Multiple Sclerosis
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`http://msj.sagepub.com/
`
`
`A prospective open-label study of glatiramer acetate: over a decade of continuous use in
`multiple sclerosis patients
`C C Ford, K P Johnson, R P Lisak, H S Panitch, G Shifroni, J S Wolinsky and The Copaxone® Study
`Group
`Mult Scler
` 2006 12: 309
`DOI: 10.1191/135248506ms1318oa
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`ARTICLE
`
`Multiple Sclerosis 2006; 12: 309 320
`
`A prospective open-label study of glatiramer acetate:
`over a decade of continuous use in multiple sclerosis
`patients
`
`CC Ford1, KP Johnson2, RP Lisak3, HS Panitch4, G Shifroni5, JS Wolinsky6 and
`The Copaxone† Study Group
`
`A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS)
`patients was evaluated in this ongoing, prospective study, and the neurological status of
`‘Withdrawn’ patients was assessed at a 10 year long term follow up (LTFU) visit. Modified
`intention to treat (mITT, n232) patients received ]1 GA dose since 1991; ‘Ongoing’ patients
`(n108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU.
`Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years
`for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates
`declined from 1.18/year prestudy to 1 relapse/5 years; median time to ]1 EDSS point increase
`was 8.8 years; mean EDSS change was 0.7391.66 points; 58% had stable/improved EDSS scores;
`and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased
`0.5091.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For
`Withdrawn patients at 10 year LTFU, EDSS increased 2.2491.86; 28% were stable/improved; and
`68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease
`duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than
`Ongoing patients. Multiple Sclerosis 2006; 12: 309 320. www.multiplesclerosisjournal.com
`
`Key words: disability; disease modifying therapy; EDSS; glatiramer acetate; immunomodulator;
`relapse; relapsing remitting multiple sclerosis
`
`Introduction
`
`Currently, the best therapeutic options for relap-
`sing remitting multiple sclerosis (RRMS) patients
`are the disease-modifying therapies: glatiramer
`acetate (GA) and the beta-interferons, subcutaneous
`(SC) IFNb-1b, SC IFNb-1a, and intramuscular (IM)
`IFNb-1a [1]. There is growing consensus that im-
`munomodulatory therapy should begin shortly
`after RRMS diagnosis, and to prevent or delay
`progression of disability, continuous therapy may
`be recommended for many years [1 3]. However,
`
`evidence of long-term clinical efficacy, safety, and
`patient acceptance of immunomodulatory therapy
`is scarce. Indeed, the designation ‘long-term’ to
`describe clinical data for immunomodulators is
`arbitrary three to five years [4 6], is a relatively
`short interval considering the predicted treatment
`duration and disease course noted in MS natural
`history studies [2].
`The ongoing US Glatiramer Acetate Trial began
`in 1991 and is unique in that it is the only
`organized, ongoing, open-label
`study of more
`than 10 years duration to prospectively evaluate
`
`1 MIND Imaging Center, Albuquerque, NM, USA
`2 Maryland Center for MS, Baltimore, MD, USA
`3 Wayne State University, Detroit, MI, USA
`4 University of Vermont, Burlington, VT, USA
`5 Teva Pharmaceutical Industries Ltd., Petah Tiqva, Israel
`6 University of Texas Health Science Center at Houston, Houston, TX, USA
`Author for correspondence: Kenneth P Johnson, MD, Maryland Center for Multiple Sclerosis, 11 S. Paca Street, 4th
`Floor, Baltimore, MD 21201, USA. E mail: kjohnson@som.umaryland.edu
`Received 30 June 2005; accepted 22 November 2005
`
`– 2006 Edward Arnold (Publishers) Ltd
`
`10.1191/135248506ms1318oa
`
` EXHIBIT NO. 1038 Page 2
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`
`continuous immunomodulatory therapy in RRMS
`patients. Prospective clinical efficacy data were
`reported for continuous IFNb-1b (Betaseron†) use
`at four to five years, continuous IFNb-1a SC (Re-
`bif†) at four years, and continuous IFNb-1a IM
`(Avonex†) at approximately two years after initia-
`tion of their respective pivotal double-blind trials
`[4 6]. Further data have since been collected
`in non-continuous and/or retrospective, open-label
`extensions of these studies. In some cases, data
`were collected retrospectively after considerable
`intervals in which patients were not monitored
`and during which they may have discontinued,
`switched, or added other medications to the im-
`munomodulatory therapy under study. Another
`MS treatment, natalizumab (Tysabri†)
`remains
`under investigation; reported efficacy data reflect
`only two years of clinical experience and the full
`serious side effect profile of this drug remains
`uncertain [7].
