GA
`were affected by therapeutic strategies and patient selec-
`tion in different geographic locations: Latin America
`(LA), Canada and Western Europe (CWE), and Eastern
`Europe (EE).
`
`Methods
`Study design
`Study design, patient eligibility criteria, and conduct of
`the COPTIMIZE have been previously reported [14].
`Briefly, this post-hoc subgroup analysis attempted to de-
`scribe any variation in results that might exist between
`three predefined geographical areas: LA (Argentina, Brazil,
`Chile, Mexico, Venezuela), CWE (Belgium, Canada,
`Denmark, France, Greece, Ireland, Portugal, Netherlands,
`Norway, Sweden), and EE (Hungary, Romania, Slovakia).
`Countries were grouped into regions based on similarity
`of healthcare systems, physician approaches [15], available
`treatment options [10, 16], and epidemiological character-
`istics of the population (disease prevalence, demographics,
`etc.) [2]. All countries investigated in this observational
`study reported the use of IFN-β and GA at baseline, with
`no anticipated systematic differences between regions.
`This study was conducted in accordance with the 18th
`World Medical Assembly (Helsinki) recommendations
`and amendments, as well as guidelines for Good Epidemi-
`ology Practice. The study protocol was approved by the
`institutional review boards and independent ethics com-
`mittees at all participating study locations
`in each
`
`individual country; each site ensured all necessary regula-
`tory submissions in accordance with local regulations in-
`cluding local data protection regulations. All patients
`provided informed, written consent according to local in-
`dependent review board ruling.
`
`Study endpoints
`The primary objective was to assess the disease course
`in RRMS patients converting from IFN treatment to GA
`as measured by the primary endpoints of ARR and annu-
`alized rate of deterioration (ARD) (confirmed progression
`of Expanded Disability Status Scale [EDSS]/worsening
`mobility scores). Secondary data collected included rea-
`sons for DMT conversion, characteristics of patients fail-
`ing to benefit from previous DMT, and change in EDSS
`and modified fatigue impact scale (MFIS) scores. Also re-
`corded were quality of life (QoL) changes following GA
`conversion as measured by the Functional Assessment of
`Multiple Sclerosis (FAMS), cognition changes as evaluated
`by the Paced Auditory Serial Addition Test (PASAT), de-
`pression as measured by Centre for Epidemiologic Studies
`Depression (CES-D) scale, and change in adverse events
`(AEs) following the conversion.
`
`Statistical analyses
`Statistical analyses of parameters in this observational
`study required comparison of at least two endpoint mea-
`sures, pre- and post-GA conversion, with data represented
`by descriptive procedures and figures, if necessary. Adjust-
`ment for missing data was not required to maintain statis-
`tical
`integrity of
`the analyses, and annualized rates
`(primary endpoints) were calculated for each subject using
`all the available data. Other parameters, which provide
`additional data for evaluation of the patient status prior to
`and following conversion to GA, were reported in a non-
`obligatory manner. Tests of significance (signal rank test
`and binominal test) were used to measure changes in effi-
`cacy parameters from baseline to final examination. ARR
`and ARD pre- and post-conversion were analyzed using
`repeated measures analysis of covariance using the max-
`imum likelihood ratio. Log transformation was imple-
`mented to the ARR and ARD to establish if there was a
`significant deviation from normality (i.e., P < .001 using
`the Shapiro-Wilk test). The Wilcoxon signed rank test
`was used within groups for EDSS, MFIS, FAMS, PASAT,
`and CES-D.
