RAPID COMMUNICATION
`
`Three Times Weekly Glatiramer Acetate
`in Relapsing–Remitting Multiple Sclerosis
`
`Omar Khan, MD,1 Peter Rieckmann, MD,2 Alexey Boyko, MD,3
`Krzysztof Selmaj, MD,4 and Robert Zivadinov, MD, PhD,5
`for the GALA Study Group
`
`Objective: To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 33 weekly (tiw) compared
`with placebo in patients with relapsing–remitting multiple sclerosis (RRMS).
`Methods: This randomized, double-blind study was conducted in 142 sites in 17 countries. Patients with RRMS with
`at least 1 documented relapse in the 12 months before screening, or at least 2 documented relapses in the
`24 months before screening, and an Expanded Disability Status Scale score  5.5, were randomized 2:1 to receive
`either subcutaneous (sc) GA 40mg tiw (1ml) or placebo for 12 months.
`Results: Of 1,524 patients screened, 1,404 were randomized to receive GA 40mg sc tiw (n 5 943) or placebo
`(n 5 461). Ninety-three percent and 91% of patients in the placebo and GA groups, respectively, completed the
`12-month study. GA 40mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with
`placebo (mean annualized relapse rate 5 0.331 vs 0.505; p < 0.0001). Patients who received GA 40mg tiw experi-
`enced highly significant reduction (p < 0.0001) in the cumulative number of gadolinium-enhancing T1 (44.8%) and
`new or newly enlarging T2 lesions (34.7%) at months 6 and 12. GA 40mg tiw was safe and well tolerated. The most
`common adverse events in the GA group were injection site reactions (35.5% with GA vs 5.0% with placebo).
`Interpretation: GA 40mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the conven-
`ience of fewer sc injections per week.
`
`ANN NEUROL 2013;73:705–713
`
`Multiple sclerosis (MS) is a chronic relapsing disorder
`
`system characterized by
`the central nervous
`of
`inflammation, multifocal demyelination, astrocytic prolif-
`eration, and neuronal and axonal damage.1,2 MS affects
`>2 million people worldwide, with about 85% of patients
`presenting with a relapsing–remitting (RR) course, defined
`by acute attacks and intervening periods of full or partial
`recovery without disease progression.3,4 Although there is
`no cure for MS, current disease-modifying therapies aimed
`at reducing relapse rates and slowing disease progression
`have improved the prognosis for patients with MS.3
`
`Glatiramer acetate (GA), a heterogeneous mixture
`of synthetic polypeptides composed of 4 amino acids, is
`approved for reducing relapse frequency in patients with
`RRMS, including patients who have experienced a first
`clinical episode and have magnetic resonance imaging
`(MRI) features consistent with MS (clinically isolated
`syndromes).5 Although the precise mechanism by which
`GA mediates clinical benefit in MS has not been fully
`elucidated,
`it
`is known to have multiple coordinated
`immunomodulatory effects involving T cells and B cells
`of the adaptive immune system, and antigen-nonspecific
`
`Members of the GALA Study Group are listed in the Appendix on page 8.
`
`View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.23938
`
`Received Feb 8, 2013, and in revised form Apr 28, 2013. Accepted for publication May 10, 2013.
`
`Address correspondence to Dr Khan, Department of Neurology, Wayne State University School of Medicine, 4201 St Antoine, 8D-University Health
`Center, Detroit, MI 48201. E-mail: okhan@med.wayne.edu
`
`From the 1Department of Neurology and Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI; 2Department of Neurology,
`Bamberg Academic Hospital, University of Erlangen, Bamberg, Germany; 3Department of Neurology and Neurosurgery, Russian National Medical
`Research University and Moscow Multiple Sclerosis Center, Moscow, Russia; 4Department of Neurology, Medical University of Lodz, Lodz, Poland;
`5Department of Neurology, Buffalo Neuroimaging Analysis Center, Department of Neurology, University of Buffalo, Buffalo, NY.
`
`Additional supporting information can be found in the online version of this article.
`
`VC 2013 American Neurological Association 705
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`ANNALS of Neurology
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`alteration of the function of antigen-presenting cells of
`the innate immune system.6,7
`GA is approved as a 20mg daily subcutaneous (sc)
`injection.5 Three randomized, double-blind, placebo-
`controlled studies with this dosing regimen and a meta-
`analysis of those studies demonstrated reduced annualized
`relapse rates (ARRs) and disease activity on MRI in
`patients with RRMS.8–11 In a subsequent phase 3 study,
`GA 20mg significantly delayed progression to clinically
`definite MS and reduced MRI disease activity in patients
`with clinically isolated syndromes.12
`A recent phase 3 dose comparison study of GA
`40mg once daily in patients with RRMS showed similar
`safety and efficacy profiles compared with the 20mg,
`once-daily approved dose.13 Two randomized exploratory
`studies have compared GA 20mg sc daily to GA 20mg
`sc administered on alternate days or twice weekly for 2
`years.14,15 Both studies showed no significant difference
`in the ARR and brain MRI T2 lesion volume between
`the alternate GA dosing regimens compared to daily GA.