`This GA study began with a double-blind, pla-
`cebo-controlled phase in which 251 RRMS patients
`were randomized to receive GA (20 mg) or placebo
`by SC injection daily [8,9]. After double-blind
`treatment for a mean of 30 months, all patients
`were offered active treatment as part of an ongoing,
`prospective, open-label study. Reported clinical
`efficacy results six and eight years after randomiza-
`tion of GA therapy comparing differences in clin-
`ical outcomes between patients who received GA
`from study inception versus those in patients who
`began treatment approximately 2.5 years later (ie,
`patients originally randomized to placebo), demon-
`strate the benefits of early GA therapy compared
`with delayed therapy [10 12].
`This paper describes long-term experience with
`GA in all patients who received it during the
`double-blind and/or open-label phases of the study.
`The primary aim was to determine the long-term
`effects of GA in carefully monitored patients who
`had received continuous GA for a mean of 10 years.
`A secondary goal was to gather information on
`patients who had withdrawn from the study their
`disease course while in the study and why they
`discontinued. Those who agreed to return for the
`long-term follow-up (LTFU) visit were evaluated for
`their neurologic status approximately 10 years after
`they had initiated GA therapy.
`
`Methods
`
`Patients in this study were originally enrolled in
`the US Glatiramer Acetate Pivotal Trial, a double-
`blind,
`randomized,
`placebo-controlled
`study
`that began in October 1991. RRMS patients who
`had experienced two or more medically docu-
`mented relapses in the previous two years and had
`
`EDSS scores between 0 and 5 at entry, were
`randomized to receive SC GA (20 mg) or placebo
`daily, administered by self-injection. After double-
`blind treatment, all patients who had entered the
`study were given the option to continue in an
`open-label extension phase. Those patients origin-
`ally randomized to GA continued to take the drug
`and those randomized to placebo switched to GA.
`Details of the double-blind and open-label phases of
`the study are described elsewhere [8 12]. The
`modified intention-to-treat (mITT) population in
`the study reported here differs from the original ITT
`cohort in the pivotal trial [8], in that this analysis
`includes only patients who have received at least
`one dose of GA (19 patients initially randomized to
`placebo in the pivotal study declined entry into the
`open-label extension and are excluded from this
`mITT cohort).
`Data cut-off for this analysis occurred in Novem-
`ber 2003, a mean of 10.1 years from the beginning
`of GA therapy for the 108 patients continuing in
`the ongoing study. Because 10 years was the mean
`treatment duration, patients who had received GA
`from randomization had been treated for up to
`12 years and patients originally randomized to
`placebo had been actively treated for approximately
`eight to nine years.
`This organized, prospective study is ongoing.
`The 11 original US academic centers continue to
`participate, and the Institutional Review Boards at
`all centers continue to approve the study.
`
`Study design
`
`Ongoing study procedure
`
`Briefly, in the open-label study, neurological status
`is evaluated in the clinic every six months using the
`Kurtzke Expanded Disability Status Scale (EDSS)
`[13]. Patients are examined, usually within seven
`days, if they experience symptoms suggestive of a
`relapse (appearance or reappearance of one or more
`neurologic abnormalities persisting for at least 48
`hours, preceded by a stable or improving neurolo-
`gical state of at least 30 days duration [8 12]).
`Incidence, severity, and potential cause of adverse
`events are recorded; serious adverse events are
`reported to the sponsor and to the FDA as required
`by protocol. The safety of GA therapy in these
`patients at 2 [8], 3 [9], 6 [10], and 8 [12], years has
`been reported previously. During the open-label
`phase,
`laboratory assessments (chemistry panel)
`and vital signs are documented at six-month study
`visits. In most cases, the same neurologists and
`study co-ordinators continue to assess patients at
`each visit.
`
`Multiple Sclerosis 2006; 12: 309 320
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`Prospective study of 10 years of glatiramer acetate in RRMS
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`311
`
`Any patient who discontinued daily GA, for
`whatever reason, and/or took another immuno-
`modulator was withdrawn. Therefore, those who
`remain in the study represent a group of RRMS
`patients receiving only continuous GA monother-
`apy for disease modification.
