Patient Experience with Glatiramer Acetate 40 mg/1 mL
`Three-Times Weekly Treatment for Relapsing-Remitting
`Multiple Sclerosis: Results from the GLACIER Extension Study
`Daniel Wynn, MD1; Scott Kolodny, MD2; Svetlana Rubinchick3; Joshua R. Steinerman, MD4; Jerry S. Wolinsky, MD5;
`Augusto Grinspan, MD4 on behalf of the GLACIER study group
`
`1Consultants in Neurology, Northbrook, Illinois, USA; 2Teva Pharmaceutical Industries, Cleveland, Ohio, USA; 3Teva Pharmaceutical Industries, Netanya, Israel;
`4Teva Pharmaceutical Industries, Frazer, Pennsylvania, USA; 5University of Texas, Health Science Center at Houston, Houston, Texas, USA
`
`Support for the study was provided
`by Teva Pharmaceutical Industries,
`Israel
`
`84.9
`
`82.2
`
`Converters (n=95)
`Non-converters (n=101)
`
`Last
`observation
`
`Figure 3. Change in TSQM-9 Convenience Score
`
`90
`
`85
`
`80
`
`75
`
`75.6
`75.9
`
`90
`
`85
`
`85.1
`
`80
`
`78.0
`
`75
`
`84.7
`
`77.6
`
`GA20 (n=100)
`GA40 (n=108)
`
`0
`
`0
`
`1
`
`2
`
`3
`
`4
`
`0
`Extension phase
`baseline
`
`Unadjusted Mean TSQM-9
`
`Convenience Score
`
`Statistical Analyses
`• There were no additional sample size considerations, and no formal statistical testing was
`conducted on data from the extension phase
` — Descriptive statistics were calculated for continuous and categorical variables
`• The analysis for the rate of IRAEs during the extension phase was performed on the
`intent-to treat-extension analysis set (converters, n=97; non-converters, n=101), which
`included all patients randomized in the core phase who continued into the extension
`phase of the study
`• The analysis of the changes in TSQM-9 convenience scores was performed on the full
`analysis set extension cohort (converters, n=95; non-converters, n=101), which included
`all patients in the intent-to-treat-extension analysis who had at least one post-baseline
`measurement of MSIS-29 or TSQM-9 assessments in the extension phase of the study
`
`P-40
`
`Presented at
`The 8th Congress of the Pan-Asian Committee
`for Treatment and Research in Multiple Sclerosis
`(PACTRIMS)
`Seoul, Republic of Korea
`November 19–21, 2015
`
`BACKGROUND
`
`Core Phase Month
`
`Extension Phase Visit
`
`Error bars represent standard error.
`Converters, patients converting from GA20 during the core phase to GA40 in the extension phase; GA20, glatiramer acetate 20 mg/mL
`daily; GA40, glatiramer acetate 40 mg/mL three-times weekly; non-converters, patients continuing with GA40 treatment from the core
`phase to the extension phase.
`Rate of IRAEs
`• Converters and non-converters had similar annualized IRAE rates on GA40 during the
`extension phase (23.1 and 28.0 events per year, respectively) (Figure 4)
` — During the core phase, patients converting to GA40 had a 50% lower rate of IRAEs than
`those randomized to continue GA20
`• Most IRAEs were ISRs, and, consequently, the ISR rates for converters and for non-
`converters during the extension phase were almost identical to the IRAE rates observed
`for each group during this period (22.9 and 28.0 events per year, respectively)
`
`Figure 4. Annualized Rates of IRAEs during Extension Phase for Converters
`and Non-converters
`
`23.1
`
`28.0
`
`50
`
`40
`
`30
`
`20
`
`Annualized IRAE Rate
`
`(Events per Year)
`
`Very
`easy
`6
`
`Very
`easy
`6
`
`Very
`convenient
`6
`
`Extremely
`easy
`7
`
`Extremely
`easy
`7
`
`Extremely
`convenient
`7
`
`Box 1. Definitions of Severity of IRAEs
`Severity
`Definition
`Mild
`Symptoms that are easily tolerated
`Moderate
`Symptoms sufficiently discomforting to interfere with daily activity
`Severe
`Symptoms that prevent normal daily activities
`IRAE, injection-related adverse event.