`However,
`less
`frequent weekly administration of GA
`showed significantly fewer localized injection reactions
`including lipoatrophy compared to daily GA.14,15 The
`GALA (Glatiramer Acetate Low-frequency Administra-
`tion) study was designed to investigate the efficacy and
`safety of GA 40mg administered 33 weekly (tiw) in
`patients with RRMS. This dosing regimen would provide
`the convenience of fewer weekly injections while main-
`taining a similar weekly dose as the approved 20mg
`regimen.
`
`Patients and Methods
`
`Study Design and Patients
`The GALA study was a randomized, placebo-controlled (PC),
`parallel-group, phase 3 study. It was conducted at 142 sites in
`17 countries,
`including the United States, Bulgaria, Croatia,
`Germany, Poland, Romania, and Ukraine.
`Patient eligibility criteria were previously described.13
`Briefly, patients were eligible for study participation if they
`were 18 to 55 years of age, had a confirmed RRMS diagnosis
`revised McDonald criteria16), had an
`(according to the
`Expanded Disability Status Scale (EDSS) score of 5.5, and
`were relapse-free for 30 days. Patients also were required
`to have 1 documented relapse in the 12 months prior to
`screening, 2 documented relapses in the 24 months prior to
`screening, or 1 documented relapse between 12 and 24 months
`prior to screening with at least 1 documented T1 gadolinium
`(Gd)-enhancing lesion in an MRI performed within 12 months
`of screening. Women of childbearing potential were required to
`practice an acceptable method of birth control.
`Patients with progressive forms of MS and previous treat-
`ment with GA or any other glatiramoid were excluded. Other
`exclusion criteria included treatment with immunomodulators,
`
`including interferon-b and intravenous immunoglobulin, within
`2 months of
`screening; use of
`immunosuppressive agents,
`including mitoxantrone and fingolimod, cytotoxic agents, or
`chronic (>30 days) systemic corticosteroid treatment within
`6 months of screening; treatment with cladribine, natalizumab,
`or any other monoclonal antibody treatment within 2 years of
`screening; known sensitivity to Gd or mannitol; and inability
`to successfully undergo MRI scanning.
`All
`institutional review boards or ethics committees of
`the participating centers approved the protocol, and all patients
`gave written informed consent before
`any
`study-related
`procedures were performed. Study progress was overseen by an
`independent data-monitoring committee.
`
`Randomization and Blinding
`Patients were treated with a tiw sc injection of either a
`single-use, prefilled syringe containing GA 40mg (Teva Pharma-
`ceutical Industries, Petah Tikva, Israel) in a 1ml suspension
`containing 40mg of mannitol dissolved in water, or matching
`placebo (40mg of mannitol dissolved in water). During the ran-
`domization period, eligible patients were assigned to treatment
`groups in a 2:1 ratio (GA 40mg tiw or placebo) according to
`the randomization scheme produced by the study sponsor (Teva
`Pharmaceuticals). The randomization scheme used constrained
`blocks stratified by center.
`and any personnel
`sponsor,
`the
`The
`investigators,
`involved in patients’ assessments, monitoring, analysis, and data
`management were blinded to treatment assignment. Study
`drugs were packaged and labeled in a way that maintained the
`masked nature of the study; the appearance, shape, color, and
`smell were identical. Patients’ general medical assessments were
`performed separately from the neurological assessments by 2
`neurologists or physicians. The examining neurologist=physician
`was responsible for all neurological assessments.
`Seven scheduled site visits occurred during the 12-month
`PC phase: at screening, baseline, and months 1, 3, 6, 9, and
`12. Patients who completed the PC phase were given the
`opportunity to participate in an open-label phase, during which
`they would continue treatment with GA 40mg tiw until either
`the dose formulation is commercially available for the treatment
`of RRMS or development is stopped by the sponsor. The open-
`label phase is ongoing.
`
`Procedures
`A complete neurological assessment, including Kurtzke’s EDSS
`and functional
`system (FS) assessment, was performed at
`screening, baseline, and months 3, 6, 9, and 12. Patients were
`instructed to contact their local center within 48 hours of onset
`of any symptoms suggestive of relapse. Patients with suspected
`relapses were evaluated within 7 days of symptom onset.