`Upon withdrawal, patients were classified by
`study personnel as: (1) withdrawal due to adverse
`event; (2) lost-to-follow-up, which included with-
`drawal from the study without attending a final
`visit or providing a reason for withdrawal; (3)
`withdrawal due to ‘patient decision’; or (4) with-
`drawal for other reason(s). Because of overlap in
`reasons for leaving, the ‘patient decision’ and
`‘other’ categories were combined. The ‘patient
`decision/other’ category was divided into subcate-
`gories based on comments patients provided at
`termination. Subcategories included (but were not
`limited to) pregnancy, inability to adhere to study
`protocol
`(eg,
`lack of transportation or moving
`away), a desire to switch or combine therapies,
`and perceptions of disease worsening. Patients were
`assigned to a subcategory based on the consensus
`judgment of three study personnel who indepen-
`dently reviewed patient comments provided at the
`final visit.
`
`Long-term follow-up visit procedure
`
`Personnel at each center made repeated attempts
`to contact all study patients who had received GA
`and withdrawn, to invite them to return for a
`single LTFU visit at approximately 10 years after
`GA start. LTFU visits were conducted between July
`and December 2003. At the LTFU visit, patients
`underwent neurological evaluation by EDSS, med-
`ical history during the time between study discon-
`tinuation and LTFU was recorded, and patients
`were asked what MS medications they had taken
`during the period between withdrawal and the
`LTFU visit.
`
`Patient cohorts
`
`The mITT cohort (n232) included all patients
`who had received at least one GA dose since study
`inception. Data reported for the mITT cohort reflect
`outcomes measured while patients were receiving
`GA. The mITT cohort was subdivided into the
`following cohorts: Ongoing, which comprised pa-
`tients continuing in the study (and, by definition,
`continuing on GA) at the time of data cut-off,
`November 2003; Withdrawn Total, which com-
`prised all patients who withdrew from the study
`before November 2003; Withdrawn with LTFU
`cohort, which included patients who withdrew
`
`from the study and returned for a single LTFU visit
`10 years after GA start; and Withdrawn without
`LTFU cohort, which included patients who with-
`drew from the study and could not be reached or
`declined LTFU.
`
`Statistical methods
`
`Baseline demographic and disease characteristics
`were analysed using descriptive statistics and statis-
`tical inference tests (SAS† software, SAS Institute,
`Cary, NC, USA); comparisons among cohorts were
`performed using x2 for categorical variables and the
`Wilcoxon non-parametric test for continuous vari-
`ables. Time to study withdrawal was estimated
`using Kaplan Meier survival analysis.
`
`Outcome measures
`
`The yearly relapse rate was calculated by dividing
`the total number of relapses by the total number
`of patients in the mITT cohort entering a given
`treatment year. Accumulated disability was mea-
`sured by mean EDSS and mean change in EDSS
`from GA start to the last observation while on
`GA in all study cohorts, and at LTFU in the
`Withdrawn with LTFU cohort. Confirmed pro-
`gression of disability was defined as an increase
`of ]1.0 EDSS point sustained for at least two
`clinical assessments, six months apart. Categorical
`analyses of patients’ neurological
`status were
`performed; patients were classified as ‘stable/im-
`proved’ if EDSS scores increased by 50.5 EDSS
`points, did not change, or decreased from onset
`of treatment. Categorical analyses were repeated
`with patients stratified by entry EDSS score (0 2
`or ]2.5).
`The number of patients who reached confirmed
`scores of EDSS 4, 6 or 8 while on GA were obtained
`for the mITT, Ongoing, and Withdrawn Total
`cohorts (only patients who began GA therapy
`with EDSS scores lower than the endpoint were
`included in these analyses). Additionally, Kaplan
`Meier survival analysis was used to estimate the
`time to EDSS 4, 6 and 8 while on GA.
`For comparison at 10 years between Ongoing
`and Withdrawn with LTFU patients, numbers of
`patients who reached predefined EDSS thresholds
`by the last observation for Ongoing patients and at
`the single LTFU visit for Withdrawn with LTFU
`patients were assessed. Efficacy comparisons at 10
`years were made using analysis of covariance
`(ANCOVA) for change from GA start in EDSS, in
`which EDSS at GA start was a covariate in the
`model; x2; and when appropriate, Fisher’s Exact
`
`www.multiplesclerosisjournal.com
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`Test for categorical change in EDSS and for attain-
`ment of predefined EDSS thresholds.