`
`Results
`Patient disposition
`Overall, 672 patients from 148 centers across 19 coun-
`tries were enrolled, with 668 patients included in the
`analysis (excluding four patients from Taiwan): 263 LA,
`248 CWE, and 157 EE patients (Table 1). Patient charac-
`teristics were comparable at baseline between regions,
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`
`Table 1 Baseline patient demographics, disease characteristics, and DMT history
`LA (n = 263)
`Characteristics
`Female gender, n (%)
`189 (71.9)
`Mean age, years (± SD)
`Patients with comorbidities at recruitment, n (%)
`Depression
`
`40.1 (10.1)
`
`27 (10.3)
`
`13 (4.9)
`
`Anxiety
`
`Hypertension
`Patients with concomitant therapies at time of recruitment, n (%)
`Psychoanaleptics
`
`Antiepileptics
`
`Thyroid therapy
`Mean disease duration since onset, months (± SD)a
`Mean disease duration since diagnosis, months (± SD)b
`Mean ARR, events/year (± SD)c
`Patients in ARR range, n (%*)
`0.00–1.25
`1.25–3.25
`>3.25
`
`Data unavailable
`Clinical type of MS, n (%d)
`RRMS with incomplete remissions
`
`RRMS with complete remission
`
`2 (0.8)
`
`1 (0.4)
`
`24 (9.1)
`
`14 (5.3)
`
`6 (2.3)
`
`3 (1.1)
`
`98.0 (82.9)
`
`68.9 (59.6)
`
`1.0 (0.8)
`
`166 (67.5)
`
`78 (31.7)
`
`2 (0.8)
`
`17
`
`171 (67.6)
`
`80 (31.6)
`
`CWE (n = 248)
`175 (70.6)
`
`43.0 (10.2)
`
`19 (7.7)
`
`6 (2.4)
`
`1 (0.4)
`
`4 (1.6)
`
`15 (6.1)
`
`5 (2.0)
`
`2 (0.8)
`
`3 (1.2)
`
`100.1 (84.4)
`
`72.1 (70.7)
`
`0.8 (0.6)
`
`193 (84.6)
`
`35 (15.4)
`
`0 (0.0)
`
`20
`
`117 (47.6)
`
`122 (49.6)
`
`EE (n = 157)
`108 (68.8)
`
`34.7 (8.4)
`
`8 (5.1)
`
`1 (0.6)
`
`1 (0.6)
`
`2 (1.3)
`
`7 (4.5)
`
`1 (0.6)
`
`1 (0.6)
`
`N/A
`
`92.3 (63.9)
`
`67.9 (48.5)
`
`0.7 (0.5)
`
`130 (88.4)
`
`17 (11.6)
`
`0 (0.0)
`
`10
`
`91 (59.1)
`
`62 (40.3)
`
`Clinically isolated syndrome
`
`Other
`
`Data unavailable
`Diagnosed with MS by criteria, n (%d)
`McDonald
`
`Poser
`
`Data unavailable
`Mobility, n (%d)
`Asymptomatic
`
`Able to walk unaided for >500 m
`
`Able to walk unaided for <500 m
`
`Walking with bilateral support
`
`Walking with unilateral support
`
`Need of a wheelchair outdoors
`
`Data unavailable
`Mean EDSS score (± SD)e
`Mean CES-D score (0–60) (± SD)f
`Mean MFIS score (0–84) (± SD)g
`Mean FAMS score (0–176) (± SD)h
`Mean PASAT score (0–60) (± SD)i
`
`0 (0.0)
`
`2 (0.8)
`
`10
`
`217 (83.8)
`
`42 (16.2)
`
`4
`
`45 (19.8)
`
`96 (42.3)
`
`30 (13.2)
`
`13 (5.7)
`
`33 (14.5)
`
`10 (4.4)
`
`36
`
`3.5 (2.2)
`
`16.0 (11.7)
`
`32.3 (19.7)
`
`109.4 (37.8)
`
`35.6 (13.6)
`
`0 (0.0)
`
`7 (2.8)
`
`2
`
`194 (78.5)
`
`53 (21.5)
`
`1
`
`46 (20.0)
`
`126 (54.8)
`
`27 (11.7)
`
`9 (3.9)
`
`18 (7.8)
`
`4 (1.7)
`
`18
`
`2.8 (1.9)
`
`16.0 (10.3)
`
`31.4 (19.1)
`
`100.8 (34.3)
`
`36.7 (15.7)
`
`1 (0.6)
`
`0 (0.0)
`
`3
`
`143 (92.3)
`
`12 (7.7)
`
`2
`
`20 (14.9)
`
`112 (83.6)
`
`2 (1.5)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`23
`
`2.6 (1.0)
`
`20.6 (19.5)
`
`33.7 (27.9)
`
`77.7 (59.4)
`
`51.8 (5.9)
`
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`Table 1 Baseline patient demographics, disease characteristics, and DMT history (Continued)
`Mean observation duration, months (± SD)j
`
`20.5 (6.3)
`
`18.6 (7.7)
`
`19.2 (7.8)
`
`Number of DMT classes used (%) (converters only)
`
`1
`
`2
`
`3
`
`Non-converters
`Previous type and mode of IFN-β used, %k
`IFN-β-1a (i.m.)