`Relapse was defined as the appearance of 1 new neuro-
`the reappearance of 1 previously
`logical abnormalities or
`observed neurological abnormalities lasting at least 48 hours and
`preceded by an improving neurological state of at least 30 days
`from the onset of previous relapse. An event was counted as a
`relapse when the patient’s
`symptoms were accompanied by
`
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`TABLE 1. Baseline Patient and Disease Characteristicsa
`
`ITT Population
`
`Age, mean yr (6 SD)
`Female gender, No. [%]
`
`Race/ethnicity, No. [%]
`
`Caucasian
`
`Black/African American
`
`Asian
`
`Native American/Alaskan Native
`Body mass index, mean (6 SD)
`Prior DMT treatment, No. [%]
`EDSS, mean (6 SD)
`Years from onset of first MS symptoms, mean (6 SD)
`Exacerbations over 1 year prior to study initiation, mean (6 SD)
`Exacerbations over 2 years prior to study initiation, mean (6 SD)
`Number of GdE T1 lesions, mean (6 SD)
`Patients with >0 GdE T1 lesions, No. [%]
`Volume of T2 lesion, mean ml (6 SD)
`
`Khan et al: Glatiramer Acetate in RRMS
`
`GA 40mg tiw,
`n 5 943
`37.4 (9.4)
`
`641 [68.0]
`
`Placebo,
`n 5 461
`38.1 (9.2)
`
`313 [67.9]
`
`916 [97.1]
`
`455 [98.7]
`
`12 [1.3]
`
`2 [0.2]
`
`1 [0.1]
`
`24.4 (4.7)
`
`128 [13.6]
`
`2.8 (1.2)
`
`7.7 (6.7)
`
`1.3 (0.6)
`
`1.9 (0.9)
`
`1.7 (4.7)
`
`336 [35.6]
`
`19.7 (20.7)
`
`3 [0.7]
`
`0 [0.0]
`
`0 [0.0]
`
`24.4 (4.8)
`
`63 [13.7]
`
`2.7 (1.2)
`
`7.6 (6.4)
`
`1.3 (0.6)
`
`1.9 (0.9)
`
`1.4 (3.7)
`
`154 [33.4]
`
`17.4 (17.4)
`
`aNo significant differences between the 2 groups at baseline.
`DMT 5 disease-modifying therapy; EDSS 5 Expanded Disability Status Scale; GA 5 glatiramer acetate; GdE 5 gadolinium-
`enhancing; ITT 5 intent-to-treat; MS 5 multiple sclerosis; SD 5 standard deviation; tiw 5 33 weekly.
`
`observed objective neurological changes consistent with an
`increase of 0.5 points in the EDSS score compared with previ-
`ous evaluation, or an increase of 1 grade in the actual score of
`2 or more of the 7 FSs; or an increase of 2 grades in the score
`of 1 FS, compared with the previous assessment. The patient
`must not have had any acute metabolic changes, and a change
`in bowel=bladder function or cognitive function must not have
`been entirely responsible for confirmation of a relapse.
`The treatment of relapses was determined by the examining
`neurologist, and the per-protocol allowed treatment consisted of
`intravenous methylprednisolone, 1g=day for 5 days. In addition
`to neurological assessment at the next scheduled visit, follow-up
`visits to monitor the course of the relapse were made at the discre-
`tion of the treating neurologist. All follow-up neurological exami-
`nations were performed by the blinded examining neurologist.
`Brain MRI assessments were performed at baseline, and
`months 6 and 12. Before scanning study participants, MRI
`facilities underwent a qualification procedure to ensure that
`image acquisition was optimized and standardized per protocol,
`for measuring the endpoints specified by the study protocol.
`The MRI protocol
`included dual echo T2-weighted image
`(WI), 3-dimensional inversion recovery spoiled-gradient recalled
`T1-WI, fluid attenuated inversion recovery, and spin-echo T1-
`WI with and without Gd contrast. Brain MRI scans were
`obtained according to a protocol provided by the MRI reading
`
`center (Buffalo Neuroimaging Analysis Center, Buffalo, NY)
`that also performed all MRI analysis. The details of the MRI
`procedures are provided in the Supplementary Material.
`Safety assessments included adverse events (AEs), standard
`clinical
`laboratory tests, vital signs, and electrocardiographic
`(ECG) measurements.
`
`Statistical Analysis
`A sample size of 1,350 patients (900 patients in the GA treat-
`ment group and 450 in the placebo group) was considered nec-
`essary to provide 90% power to detect a statistically significant
`difference in the total number of confirmed relapses between
`the
`treatment groups. The
`calculation accounted for
`an
`expected ARR of 0.35 in an untreated population, an expected
`ARR of 0.245 in the GA-treated population, and a dropout
`rate of 15%.