`
`Results
`
`Patient characteristics
`
`A total of 232 patients from 11 US study sites
`who had received at least one dose of GA since
`study inception comprised the mITT cohort
`(Figure 1). One patient discontinued after receiv-
`ing GA but before undergoing neurological eva-
`luation;
`therefore,
`the efficacy evaluable mITT
`cohort included 231 patients. As of November
`2003, 108/232 patients (47%) remained in the
`study and comprised the Ongoing cohort. Of 124
`(53%) patients in the Withdrawn Total cohort, 50
`returned for
`the LTFU visit
`(Withdrawn with
`LTFU cohort). In the Withdrawn without LTFU
`cohort (n74), 27 patients declined the LTFU
`visit and 47 could not be reached, including five
`patients known to have died. Deaths occurred one
`to six years after study withdrawal; three deaths
`were at least partly attributed to MS complica-
`tions, there was no information about one death,
`and one death was listed as sudden and unex-
`plained.
`There were no differences among study cohorts
`in age, gender, disease duration, or annualized
`relapse rate in the two years before beginning GA
`(Table 1). Mean MS disease duration at GA start was
`8.3 years in the mITT cohort.
`
`Patient withdrawal
`
`The Kaplan Meier estimate of the median time
`from GA start to withdrawal in the mITT cohort was
`9.2 years. Patients who withdrew had slightly
`higher EDSS scores at GA start than those who
`remained in the study (3.0091.59 [SD] versus
`2.5691.35, respectively; P0.03). Mean duration
`of GA treatment was 4.2693.13 [SD] years (range:
`0.2 11.5 years) in the Withdrawn Total cohort
`(Table 2). When separated into subcohorts, GA
`exposure was 4.4792.95 years (range: 0.2 10.4) in
`the Withdrawn with LTFU cohort, and 4.1393.26
`years (range: 0.2 11.5) in the Withdrawn without
`LTFU cohort. There were no statistical differences in
`demographic or disease characteristics at GA start
`between Withdrawn patients who returned for
`LTFU and Withdrawn patients who did not return
`(Table 1).
`Reasons for patient withdrawal are listed in
`Table 3. The most common (]1%) adverse events
`leading to discontinuation were local injection-site
`reactions (eg, erythema, pain), vasodilation, dys-
`pnea, and urticaria. Patients who left due to the
`perception that their disease was worsening were
`not evaluated by objective neurological testing at
`the time of withdrawal; therefore, whether indivi-
`dual patients had worsened by objective criteria is
`unknown. The mean change in EDSS score from
`GA start to the last observed on-treatment EDSS
`value for all patients in the patient decision/
`other category (n87) was 1.1691.65 [SD] and
`mean EDSS changes in the Withdrawn Total and
`
`taerT-ot-noitnetnI deifidoM
`*trohoC )TTIm(
`tsael ta deviecer ohw enoynA(
`232 = N )esod AG 1
`
`trohoC gniognO
`801 = n
`
`trohoC latoT nwardhtiW
`421 = n
`
`UFTL htiw nwardhtiW
`trohoC
`05 = n
`
`tuohtiw nwardhtiW
`trohoC UFTL
`*47 = n
`
`Figure 1 Study cohorts. One patient (in the Withdrawn without LTFU cohort) withdrew after a single GA dose and before an
`on treatment neurological evaluation; therefore, 231 patients comprised the efficacy evaluable mITT cohort.
`
`Multiple Sclerosis 2006; 12: 309 320
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`
`Table 1 Patient characteristics at GA start
`
`mITT
`(n232)
`
`Ongoing
`(n108)
`
`Withdrawn total
`(n124)
`
`P valuea
`
`Withdrawn with
`LTFU (n50)
`
`Withdrawn without
`LTFU (n74)
`
`P valueb
`
`Age (years)
`Mean9SD
`Range
`Female n (%)
`
`35.596.4
`19.0 48.6
`170 (73%)
`
`36.695.7
`22.0 48.6
`77 (71%)
`
`34.896.8
`19.0 47.9
`93 (75%)
`
`Disease duration (years) at GA start
`Mean9SD
`8.395.1
`Median
`7.23
`Range
`0.6 25.7
`
`8.495.1
`6.85
`1.1 23.9
`
`8.195.2
`7.49
`0.6 25.7
`
`Annualized relapse rate two years before GA start
`Mean9SD
`1.1890.82
`1.1190.82
`1.00
`1.00
`Median
`Range
`0 5.5
`0 3.5
`
`1.2490.83
`1.00
`0 5.5
`
`aOngoing versus Withdrawn Total.