`IFN-β-1b (s.c.)
`IFN-β-1a (s.c.)
`Reason for conversion to GA, n (%)l
`Lack of previous DMT efficacy
`
`Presence of neutralizing antibodies
`
`Intolerable adverse events associated with previous DMT
`Flu–like symptoms
`Subjective
`
`Skin reactions
`
`Blood work
`
`Others
`
`Not specified
`
`Other
`
`Non-converters
`Discontinuation of GA, n (%)
`Perceived lack of efficacy by physician
`
`Perceived lack of efficacy by patient
`
`Adverse events
`
`Lost to follow-up
`
`206 (85.5)
`
`32 (13.3)
`
`3 (1.2)
`
`22
`
`30.3
`
`30.3
`
`35.5
`
`171 (71.0)
`
`1 (0.4)
`
`98 (40.7)
`
`67 (27.8)
`
`29 (12.0)
`
`15 (6.2)
`
`7 (2.9)
`
`21 (8.7)
`
`1 (0.4)
`
`8 (3.3)
`
`22
`
`66 (25.1)
`
`19 (7.2)
`
`7 (2.7)
`
`9 (3.4)
`
`14 (5.3)
`
`201 (83.4)
`
`38 (15.8)
`
`2 (0.8)
`
`7
`
`36.0
`
`25.9
`
`30.7
`
`78 (32.4)
`
`44 (18.3)
`
`132 (54.8)
`
`73 (30.3)
`
`37 (15.4)
`
`14 (5.8)
`
`18 (7.5)
`
`39 (16.2)
`
`1 (0.4)
`
`21 (8.7)
`
`7
`
`77 (31.1)
`
`7 (2.8)
`
`14 (5.7)
`
`17 (6.9)
`
`24 (9.7)
`
`143 (92.9)
`
`10 (6.5)
`
`1 (0.6)
`
`3
`
`47.4
`
`30.5
`
`21.4
`
`92 (59.7)
`
`2 (1.3)
`
`55 (35.7)
`
`40 (26.0)
`
`17 (11.0)
`
`20 (13.0)
`
`4 (2.6)
`
`4 (2.6)
`
`0 (0.0)
`
`36 (23.4)
`
`3
`
`30 (19.1)
`
`16 (10.2)
`
`6 (3.8)
`
`4 (2.5)
`
`2 (1.3)
`
`15 (5.7)
`
`8 (3.2)
`
`Other
`aMissing data in 24 LA, 28 CWE, and 5 EE patients
`bMissing data in 15 LA, 21 CWE, and 4 EE patients
`cMissing data in 7 LA, 2 CWE, and 3 EE patients
`dAdjusted percentage of patients with data available
`eMissing data in 55 LA, 9 CWE, and 8 EE patients
`fMissing data in 116 LA, 103 CWE, and 150 EE patients
`gMissing data in 113 LA, 118 CWE, and 150 EE patients
`hMissing data in 55 LA, 9 CWE, and 8 EE patients
`iMissing data in 197 LA, 103 CWE, and 150 EE patients
`jMissing data in 11 LA, 17 CWE, and 10 EE patients
`kMissing data in 32 LA, 20 CWE, and 3 EE patients
`lAdjusted percentage of patients with data available. Patients were allowed to cite ≥1 reason for conversion to GA. Therefore, the percentage may exceed 100 %
`
`3 (1.9)
`
`excluding EE patients, who were younger and reported
`fewer comorbidities and concomitant medications than
`LA and CWE patients. Baseline disease characteristics
`that were similar across regions (Table 1) included dis-
`ease duration from onset, diagnosis, and mean ARR.