`The principal analysis for the primary endpoint of total
`number of confirmed relapses during the 12-month PC phase
`was performed on the intent-to-treat (ITT) cohort, defined as
`all randomized patients. The GA group was compared with the
`placebo group using a baseline-adjusted quasi-likelihood (over-
`dispersed) negative binomial regression analysis with an offset
`based on the log of the patient’s exposure to treatment. In addi-
`tion to treatment group, the negative binomial regression model
`included the following covariates: baseline EDSS score, log of
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`FIGURE 1: Patient disposition.
`
`the number of relapses in the previous 2 years, volume of T2
`lesions at baseline, status of Gd-enhancing T1 activity at base-
`line, and country or geographical region.
`Significance testing of the prospectively defined secondary
`endpoints and their hierarchical order was predefined in the
`protocol. All secondary analyses were performed on the ITT
`population where data were available. The first 2 secondary
`endpoints, the cumulative number of new=newly enlarging T2
`lesions at months 6 and 12 and the cumulative number of
`Gd-enhancing lesions on T1-WI taken at months 6 and 12,
`were analyzed using a baseline-adjusted negative binomial
`regression, with an offset employing the log of the proportion
`of the number of available postbaseline scans to adjust for miss-
`ing scans. Patients who missed both 6- and 12-month scans
`were excluded from the analysis. The regression model included
`the number of Gd-enhancing lesions on T1-WI at baseline,
`and country or geographical region as covariates. The third
`endpoint, brain atrophy—defined as the percentage brain vol-
`ume change from baseline to month 12—was analyzed using a
`baseline-adjusted analysis of covariance, with normalized brain
`volume at baseline, the number of Gd-enhancing lesions on
`T1-WI at baseline, and country or geographical region as
`
`covariates. Patients who missed brain volume measurements at
`12 months were excluded from the analysis.
`Exploratory endpoints included the time to the first con-
`firmed relapse, the proportion of relapse-free patients, and the
`total number of severe confirmed relapses (defined as those
`requiring hospitalization or intravenous steroids). All explora-
`tory analyses were performed on the ITT population during
`the PC phase. The time to the first confirmed relapse for the
`GA group versus the placebo group was compared using Cox’s
`proportional hazards model. Censoring time was defined as the
`time from randomization until the PC phase termination date.
`In several cases, the PC phase termination date exceeded the
`study drug stop date. Baseline-adjusted logistic regression was
`used to analyze the proportion of relapse-free patients. Baseline-
`adjusted quasi-likelihood negative binomial regression with an
`offset based on the log of the patient’s exposure to treatment
`was used to analyze the total number of severe relapses. Covari-
`ates included in all 3 exploratory models were baseline EDSS
`score, log of the number of relapses over the previous 2 years,
`volume of T2 lesions at baseline, status of Gd-enhancing T1
`activity at baseline (0 if no lesions and 1 if lesions present), and
`country or geographical region.
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`Khan et al: Glatiramer Acetate in RRMS
`
`TABLE 2. Annualized Relapse Rate/Severe Relapse Rate, Time to First Relapse, and Proportion of Relapse-
`Free Subjects
`
`Endpoint
`
`Primary
`
`Annualized
`relapse rate
`
`Exploratory
`
`Annualized
`severe relapse rate
`
`Time to first
`relapse, days
`
`Relapse-free
`patients, %
`
`GA 40mg tiw,
`n 5 943
`
`Placebo,
`n 5 461
`
`RR, GA vs
`placebo
`
`p
`
`RRR, GA vs
`placebo
`
`Analysis Estimate (95% CI)
`
`0.331 (0.280–0.392)
`
`0.505 (0.418–0.609)
`
`0.656 (0.539–0.799) <0.0001
`
`34.0%
`
`0.301 (0.252–0.359)
`
`0.466 (0.383–0.568)
`
`0.644 (0.526–0.790) <0.0001
`
`35.4%
`
`393
`
`77.0
`
`377
`
`65.5
`
`0.606a (0.493–0.744) <0.0001 NA
`
`1.928b (1.491–2.494) <0.0001 NA
`
`aHazard ratio.
`bOdds ratio.
`CI 5 confidence interval; GA 5 glatiramer acetate; NA 5 not applicable; RR 5 risk ratio; RRR 5 relative risk reduction;
`tiw 5 33 weekly.
`
`the exploratory endpoints was analyzed at a
`Each of
`nominal significance level of 5%. As the exploratory endpoints
`were not part of the primary and secondary objectives, this did
`not affect the study’s overall type I error.