`bWithdrawn with LTFU versus Withdrawn without LTFU.
`
`mITT cohorts were 0.9491.65 and 0.7391.66, res-
`pectively (Table 2).
`The LTFU visit for Withdrawn patients occurred
`at a mean of 10.0 years after GA start. These patients
`were asked about other disease modifying therapies
`they had taken for MS in the interval between
`leaving the study and the LTFU visit. Of the 50
`Withdrawn with LTFU patients, four patients re-
`ported taking no medications, no data were avail-
`able for eight patients, and 38 reported they took a
`variety of agents over the interval, often in combi-
`nation, for varying lengths of time: 13 patients took
`GA, 32 took an IFNb drug, 14 took an immunosup-
`pressive
`agent
`(mitoxantrone, methotrexate,
`azathioprine, cyclophosphamide), 10 took corticos-
`teroids, and five took ‘other’ drugs for MS. At the
`time of the LTFU visit, 10 patients were taking GA,
`16 were taking an IFNb drug, four were taking an
`immunosuppressor agent (mitoxantrone, metho-
`trexate), and one was receiving intravenous immu-
`noglobulin (IVIg).
`
`Efficacy
`
`mITT cohort while on GA
`
`Relapse rate . The medically documented annual-
`ized relapse rate in the mITT cohort during the two
`years before beginning GA therapy was 1.1890.82
`[SD] (Table 1). While on GA, yearly relapse rates
`declined approximately 50% to 0.6190.85 in treat-
`ment year 1 and continued to decline so that in
`treatment year 4, patients experienced the equiva-
`lent of one relapse every four years. Yearly relapse
`rates are shown in Figure 2 (after year 9, the mITT
`cohort comprised only patients who had received
`GA from randomization). Low relapse rates were
`
`0.0918
`
`0.5248
`
`0.8013
`
`0.2286
`
`35.296.6
`19.0 46.7
`33 (66%)
`
`8.6 9 6.2
`7.34
`0.6 25.7
`
`34.697.0
`19.0 47.9
`60 (81%)
`
`7.894.3
`7.66
`0.6 18.0
`
`1.0990.68
`1.00
`0 3.0
`
`1.3490.90
`1.00
`0 5.5
`
`0.6787
`
`0.0581
`
`0.7373
`
`0.0760
`
`maintained over all subsequent years; relapse rates
`were reduced by 80% from rates at GA start to
`approximately one relapse every five years.
`
`Accumulated disability . Mean and median GA
`treatment durations for the mITT, Ongoing, and
`Withdrawn Total cohorts, overall and according to
`drug assignment at randomization, are shown in
`Table 2. Mean GA exposure time in the Ongoing
`cohort was 10.191.32 years and in the Withdrawn
`Total cohort was 4.2693.13 years. Also shown are
`EDSS scores and changes in EDSS scores from GA
`start to the last measurement while on GA.
`The Kaplan Meier estimate of the median time
`to confirmed (verified at two six-month clinical
`visits) progression of ]1.0 EDSS point while on GA
`was 8.82 years in the mITT cohort. Proportions of
`patients with at least one confirmed progression of
`1.0 EDSS point while on GA were 42% of the mITT
`cohort, 42% of the Ongoing cohort, and 43% of the
`Withdrawn Total cohort.
`Categorical analysis showed 58% of patients in
`the mITT cohort maintained stable/improved EDSS
`scores between GA start and their last on-treatment
`EDSS assessment. Proportions of patients in the
`Ongoing and Withdrawn Total cohorts with stable/
`improved EDSS scores while on GA were 62 and
`55%, respectively. When patients were stratified by
`entry EDSS (0 2 and ]2.5), proportions of patients
`with stable/improved EDSS scores while on GA were
`similar in both strata in all cohorts (Table 2),
`indicating no difference in GA effect regardless of
`disability level at GA start. Figure 3 shows a high
`proportion of patients (59 79%) in the mITT co-
`hort (cohort size each year shown in Figure 2) had
`stable/improved EDSS scores each treatment year.