`
`Box 2. Sample Questions from TSQM-9: Convenience Subscale
`4
`How easy or difficult is it to use the medication in its current form?
`Extremely
`Very
`Somewhat
`Easy
`Difficult
`difficult
`difficult
`easy
`5
`3
`1
`2
`4
`How easy or difficult is it to plan when you will use the medication each time?
`Extremely
`Very
`Somewhat
`Easy
`Difficult
`difficult
`difficult
`easy
`5
`3
`1
`2
`4
`How convenient or inconvenient is it to take the medication as instructed?
`Extremely
`Very
`Somewhat
`Inconvenient
`inconvenient
`inconvenient
`convenient
`3
`1
`2
`4
`TSQM-9, Treatment Satisfaction Questionnaire for Medication-9.
`
`5
`
`6
`
`Convenient
`5
`
`RESULTS
`
`10
`
`0
`
`Converters
`(n=97; PY=33.5)
`
`Non-converters
`(n=101; PY=34.9)
`
`Converters, patients converting from GA20 during the core phase to GA40 in the extension phase; IRAE, injection-related adverse
`event; non-converters, patients continuing with GA40 treatment from the core phase to the extension phase; PY, patient-year during
`extension phase.
`Incidence, Frequency, and Severity of IRAEs and ISRs
`• The numbers of patients experiencing IRAEs and ISRs, and the total numbers of events,
`were similar between converters and non-converters (Table 2)
`• Furthermore, the frequency of moderate or severe IRAE or ISR events occurring during the
`extension phase was low, with converters and non-converters demonstrating similar values
`(Table 2)
` — The proportion of all events that were moderate or severe during the extension phase
`was similar to that observed in the GA40 group during the core phase; in the core
`phase, the proportion of all IRAE events that were moderate or severe was lower in
`GA40-treated patients (9.1%) than in GA20-treated patients (18.8%)
`• The ISR frequency and event rates for individual ISR types (as categorized by MedDRA 16.0
`preferred terms) were small (Table 3)
` — As in the core phase, the most common ISR events included injection-site pain,
`erythema, and mass
` — During the core phase, there was a reduction in ISR frequency and event rates with
`GA40 versus with GA20 for all common ISR types
`
`Table 2. IRAE and ISR Frequency and Severitya
`
`Total number of IRAEs
`Number of moderate or severe IRAEs (% of total)
`Patients with ≥1 IRAE, n (%)
`Total number of ISRs
`Number of moderate or severe ISRs (% of total)
`Patients with ≥1 ISR, n (%)
`aThe numbers of IRAEs and ISRs represent individually reported events.
`Converters, patients converting from GA20 during the core phase to GA40 in the extension phase; IRAE, injection-related adverse
`event; ISR, injection-site reaction; non-converters, patients continuing with GA40 treatment from the core phase to the extension
`phase; PY, patient-year during extension phase.
`
`Non-converters
`(n=101, PY=34.9)
`1764
`117 (6.6)
`33 (32.7)
`1760
`114 (6.5)
`32 (31.7)
`
`Converters
`(n=97, PY=33.5)
`1331
`129 (9.7)
`31 (32.0)
`1318
`125 (9.5)
`31 (32.0)
`
`Table 3. ISR Frequency and Annualized Event Ratesa
`
`Number of ISRs (Annualized Event Rate)
`Injection-site bruising
`Injection-site discoloration
`Injection-site discomfort
`Injection-site erythema
`Injection-site hemorrhage
`Injection-site mass
`Injection-site pain
`Injection-site pruritus
`Injection-site rash
`Injection-site scab
`Injection-site swelling
`Injection-site urticaria
`Injection-site vesicles
`Injection-site warmth
`aThe numbers of ISRs represent individually reported events.
`ISR, injection site reaction; PY, patient-year during extension phase.