`
`Results
`In total, 1,524 patients were screened for entry into
`the
`study
`(Fig). Of
`these patients,
`1,404 were
`
`randomized to study treatment (GA 40mg tiw, n 5 943;
`placebo, n 5 461) and received at least 1 dose of treat-
`ment. Baseline demographics
`showed no significant
`differences between the 2 groups (Table 1). The majority
`of screening failures occurred because of study ineligibil-
`ity (4.5%) and consent withdrawal (2.0%). The propor-
`tions of patients who discontinued were similar for the
`GA 40mg tiw (8.9%) and placebo (6.7%) groups. The
`
`TABLE 3. Secondary Magnetic Resonance Imaging Endpoints
`
`Endpoint
`
`Analysis Estimate (95% CI)
`
`GA 40mg tiw,
`n 5 884a
`0.905
`(0.750 to 1.093)
`
`Placebo,
`n 5 441a
`1.639
`(1.300 to 2.066)
`
`RR, GA vs
`placebo
`0.552
`(0.436 to 0.699)
`
`p
`
`<0.0001
`
`RRR, GA
`vs placebo
`44.8%
`
`3.650
`(3.176 to 4.194)
`
`5.592
`(4.710 to 6.640)
`
`0.653
`(0.546 to 0.780)
`
`<0.0001
`
`34.7%
`
`20.706
`(20.779 to 20.632)
`
`20.645
`(20.737 to 20.553)
`
`20.061
`(20.154 to 0.033)
`
`0.2058
`
`19.4%
`
`Cumulative GdE T1
`lesions at months
`6 and 12
`
`Cumulative new or
`newly enlarging T2
`lesions at months
`6 and 12
`
`Percentage change in
`brain volume from
`baseline to month 12
`
`aFor change in brain volume from baseline to month 12, n 5 840 for GA 40mg tiw and n 5 423 for placebo.
`CI 5 confidence interval; GA 5 glatiramer acetate; GdE 5 gadolinium-enhancing; RR 5 risk ratio; RRR 5 relative risk reduc-
`tion; tiw 5 33 weekly.
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`TABLE 4. Frequency of Common AEs
`
`AE
`
`GA 40mg tiw, n 5 943
`
`Placebo, n 5 461
`
`Total
`AEs occurring in 5% in either treatment group
`Injection site erythema
`
`Nasopharyngitis
`
`Injection site pain
`
`Headache
`
`Systemic immediate postinjection reactions
`
`Injection site pruritus
`
`Urinary tract infection
`
`Upper respiratory tract infections
`
`680 (72.1)
`
`197 (20.9%)
`
`100 (10.6%)
`
`98 (10.4%)
`
`95 (10.1%)
`
`72 (7.6%)
`
`56 (5.9%)
`
`46 (4.9%)
`
`42 (4.5%)
`
`One patient death (cardiopulmonary failure) was reported in the placebo group.
`AE 5 adverse event; GA 5 glatiramer acetate; tiw 5 33 weekly.
`
`284 (61.6)
`
`7 (1.5%)
`
`39 (8.5%)
`
`9 (2.0%)
`
`55 (11.9%)
`
`8 (1.7%)
`
`0 (0.0%)
`
`23 (5.0%)
`
`25 (5.4%)
`
`main reasons for discontinuation were withdrawal of con-
`sent (3.6% for GA, 3.7% for placebo) followed by AEs
`(3.1% for GA, 1.3% for placebo).
`Patients receiving GA 40mg tiw demonstrated a
`34% reduction in the risk of confirmed relapse compared
`with placebo (mean ARR 5 0.331 vs 0.505; risk ratio
`[RR] 5 0.656, 95% confidence interval [CI] 5 0.539–
`0.799, p < 0.0001; Table 2). EDSS progression was sim-
`ilar between treatment groups (Supplementary Table 1),
`and the time to first relapse was significantly longer in
`the GA 40mg tiw group compared with placebo (393 vs
`377 days; hazard ratio 5 0.606, 95% CI 5 0.493–
`0.744, p < 0.0001). A greater proportion of patients
`were relapse-free during treatment with GA 40mg tiw
`compared with placebo (77.0% vs 65.5%). Relative to
`placebo, GA 40mg tiw was also associated with a signifi-
`cant 35% reduction in annualized rate of severe relapse
`(0.301 vs 0.466; RR 5 0.644, 95% CI 5 0.526–0.790,
`p < 0.0001).