`Distribution of baseline ARR score varied slightly, with
`the majority of patients experiencing between 0 and 1.25
`events/year. LA patients reported the highest disability
`(baseline EDSS) and the highest frequency of RRMS
`with incomplete remissions. At baseline, the majority of
`
`patients had received one previous DMT regimen in one
`class of agents (Table 1). Reports of flu-like symptoms
`were the most common reason for converting to GA.
`The majority of patients in all regions were converted
`from IFN-β therapy.
`
`Annualized relapse rate
`ARR was significantly decreased in all groups following
`the conversion to GA (Fig. 1). LA patients, who had the
`highest baseline ARR rate, also had the greatest ARR
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`Geographic region
`Baseline
`Final follow-up post-switch
`
`1.05
`
`0.86
`
`0.73
`
`0.71
`
`0.32
`
`a
`
`0.34
`
`a
`
`a
`
`0.34
`
`a
`0.24
`
`Overall population Latin America
`(n=625*)
`(n=246)
`
`Canada and
`Western Europe
`(n=228)
`
`Eastern Europe
`(n=147)
`
`1.2
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`Mean ARR, events/year
`
`Fig. 1 Reduction of annualized relapse rate by geographic region. aP < .0001 vs. baseline. *The overall population size does not each the sum of
`the three individual regions due to four patients in Taiwan that excluded from the regional analysis. ARR annualized relapse rate
`
`reduction (1.05 ± 0.78 pre-conversion to 0.34 ± 0.86
`post-conversion; P < .0001, Shapiro-Wilk test). ARR went
`from 0.73 ± 0.58 to 0.34 ± 0.84 (P < .0001)
`in CWE
`patients and 0.71 ± 0.50 to 0.24 ± 0.92 (P < .0001) in
`EE patients.
`
`Disease progression
`In total, 499 patients had ≥1 EDSS assessment after
`baseline examination, with the overall population show-
`ing a significant increase in EDSS score (i.e., progression
`to worse disability) from 2.9 at baseline to 3.02 at final
`follow-up, post-switch (P = .0256). There was a significant
`difference between regions in the degree of change in
`EDSS score while on GA therapy (P = .0230, Wilcoxon
`signed-rank test), driven by a significant increase in CWE
`patients’ EDSS score of 0.26 ± 1.18 (P = .0016). Neither LA
`nor EE patients had significant changes in mean EDSS
`score from baseline. Improved (i.e., numerically lowered)
`EDSS scores were seen in 32.5 %, 24.4 %, and 33.8 % of
`LA, CWE, and EE patients, respectively. There was no
`change from baseline in 35.8 %, 34.9 %, and 41.2 %,
`
`Table 2 MS disease activity over the 2-year study period
`Patients, n (%)
`
`Stable MS (Stage 1)
`Rare exacerbations (≤1 per year, Stage 2a)
`Slow progression (≤0.5 EDSS points per year, Stage 2b)
`Frequent exacerbations (>1 per year, Stage 3a)
`
`Fast progression (>0.5 EDSS points per year, Stage 3b)
`
`Not classified/not available
`
`respectively. Deterioration was reported in 31.8 %, 40.7 %,
`and 25.0 %, respectively.
`
`Disease activity
`Disease activity while receiving GA varied. LA patients re-
`ported the highest incidence of frequent exacerbations
`and of fast progression of MS (Table 2). Fewer LA patients
`reported rarely experiencing exacerbations (27.9 %, vs.
`43.5 % CWE and 66.0 % EE patients).
`
`Change in mobility
`The majority of patients showed no change in mobility
`scores (63.4 %, 62.8 %, and 67.5 % of LA, CWE, and EE
`patients,
`respectively). Mobility scores
`improved in
`17.1 % LA and 18.9 % CWE patients, with a significant
`improvement in 23.0 % of EE patients (P = .0079). Mo-
`bility scores deteriorated in 19.4 %, 18.4 %, and 9.5 % of
`LA, CWE, and EE patients, respectively. Data were miss-
`ing for 47 LA, 52 CWE, and 31 EE patients.