`Table 4 shows the number of patients in each
`cohort who reached predefined EDSS thresholds.
`
`www.multiplesclerosisjournal.com
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`cDefinedasanincreaseof50.5point,nochange,ordecreaseinEDSSscorefromonsetoftreatment.
`bn231inmTTcohortandn123inWithdrawntotacohort(onepatienthadnopost-GA-startEDSSscore).
`aPL,pacebo.
`
`39/74(53%)
`28/49(57%)
`67/123(55%)
`
`0.50
`0.9491.65
`
`3.5to5.5
`
`0.0 9.0
`3.50
`3.9492.25
`
`0.0 7.0
`3.00
`3.0091.59
`
`37/54(69%)
`30/54(56%)
`67/108(62%)
`
`0.50
`0.5091.65
`
`3.5to5.5
`
`0.0 8.0
`2.50
`3.0691.78
`
`0.0 6.0
`2.25
`2.5691.35
`
`76/128(59%)
`58/103(56%)
`134/231(58%)
`
`0.50
`0.7391.66
`
`3.5to5.5
`
`0.0 9.0
`3.00
`3.5392.08
`
`0.0 7.0
`2.50
`2.7991.50
`
`0.2 11.5
`4.26
`4.8193.28
`
`0.2 8.9
`2.62
`3.5092.75
`
`10.9 11.9
`11.44
`11.4490.20
`
`7.9 9.2
`8.90
`8.8490.23
`
`0.2 11.9
`9.22
`7.6394.13
`
`0.2 9.2
`8.50
`6.2593.30
`
`EDSS]2.5atGAstart
`EDSS0 2atGAstart
`Overa
`
`Cinicaystabe/improvedEDSScscorewhieonGAb
`
`EDSSchangefromGAstarttoastobservationb
`
`Range
`Median
`Mean9SD
`
`EDSSatastobservationc
`
`Range
`Median
`Mean9SD
`
`EDSSscoreatGAstart
`
`Range
`Median
`Mean9SD
`
`Range
`Median
`Mean9SD
`atrandomization(years)
`
`GA(n72)
`
`PL(n52)
`
`GA(n53)
`
`PL(n55)
`
`GA(n125)
`
`PLa(n107)
`
`GAexposurebasedondrugassignment
`
`0.2 11.5
`3.55
`4.2693.13
`
`(n124)
`WithdrawnTota
`
`7.9 11.9
`9.16
`10.1291.32
`
`(n108)
`Ongoing
`
`0.2 11.9
`8.62
`6.9993.82
`
`mTT(n232)
`
`GAexposure(years)
`
`Range
`Median
`Mean9SD
`
`WhieonGA
`
`Table2GAexposureandEDSSmeasureswhieonGA
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`
`Table 3 Reasons for patient withdrawal
`
`Reason for withdrawal
`
`Total
`Lost to follow up
`Adverse event
`Patient decision/other
`
`n
`
`124
`14
`23
`87
`
`Patient decision/other subcategoriesa
`
`Total
`Patient perception of disease worsening
`Desire to switch or combine therapies
`Difficulty, inability, or unwillingness to adhere to study protocol
`Pregnancy
`
`n
`
`87
`27
`22
`30
`8
`
`aPatient decision/other subcategories were derived from written comments provided by Withdrawn patients at their final visit.
`
`These analyses include only patients with EDSS
`scores at GA start below EDSS 8 (all patients), EDSS
`6 (n221), or EDSS 4 (n169). Inclusion criteria in
`the original double-blind phase of the study was
`limited to patients with EDSS 55, however, 10
`original placebo patients had an EDSS ]6 when
`they started GA therapy in the open-label phase of
`the study. Mean EDSS scores at GA start were 2.079
`0.95 [SD], 2.6491.34, and 2.7991.50 in patient
`groups with EDSS scores at GA start below EDSS 4, 6
`and 8, respectively. In the mITT cohort, fewer than
`25% of patients reached a score of EDSS 4, approxi-
`mately 11% reached EDSS 6, and 3% reached EDSS
`8 while on GA. Due to differences in GA exposure
`among cohorts, Kaplan Meier survival analysis was
`used to estimate the time to the predefined EDSS
`thresholds (mITT cohort shown in Figure 4). The
`time to 25% of patients reaching EDSS 4 was 6.58
`years in the mITT cohort, 9.08 years in the Ongoing
`cohort, and 5.47 years in the Withdrawn Total
`cohort. In the Withdrawn Total cohort, median
`
`time to EDSS 4 occurred at 9.91 years. Fewer than
`25% of patients in the mITT, Ongoing, and With-
`drawn Total cohorts reached EDSS 6 or 8 by the end
`of the analysis period.