`Compared with patients receiving placebo, patients
`who received GA 40mg tiw experienced 45% reduction
`in the cumulative number of Gd-enhancing T1 lesions
`(RR 5 0.552, 95% CI 5 0.436–0.699, p < 0.0001)
`and 35% reduction in the cumulative number of new or
`newly enlarging T2 lesions (RR 5 0.653; 95% CI 5
`0.546–0.780, p < 0.0001) at months 6 and 12 (Table
`3). The percentage change in normalized brain volume at
`month 12 from baseline was not statistically different
`between treatment arms (20.706 with GA vs 20.645
`with placebo; p 5 0.2058). Results of unadjusted and
`adjusted analyses for baseline characteristics, for primary
`and secondary endpoints, showed no significant differen-
`ces (Supplementary Table 2).
`
`AEs recorded in this study were consistent with the
`known safety profile of the approved 20mg formulation
`of GA. The most common AEs were injection site reac-
`tions (ISRs; 35.2% of GA 40mg tiw patients and 5.0%
`of placebo patients), 99.9% of which were mild or mod-
`erate in severity. The most common ISRs, with an inci-
`dence of >5% in the GA group, were
`erythema
`(20.9%), injection site pain (10.4%), and pruritis (5.9%;
`Table 4). At least 1 symptom related to systemic immedi-
`ate postinjection reactions occurred in 7.6% of patients
`
`TABLE 5. Immediate Postinjection Reactions
`
`Adverse Event
`
`Total
`
`Dyspnea
`
`Feeling hot
`
`Tachycardia
`
`Flushing
`
`Palpitations
`
`Chest pain
`
`Hyperemia
`
`Chest discomfort
`
`Musculoskeletal
`chest pain
`
`GA 40mg tiw,
`n 5 943
`72 (7.6%)
`
`29 (3.1%)
`
`12 (1.3%)
`
`10 (1.1%)
`
`9 (1.0%)
`
`9 (1.0%)
`
`8 (0.8%)
`
`6 (0.6%)
`
`5 (0.5%)
`
`4 (0.4%)
`
`Hot flush
`
`3 (0.3%)
`
`Heart rate increased
`
`2 (0.2%)
`
`GA 5 glatiramer acetate; tiw 5 33 weekly.
`
`Placebo,
`n 5 461
`8 (1.7%)
`
`2 (0.4%)
`
`0 (0.0%)
`
`1 (0.2%)
`
`1 (0.2%)
`
`0 (0.0%)
`
`3 (0.7%)
`
`0 (0.0%)
`
`1 (0.2%)
`
`0 (0.0%)
`
`0 (0.0%)
`
`0 (0.0%)
`
`710
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`
`who received GA 40mg tiw and 1.7% of patients who
`received placebo (see Tables 4 and 5).
`Serious AEs occurred in approximately 4.5% of
`patients in each treatment group (see Table 4, Supple-
`mentary Table 3). During the PC phase, 1 patient in the
`placebo group died of cardiopulmonary failure during
`the study. AEs leading to discontinuation of treatment
`occurred in 3.1% of patients in the GA group and 1.3%
`of patients in the placebo group. The highest rate of dis-
`continuation was attributed to ISRs, which led to discon-
`tinuation of GA 40mg tiw in 1.0% of patients. There
`was no increase in the incidence of infections or malig-
`nant diseases, or clinically significant changes or safety
`concerns, in either treatment group with regard to labo-
`ratory values, ECG readings, and vital signs.
`
`Discussion
`This study demonstrated that, compared with placebo,
`treatment with GA 40mg sc tiw was associated with a
`significant reduction in the total number of confirmed
`relapses in patients with RRMS over a 12-month period.
`The efficacy of GA 40mg tiw was also supported by
`secondary endpoints
`that demonstrated reduction of
`MRI-measured disease activity. The safety profile of GA
`40mg tiw in this study was consistent with that of the
`approved 20mg once-daily dose.