`
`LA
`(n = 251)
`37 (14.7)
`
`70 (27.9)
`
`48 (19.1)
`
`80 (31.9)
`
`11 (4.4)
`
`5 (2.0)
`
`CWE
`(n = 246)
`47 (19.1)
`
`107 (43.5)
`
`35 (14.2)
`
`43 (17.5)
`
`3 (1.2)
`
`11 (4.5)
`
`EE
`(n = 153)
`22 (14.4)
`
`101 (66.0)
`
`6 (3.9)
`
`21 (13.7)
`
`1 (0.7)
`
`2 (1.3)
`
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`Latin America (n=150)
`Canada and WE (n=130)
`Eastern Europe (n=7)
`
`Latin America (n=147)
`Canada and WE (n=145)
`Eastern Europe (n=7)
`
`Latin America (n=20)
`Canada and WE (n=47)
`Eastern Europe (n=5)
`
`52.60
`
`de
`
`41.85
`40.55
`
`51.80
`
`36.72
`35.60
`
`18.14
`17.70
`c
`
`11.43
`
`33.71
`32.33
`31.41
`
`31.85
`
`27.00
`25.40
`a,b
`
`20.57
`16.04
`16.00
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`(Worse)
`
`Mean Scores
`
`(Better)
`
`Baseline
`
`Final
`
`Baseline
`
`Final
`
`Baseline
`
`Final
`
`MFIS
`PASAT
`CES-D
`(Fatigue)
`(Cognition)
`(Depression)
`Fig. 2 Change in fatigue, depression, and cognition scores by geographic region. aP < .0001 for Latin America vs. Canada/Western Europe at final
`follow-up. bP < .0001 for change from baseline. cP < .0001 for change from baseline. dP = .0030 for change from baseline. eP = .0024 for change
`from baseline. CES-D Centre for Epidemiologic Studies Depression, MFIS Modified Fatigue Impact Scale, PASAT Paced Auditory Serial Addition Test,
`WE Western Europe
`
`P < .0001). LA patients reported the lowest percentage of
`“feeling worse” on GA therapy (3.9 %), with EE patients
`reporting the highest percentage (15.2 %), followed by
`CWE patients (6.1 %). There was no change in percep-
`tion of efficacy in 26.2 %, 52.2 % and 42.4 % of LA,
`CWE, and EE patients, respectively (Additional file 1).
`
`Latin America (n=66)
`Canada and Western Europe (n=145)
`Eastern Europe (n=7)
`
`109.44
`100.80
`
`77.71
`
`127.94
`
`a,b
`
`101.42
`
`75.43
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Mean FAMS score
`
`Baseline
`
`Final
`
`QoL
`Fig. 3 Change in quality of life score by geographic region. aP = .0012
`for Latin America vs. Canada/Western Europe at final follow-up.
`bP = .0008 for change from baseline. FAMS Functional Assessment
`of Multiple Sclerosis
`
`Secondary endpoints
`In LA patients, there was a significant improvement in the
`mean difference in MFIS score from baseline (6.9 ± 15.4;
`P < .0001) (Fig. 2). EE patients and CWE patients experi-
`enced a nonsignificant increase from baseline of 6.7 ± 18.2
`and 0.4 ± 13.6, respectively.
`Only LA patients showed a significant change in QoL,
`with an improvement in mean FAMS score of 18.5 ±
`46.5 from baseline (P = .0008). CWE patients had a mean
`FAMS increase of 0.6 ± 20.5, while EE patients showed a
`decrease of 2.3 ± 8.8 (Fig. 3).
`LA patients reported a significant improvement in de-
`pression symptoms, with a decrease in mean CES-D
`score of 4.6 ± 10.9 (P < .0001) (Fig. 2). CWE patients
`showed a numerical increase in mean CES-D score of
`1.7 ± 9.9, while EE patients showed a decrease of 2.4 ±
`10.8. These changes were not statistically significant.
`Patients from all regions showed an improvement in
`mean PASAT (cognition) scores (Fig. 2). LA patients had
`the greatest improvement, with a statistically significant
`mean increase of 6.3 ± 9.1 in PASAT score (P = .0030).
`CWE patients also showed a statistically significant
`mean increase of 3.8 ± 9.6 (P = .0024), while EE patients
`had a smaller mean increase of 0.8 ± 5.3 (NS).