`
`Clinical comparison between Ongoing and
`Withdrawn patients at ten years/LTFU
`
`Accumulated disability
`
`The occurrence of relapse after leaving the study
`was not systematically documented by prospective
`neurological assessments; therefore, these data were
`not available. Neurological assessments of disability
`at LTFU for Withdrawn patients were made at a
`mean of 10.0 years from starting GA therapy. For
`Ongoing patients, EDSS data reflected the last
`observation before data cut-off.
`At LTFU, patients who had withdrawn showed
`significantly increased disability compared with
`
`232
`
`*
`
`132
`
`802
`
`691
`
`571
`
`361
`
`941
`
`341
`
`831
`
`521
`
`46
`
`75
`
`15
`
` 9 8 7 6 5 4 3 2 1 * 21 11 01
`
`
`raeY
`†
`
`52.1
`
`1
`
`57.0
`
`5.0
`
`52.0
`
`0
`
`Mean Relapse Rate
`
`Figure 2 Yearly Relapse Rate from GA Start (mITT Cohort, n=231). *Mean [SD] annualized relapse rate in the mITT cohort in
`the 2 years before GA start was 1.1890.82. $Reflects treatment duration from GA start to the year listed. Numbers of patients
`evaluated in each treatment year are shown above bars; after year 9, the mITT cohort comprised only patients randomized to
`GA in the double blind phase of the study (placebo/active group had a shorter duration of GA exposure).
`
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`
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`
`%97
`
`%96%86%07%27%57
`
`%66%66
`
`%16%95%26
`
`%56
`
`8 7 6 5 4 3 2 1
`*raeY
`
`
`
`1 11 01 9 2
`
`001
`
`57
`
`05
`
`52
`
`0
`
`% of Patients Clinically Stable/Improved
`
`Figure 3 Yearly Percent of Patients on GA with stable/improved EDSS. Scores from GA start (mITT cohort: n231). *Reflect
`treatment duration from GA start to the year listed (the number of patients in the mITT cohort each treatment year is shown in
`Figure 2). Clinically stable/improvedan increase of 50.5 point, no change, or decrease in EDSS score from onset of GA
`treatment.
`
`Ongoing patients (Table 5). The mean increase in
`EDSS score was 2.2491.86 [SD] points in the
`Withdrawn with LTFU cohort compared with a
`0.5091.65 point increase in Ongoing patients.
`Similarly, 62% of Ongoing patients had stable or
`improved EDSS scores compared with 28% of With-
`drawn with LTFU patients (while receiving GA, 56%
`of patients in the Withdrawn with LTFU cohort had
`stable/improved EDSS scores). Finally, at 10 years,
`24% of patients in the Ongoing cohort had reached
`EDSS 4, 8% had reached EDSS 6, and 1% had
`reached EDSS 8, compared with 68, 50 and 10%,
`respectively, in the Withdrawn with LTFU cohort.
`
`Safety
`
`The most commonly reported adverse events in
`patients
`receiving long-term GA,
`regardless of
`
`judged them to be
`the investigator
`whether
`related to GA therapy or not, were accidental
`injury, asthenia, paresthesia, upper
`respiratory
`and urinary tract infections, headache, and pain.
`Adverse events thought
`to be associated with
`GA therapy included local injection-site reactions
`(eg, erythema, pain, mass, edema) and symptoms
`associated with an immediate post-injection reac-
`tion (IPIR), which may have included vasodila-
`tion, chest pain, palpitation,
`tachycardia, or
`dyspnea. Reporting of
`injection-site reactions
`and symptoms associated with IPIR declined
`over time. No apparent time-dependent adverse
`events emerged. Moreover, no evidence of hema-
`tologic, hepatic, or renal dysfunction;
`immuno-
`suppression; emergence of malignancy; or deve-
`lopment of other autoimmune disease was ob-
`served.