`The 40mg tiw schedule of GA was selected for the
`study because it provided a cumulative weekly dose of
`120mg, similar to the 140mg cumulative weekly dose
`provided with the approved 20mg daily regimen. This
`alternative dosing regimen of GA provides the conven-
`ience of 4 fewer sc injections per week while maintaining
`a similar weekly dose. In the absence of adequate data
`regarding the efficacy of reduced injection frequency of
`GA 20mg in large, well-controlled studies, the conserva-
`tive 40mg approach adopted by the GALA study was
`deemed most appropriate, in that a reduction in injection
`frequency would be offset by the use of a higher dose
`that had already been shown to be effective and safe
`when administered on a daily basis.13,17
`The efficacy and safety of a 40mg dose of GA is
`supported by previous phase 2 and 3 dose comparison
`studies in which patients with RRMS were randomized
`to daily treatment with GA 40mg or 20mg.12,17 The
`phase 2 study showed a trend toward an increased effect
`on clinical and MRI activity of the 40mg dose compared
`with the approved 20mg dose.17 However, these findings
`were not supported by the phase 3 study, in which both
`doses of GA were equally effective in terms of ARR and
`MRI activity.12
`In addition to the significant reduction of ARR
`observed with GA 40mg tiw versus placebo in the current
`
`Khan et al: Glatiramer Acetate in RRMS
`
`study, secondary MRI analyses also support the conclu-
`sion that GA 40mg tiw was significantly more effective
`than placebo as demonstrated by significant reductions in
`cumulative numbers of Gd-enhancing lesions and new or
`enlarging T2 lesions at 6 and 12 months. These findings
`are consistent with previously reported reductions in ARR
`values (28–33% reduction) and improved MRI outcomes
`in patients
`treated with GA 20mg and 40mg once
`daily.8,10,11,13 However,
`the differences between the
`designs of the previous studies with daily GA and the
`GALA study limit meaningful comparisons. Exploratory
`endpoints provided additional insight into the therapeutic
`effect of GA 40mg tiw, revealing significant advantages
`over placebo in the rate of severe relapse, time to first
`relapse, and the incidence of relapse-free patients.
`Treatment with GA 40mg tiw was safe and well tol-
`erated. The safety profile was comparable with that of
`GA 20mg once daily, which has been well established in
`patients with RRMS in previous clinical trials and post-
`marketing clinical experience.5 Fewer than 5% of patients
`in either study group discontinued treatment because of
`AEs. Similar to this and other previous studies of GA
`20mg once daily, ISRs remained the most commonly
`reported AE with GA 40mg tiw.5,8,10,13 These reactions,
`which were predominantly mild, led to the discontinua-
`tion in the GA 40mg tiw arm in a small proportion of
`patients
`(1.0%). Notably,
`the incidence of
`ISRs
`in
`patients treated with GA 40mg tiw was approximately 20
`to 50% less compared with previous studies of patients
`treated with GA 20mg and 40mg once daily.8,10,13 The
`incidence of systemic immediate postinjection reactions
`in this
`study (7.6%) was
`lower
`than the approx-
`imately15% reported in other placebo-controlled studies
`with GA 20mg.8,10
`In conclusion, this study has established GA 40mg
`tiw as a safe and effective alternative regimen for the
`treatment of RRMS. The use of GA 40mg tiw offers a
`treatment alternative for RRMS patients who prefer a
`less-frequent injection schedule.
`
`Acknowledgment
`This study was funded by Teva Pharmaceutical Industries,
`Petah Tikva, Israel. All members of the clinical advisory
`board, the country principal investigators, the Data Moni-
`toring Committee (DMC), and the MRI Reading Center
`were reimbursed for their specific services on a contrac-
`tual basis by Teva Pharmaceutical Industries.
`We thank the patients and site personnel involved with
`this study; Dr A. Vainstein, Dr Y. Gilgun-Sherki, and N.
`Sasson for assistance with study conduct and statistical
`analyses; Dr J. Levy for work on the statistical analysis
`
`June 2013
`
`711
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`YEDA EXHIBIT NO. 2089
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`
`ANNALS of Neurology
`
`plan; and Dr A. Nair and L. Grauer for editorial assis-
`tance in the preparation of this report for submission.
`Preliminary results were presented at the annual meet-
`ing of
`the European Committee for Treatment and
`Research in Multiple Sclerosis, Lyon, France, October
`10–13, 2012.
`
`Authorship
`All authors were members of the steering committee and
`site investigators. All authors reviewed the study report
`and contributed to its preparation.
`
`Potential Conflicts of Interest
`Idec, Genzyme,
`O.K.:
`consultancy, Teva, Biogen
`Novartis; grants=grants pending, NIH, NINDS, NMSS
`(USA), Teva, Novartis, Biogen Idec, Genzyme, Roche,
`Genentech, Sanofi-Aventis, Acorda Therapeutics; speak-
`ing fees, Teva, Novartis, Biogen Idec. P.R.: speaking fees,
`Bayer, Biogen Idec, Boehringer
`Ingelheim, Novartis,
`Merck Serono, Teva, Genzyme; clinical
`trial
`steering
`committees, Novartis, Merck
`Serono, Teva. A.B.:
`advisory boards, Bayer Schering, Merck Serono, Teva,
`Novartis, Biogen Idec, Nycomed, Genzyme. K.S.: board
`membership, Biogen Idec, Novartis, Genzyme, ONO
`Pharma, Roche, Synthon; consultancy, Bayer, Hoffman-
`La Roche, Biogen Idec, Merck Serono; speaking fees,
`Biogen Idec, Novartis, Merck Serono. R.Z.: consultancy,
`Teva, Biogen Idec, EMD Serono, Genzyme-Sanofi,
`Bayer, Questcor Pharmaceuticals, Novartis; grants=grants
`pending, Biogen Idec, Teva, Novartis, Genzyme-Sanofi,
`Bracco, Questcor Pharmaceuticals, EMD Serono; speak-
`ing fees, Teva, Biogen Idec, EMD Serono, Genzyme-
`Sanofi, Bayer, Questcor Pharmaceuticals, Novartis.