`LA patients reported the highest efficacy with GA than
`the previous drug (70.0 %; P < .0001), followed by EE
`and CWE patients (42.4 % and 41.6 %, respectively; both
`
`MYLAN PHARMS. INC. EXHIBIT 1080 PAGE 6
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`

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`Ziemssen and Gilgun-Sherki BMC Neurology (2015) 15:189
`
`Page 7 of 9
`
`Safety
`AEs reported in all three regions are listed in Table 3.
`Patients from all regions experienced statistically signifi-
`cant improvements in AEs with GA use (P < .0001).
`
`Discussion
`Converting to another class of immunomodulatory ther-
`apy represents one treatment strategy in MS patients
`who fail to respond adequately to first-line treatments
`[10]. However, this strategy may not always be beneficial
`because of geographical variations in treatment regimens
`and therapeutic strategies. For example, GA and IFN-β
`are typically the first-line treatment options in MS treat-
`ment algorithms, regardless of the geographical region
`[11]. However, some LA neurologists prescribe azathio-
`prine because of limited DMT access or because the
`drugs are unavailable on healthcare plans [16, 17]. Ex-
`pert guidance on the specific steps of a conversion have
`begun to be published, suggesting a conversion in ther-
`apy may be considered when there is a high level of
`concern about relapse rates, progression of MS and
`
`magnetic resonance imaging outcomes, a medium
`level of concern about any two factors, or a low level
`of concern about all three factors [10]. The general
`nature of the guidelines is due to inconsistent results
`with converting.
`In this sub-analysis of the COPTIMIZE trial, convert-
`ing to GA was well tolerated, reduced disease progres-
`sion and activity,
`and improved other
`secondary
`endpoints in patients across all three regions to varying
`degrees. LA patients experienced the largest reduction
`in ARR; however, their baseline ARR was much higher
`than CWE and EE patients. Ultimately, all three regions
`reached similar ARR. LA patients had higher baseline
`rates of comorbidities and incomplete previous remis-
`sions than the other two regions, as well as significant
`improvements in QoL, depression, fatigue, and cognition
`scores. They also had a better perception of the benefits
`of a GA conversion in terms of efficacy and AEs than
`CWE and EE patients.
`These discrepancies may be due to differences in
`healthcare standards and environmental factors between
`
`Table 3 Adverse events (AEs)
`Patients, events/patients (%a)
`Most common AEs by preferred term
`
`Dyspnea
`
`Syncope
`
`Injection site reaction
`
`Injection site pain
`
`Injection site induration
`
`Fatigue
`
`Arthralgia
`
`Rash
`
`Anxiety
`
`Most common AE classified by system organ class
`
`General disorders and administration site conditions
`
`Nervous system disorders
`
`Respiratory, thoracic, and mediastinal disorders
`
`Severity of AE, events/patients
`
`Mild
`
`Moderate
`
`Severe
`
`Data unavailable
`Patient-reported assessment of AEs after glatiramer acetate treatmentb
`
`Improved with glatiramer acetate
`
`Same with glatiramer acetate
`
`Worse with glatiramer acetate
`
`Data unavailable
`aPercentage reported as the proportion of patients experiencing events
`bAdjusted percentage of patients with data available
`
`LA (n = 263)
`
`CWE (n = 248)
`
`EE (n = 157)
`
`5/4 (1.5)
`
`2/2 (0.8)
`
`2/2 (0.8)
`
`2/2 (0.8)
`
`1/1 (0.4)
`
`1/1 (0.4)
`
`1/1 (0.4)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`16/13 (4.9)
`
`10/10 (3.8)
`
`7/6 (2.3)
`
`19/12 (4.6)
`
`22/12 (4.6)
`
`13/6 (2.3)
`
`4/2 (0.8)
`
`209 (80.4)
`
`41 (15.8)
`
`10 (3.9)
`
`3
`
`4/3 (1.2)
`
`2/2 (0.8)
`
`8/8 (3.2)
`
`14/10 (4.0)
`
`5/5 (2.0)
`
`3/3 (1.2)
`
`3/3 (1.2)
`
`2/2 (0.8)
`
`1/1 (0.4)
`
`55/32 (12.9)
`
`9/8 (3.2)
`
`4/3 (1.2)
`
`40/28 (11.3)
`
`62/38 (15.3)
`
`14/9 (3.6)
`
`7/5 (2.0)
`