`
`Table 4 Number of patients reaching EDSS 4, 6 and 8 while on GA (confirmed)
`
`While
`on GA
`
`EDSS 4
`EDSS 6
`EDSS 8
`
`mITTa
`n/Nb (%)
`
`40/169 (24%)
`24/221 (11%)
`6/231 (3%)
`
`Ongoing
`n/Nb (%)
`
`20/84 (24%)
`8/106 (8%)
`1/108 (1%)
`
`Withdrawn Total
`n/Nb (%)
`
`Disease duration at GA start
`mITTa mean years9SD
`
`GA exposure mITTa
`mean years9SD
`
`20/85 (24%)
`16/115 (14%)
`5/123 (4%)
`
`7.7995.00
`8.1095.01
`8.2695.12
`
`7.1693.77
`7.1193.81
`6.9993.82
`
`amITT cohorts included all patients below the EDSS threshold at GA start.
`bnnumber of patients who reached EDSS endpoint (confirmed); Nnumber of patients who were below the EDSS threshold at GA
`start.
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`317
`
`≥≥ ≥
`
`8 SSDE
` 6 SSDE
`4 SSDE
`
`2
`
`4
`
`6
`AG no sraeY
`
`8
`
`00.1
`
`57.0
`
`05.0
`
`52.0
`
`00.0
`
`0
`
`Survival Distribution Function
`
`01
`
`04
`
`42
`6
`
`21
`
`04
`
`42
`6
`
`tniopdnE gnihcaeR stneitaP fo rebmuN evitalumuC
`12
`51
`4 SSDE
`
`11
`1
`
`71
`1
`
`03
`
`91
`2
`
`53
`
`22
`5
`
`00
`
`0
`
`6 SSDE
`8 SSDE
`
`Figure 4 Time to confirmed EDSS 4, 6 and 8 while on GA (mITT cohort: n231). The mean disease duration in the mITT
`cohort was 8.3 years at GA Start.
`
`Discussion
`
`This ongoing study is the longest prospective,
`organized evaluation of continuous immunomodu-
`latory therapy in MS [4,5,14,15]. In November
`
`2003, nine to 12 years after beginning GA therapy,
`47% of all patients who ever received GA remained
`in the study. These data provide an opportunity to
`evaluate the level of neurologic disability in pa-
`tients who have continued to take GA for an
`
`Table 5 EDSS data at 10 years/LTFU
`
`EDSS measure
`
`EDSS score
`Mean9SD
`Median
`Range
`
`EDSS change from GA start
`Mean9SD
`Median
`Range
`
`Categorical analysis
`Clinically stable/improved
`
`Patients reaching EDSS 4, 6, or 8b
`EDSS 4 n/N (%)
`EDSS 6 n/N (%)
`EDSS 8 n/N (%)
`
`Ongoing (n108)
`
`Withdrawn with LTFUa (n50)
`
`P value
`
`3.0691.78
`2.50
`0.0 8.0
`
`0.5091.65
`0.50
`3.5 to 5.5
`
`5.2292.21
`6.00
`1.0 9.0
`
`2.2491.86
`2.25
`3.0 5.5
`
`67/108 (62%)
`
`14/50 (28%)
`
`20/84 (24%)
`8/106 (8%)
`1/108 (1%)
`
`25/37 (68%)
`23/46 (50%)
`5/50 (10%)
`
`B0.0001c
`
`B0.0001c
`
`B0.0001d
`
`B0.0001d
`B0.0001d
`B0.0125e
`
`aEDSS level was not confirmed at six months in Withdrawn with LTFU patients, since LTFU comprised a single visit.
`bnnumber of patients who reached EDSS threshold (confirmed in Ongoing patients) and Nnumber of patients who were below
`the EDSS threshold at GA start.
`cFrom ANCOVA adjusted for EDSS score at GA start.
`dx2 Test.
`eFisher’s Exact Test.
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`average of 10 years and compare it with that of
`patients who withdrew from the study (and may
`have used other MS therapies) then returned for
`neurological evaluation 10 years after beginning
`GA therapy.
`Results of this study are consistent with mec-
`hanisms of action of GA, which address both the
`inflammatory and neurodegenerative aspects of MS
`pathology within the CNS. GA-reactive Th2 cells
`induce ‘bystander’ suppressio