`
`APPENDIX
`
`GALA Study Group
`
`Principal Investigators
`O. Khan, P. Rieckmann. Study Steering Committee: A.
`Boyko, O. Khan, P. Rieckmann, K. Selmaj, R. Zivadinov.
`Independent Data Monitoring Committee: G. Cutter, R.
`Gold, J. Wolinsky. MRI Analysis Center: R. Zivadinov, C.
`Kennedy, D. P. Ramasamy, M. G. Dwyer, N. Bergsland, G.
`U. Poloni, C. Magnano, J. Durfee, P. Polak, M. Andrews,
`K. Hunt, M. Cherneva, S. Hussein. L. Willis, M. Santoro,
`Buffalo Neuroimaging Analysis Center, Department of
`Neurology, University of Buffalo, Buffalo, NY.
`
`K. Kmetska-Shotekova, I. Manchev, D. Maslarov, I. Mila-
`nov, E. Nedyalkov, I. Petrov, P. Shotekov, I. Staikov, E.
`Titianova, E. Vacheva, Z. Zahariev. Croatia: S. Basic, M.
`Bosnjak Pasic, M. Habek, S. Soldo-Butkovic, A. Vladic.
`Czech Republic: P. Hradilek, P. Kanovsky, M. Vachova.
`Estonia: K. Gross-Paju, I. Kalbe, G. Zjablov. Georgia: R.
`Shakarishvili, A. Tsiskaridze. Germany: P. Flachenecker, P.
`Friedemann, F. Heidenreich, P. Oschmann, G. Reifsch-
`neider, A. Simonow, B. Tackenberg, H. Tumani, R. Wen-
`zel, T. Ziemssen. Hungary: B. Clemens, I. Deme, P.
`Imre, K. Matyas, M. Satori. Israel: J. Chapman. Italy: L.
`Grimaldi, T. Koudriavtseva, M. Rovaris, F. Salvi. Lithua-
`nia: R. Kizlaitiene, D. Rastenyte, S. Sceponaviciute.
`Poland: W. Brola, W. Fryze, E. Jasinska, A. Kaminska, J.
`Kapustecki, M. Kleczkowska, W. Kozubski, J. Krupa-
`Olchawa, E. Motta, R. Nowak, R. Podemski, A. Potem-
`kowski, K.
`Selmaj, M.
`Sobkowiak-Osinska, M.
`Strzelecka-Gorzynska, A. Tutaj, J. Zagorska, J. Zbrojkie-
`wicz. Romania: O. Bajenaru, R. Balasa, G. Boeru, A.
`Bulboaca, A. Campeanu, N. Carciumaru, A. Hancu, I.
`Marginean, M. Pereanu, W. Pop, C. Popescu, M. Simu,
`C. Zaharia. Russia: V. Alifirova, A. Boyko, A. Fedyanin,
`A. Gustov, R. Magzhanov, N. Malkova, N. Maslova, S.
`Odinak, I. Poverennova, S. Perfilyev, S. Prokopenko, T.
`Romazina, A. Shutov, A. Sokoromets, N. Spirin, I. Sto-
`lyarov, L. Volkova. South Africa: M. Isaacs, D. Lurie, C.
`Retief, Z. Sacoor. Ukraine: N. Buchakchyyska, G. Chmyr,
`S. Kareta, T. Kobys, G. Kushnir, K. Loganovskyi, O.
`Moroz, S. Moskovko, T. Nehrych, V. Pashkovskyy, I.
`Pasyura, V. Pinchuk, V. Smolanka, O. Statinova, A.
`Voloshchuk. United Kingdom: D. Rog, B. Sharrack.
`United States: G. Anderson, R. Aung-Din, M. Baker, A.
`Bass, J. Burch, H. Crayton, S. Delgado, B. Dihenia, G.
`Eubank, R. Fallis, W. Felton, J. Florin, G. Garmany, W.
`Grainger, C. Huffman, A. Jacobs, O. Khan, A. Mazhari,
`A. Minagar, A. Miravalle, R. Murray, D. Negroski, R. B.
`Neiman, G. Pardo, S. J. Shafer, C. Sheppard, D. Silver, V.
`Simnad, B. Steingo, D. Thoen, D. Wynn.
`
`References
`1. Kala