`162 (66.1)
`
`62 (25.3)
`
`21 (8.6)
`
`3
`
`1/1 (0.6)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`2/2 (1.3)
`
`1/1 (0.6)
`
`5/4 (2.6)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`0/0 (0.0)
`
`5/5 (3.2)
`
`5/3 (1.9)
`
`2/2 (1.3)
`
`58 (38.4)
`
`87 (57.6)
`
`6 (4.0)
`
`6
`
`MYLAN PHARMS. INC. EXHIBIT 1080 PAGE 7
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`

`
`Ziemssen and Gilgun-Sherki BMC Neurology (2015) 15:189
`
`Page 8 of 9
`
`Competing interests
`TZ has received speaker honoraria from Almirall, Bayer-Schering, Biogen Idec,
`Genzyme, GSK, Sanofi-Aventis, Merck Serono, MSD, Novartis, and Teva. He
`serves as a consultant for Bayer-Schering, Biogen Idec, Novartis, and Teva,
`and he receives research support from the Deutsche Diabetes Stiftung, Hertie
`Foundation, the Robert Pfleger Foundation, and the Roland Ernst Founda-
`tion. YG-S is an employee of Teva Pharmaceutical Industries.
`
`Authors’ contributions
`TZ and YG-S contributed equally to the development of this manuscript and
`have approved the manuscript for submission.
`
`Authors’ information
`Not applicable.
`
`Acknowledgements
`The Authors would like to thank Rhonda Charles, PhD and Bryan Sepulveda,
`PhD, who provided editorial support with funding from Teva
`Pharmaceuticals Industries Ltd., Petach Tikva, Israel. The participating centers
`are listed in Additional file 2.
`
`Role of the funding source
`This study was funded locally by Teva affiliates for database administration.
`Teva Pharmaceuticals Industries Ltd. funded the study design, collection,
`interpretation, and analysis of data, and development and submission of this
`manuscript.
`
`Author details
`1Center of Clinical Neuroscience, Neurological University Clinic, University
`Clinic Carl Gustav Carus, University of Technology Dresden, Fetscherstraße
`74, D-01307 Dresden, Germany. 2Teva Pharmaceutical Industries Ltd, 5 Basel
`Street, Petah Tikva 49131, Israel.
`
`Received: 20 March 2015 Accepted: 29 September 2015
`
`the different regions. For example, the US, Canada, and
`LA have clinical treatment guidelines that vary in the
`topics discussed and the use of GA, IFN-β, natalizumab,
`dalfampridine, and fingolimod [10, 16–18]. Also, it is pos-
`sible that patients from different regions may have differ-
`ent epidemiological characteristics and comorbidities [16].
`These regional differences cannot be adjusted in such a
`study, where the observational, non-interventional design
`carries inherent analytical limitations.
`Now that consensus guidelines have defined a subopti-
`mal treatment response, and neurodegenerative activity
`has been identified even in early stages of disease [19,
`20], converting to another DMT class represents a lo-
`gical treatment strategy in patients who fail to respond
`adequately to first-line treatments. Our results suggest
`that more attention is required regarding the importance
`of establishing formal conversion algorithms that ac-
`count for geographic variability, ensuring that all pa-
`tients who could benefit from such an approach are
`managed in a timely and optimal manner.
`Despite study limitations, our observations emphasize
`the importance of changing a therapy regimen, in par-
`ticular IFN-based, to improve efficacy and/or overcome
`treatment intolerance that would otherwise compromise
`compliance. This is in alignment with previous studies
`of this strategy [9, 21].
`
`Conclusions
`improvements in
`All patients experienced significant
`ARR regardless of geographic region. There were differ-
`ences between regions in patients’ baseline parameters,
`comorbidities, and reasons for converting to GA treat-
`ment. The evolution of guidelines regarding suboptimal
`treatment response and DMT conversion has the poten-
`tial to affect strategies for monitoring and treating pa-
`tients across all geographies and to improve clinical and
`patient-reported outcomes.
`
`Additional files
`
`Additional file 1: Patient perception of glatiramer acetate
`treatment efficacy by geographic region. aP < .0001 for Latin America
`vs. other geographic areas. (PDF 7 kb)
`Additional file 2: COPITIMIZE: Main Investigator sites. (DOCX 14 kb)
`
`Abbreviations
`AE: Adverse event; ARD: Annualized rate of deterioration; ARR: Annualized
`relapse rate; CES-D: Centre for Epidemiologic Studies Depression;
`CWE: Canada and Western Europe; DMT: Disease-modifying therapy;
`EDSS: Expanded Disability Status Scale; EE: Eastern Europe; FAMS: Functional
`Assessment of Multiple Sclerosis; GA: Glatiramer acetate; IFN: Interferon;
`i.m.: Intramuscular; LA: Latin America; MFIS: Modified Fatigue Impact Scale;
`MS: Multiple sclerosis; PASAT: Paced Auditory Serial Addition Test;
`QoL: Quality of life; RMS: Relapsing-remitting multiple sclerosis;
`s.c.: Subcutaneous; SD: Standard deviation.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`References
`1.
`Aharoni R. The mechanism of action of glatiramer acetate in multiple
`sclerosis and beyond. Autoimmun Rev. 2013;12:543–53.
`Koch-Henriksen N, Sørensen PS. The changing demographic pattern of
`multiple sclerosis epidemiology. Lancet Neurol. 2010;9:520–32.
`Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al.
`A randomized, placebo-controlled trial of natalizumab for relapsing multiple
`sclerosis. N Engl J Med. 2006;354:899–910.
`Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind,
`randomized, placebo-controlled study of the effects of glatiramer acetate on
`magnetic resonance imaging–measured disease activity and burden in
`patients with relapsing multiple sclerosis. European/Canadian Glatiramer
`Acetate Study Group. Ann Neurol. 2001;49:290–7.
`The IFNB, Group MSS. Interferon beta-1b is effective in relapsing-remitting
`multiple sclerosis. I. Clinical results of a multicenter, randomized, double-
`blind, placebo-controlled trial. Neurology. 1993;43:655–61.
`Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al.
`Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J
`Med. 2006;354:911–23.
`Coyle PK. Switching algorithms: from one immunomodulatory agent to
`another. J Neurol. 2008;255 Suppl 1:44–50.
`Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT, et al.
`Neutralizing antibodies to interferon beta: assessment of their clinical and
`radiographic impact: an evidence report: report of the Therapeutics and
`Technology Assessment Subcommittee of the American Academy of
`Neurology. Neurology. 2007;68:977–84.
`Rio J, Tintore M, Sastre-Garriga J, Nos C, Castilló J, Tur C, et al. Change in the
`clinical activity of multiple sclerosis after treatment switch for suboptimal
`response. Eur J Neurol. 2012;19:899–904.
`Freedman MS, Selchen D, Arnold DL, Prat A, Banwell B, Yeung M, et al.
`Treatment optimization in MS: Canadian MS Working Group updated
`recommendations. Can J Neurol Sci. 2013;40:307–23.
`11. Hartung HP, Montalban X, Sorensen PS, Vermersch P, Olsson T. Principles of
`a new treatment algorithm in multiple sclerosis. Expert Rev Neurother.
`2011;11:351–62.
`
`9.
`
`10.
`
`MYLAN PHARMS. INC. EXHIBIT 1080 PAGE 8
`
`

`
`Ziemssen and Gilgun-Sherki BMC Neurology (2015) 15:189
`
`Page 9 of 9
`
`12.
`
`13.
`
`Johnson KP. Glatiramer acetate for treatment of relapsing-remitting multiple
`sclerosis. Expert Rev Neurother. 2012;12:371–84.
`Scott LJ. Glatiramer acetate: a review of its use in patients with relapsing-
`remitting multiple sclerosis and in delaying the onset of clinically definite
`multiple sclerosis. CNS Drugs. 2013;27:971–88.
`14. Ziemssen T, Bajenaru OA, Carrá A, de Klippel N, de Sá JC, Edland A, et al.
`A 2-year observational study of patients with relapsing-remitting multiple
`sclerosis converting to glatiramer acetate from other disease-modifying
`therapies: the COPTIMIZE trial. J Neurol. 2014;261:2101–11.
`Kule