`
`CONCLUSIONS
`
`All Patients
`(n=198, PY=68.3)
`15 (0.2)
`21 (0.3)
`3 (0.0)
`689 (10.1)
`15 (0.2)
`456 (6.7)
`1220 (17.9)
`166 (2.4)
`5 (0.1)
`1 (0.0)
`197 (2.9)
`240 (3.5)
`3 (0.0)
`47 (0.7)
`
`• Over 99% of GLACIER core-phase completers elected to receive GA40 during the
`extension phase
`• The low overall discontinuation rate and robust participation in the extension phase
`provides evidence of the clinical appeal of the low-frequency dose regimen GA40
`• The TSQM-9 convenience score showed positive changes for converters to GA40 and
`was sustained for non-converters continuing GA40 during the extension phase
` — The perception of increased convenience with conversion to GA40 in the extension
`phase supports the findings of the core phase, in which patients treated with
`GA40 demonstrated a nominally greater increase in perception of convenience
`versus GA20 patients
` — The sustained perception of increased convenience for non-converters through both
`the core phase and the extension phase demonstrates the sustained benefits of
`converting to GA40
`• Low IRAE rates were observed during the extension phase, predominantly driven by the
`well-recognized ISR types seen with GA therapy
` — Furthermore, only a small proportion of IRAEs were severe enough to interfere with
`or prevent daily activity
`• These outcomes demonstrate the clinical value of GA40 and the favorable therapeutic
`profile and convenience of this regimen for the treatment of RRMS
`
`Patients
`• During the core phase of the GLACIER study, 209 patients were randomized to the study
`treatment (GA20, n=101; GA40, n=108) (Figure 2)
` — 98 patients (97%) treated with GA20 and 101 patients (94%) treated with GA40
`completed the 4-month core phase
`• 97 GA20 completers (99%) elected to participate in the extension phase, and all 101 of
`the GA40 completers (100%) elected to continue GA40 treatment during the extension
`phase (Figure 2)
` — 91 converters (93.8%) and 97 non-converters (96.0%) completed the study
` — 46 converters (47.4%) and 51 non-converters (50.5%) returned to the study site for
`the extension phase Month 4 assessment
`• Converters and non-converters had the same mean duration of drug exposure (126 days)
`during the extension phase
` — More than 40% of patients in each group had ≤4 months of exposure to GA40
`during the extension phase (Figure 2)
`• Baseline patient demographics and disease characteristics in the extension phase were similar
`to those in the core phase and showed no differences between the converters and non-
`converters (Table 1)
` — Most patients were female (82.3%) and white (93.9%)
` — The mean ± standard deviation (SD) patient age was 50.5±10.3 years, and the mean
`± SD time from MS diagnosis was 11.3±9.3 years
`
`Figure 2. GLACIER Patient Disposition and GA40 Exposure during Extension Phase
`
`• Inconvenient treatment regimens may present a barrier to maintaining appropriate adherence
`to therapies for relapsing-remitting multiple sclerosis (RRMS)1,2
` — Non-adherence to treatment is associated with increased risk of relapse and poor
`clinical outcomes3,4
`• The development of modified treatment regimens, alternative dosages, and low-
`frequency administration schedules for drugs with proven long-term efficacy may be a
`viable strategy for promoting adherence and reducing medication gaps4,5
` — Such treatment strategies are aimed at improving patient experience by reducing the
`risk of adverse events and increasing the overall convenience of treatment5
`• Glatiramer acetate (GA), a first-line therapy approved for the treatment of RRMS,6
`has a well-characterized long-term safety profile and established efficacy, with more
`than 2 million patient-years of overall exposure to GA 20 mg/mL administered daily by
`subcutaneous injection (GA20)7,8
`• Since 2014, based largely on the results of the GALA (Glatiramer Acetate Low-frequency
`Administration) study, GA 40 mg/mL administered three-times weekly by subcutaneous
`injection (GA40) has been approved for the treatment of RRMS by regulatory authorities in
`the United States, Australia, Israel, Argentina, Chile, Mexico, South Korea, and 18 European
`countries (as of March 2015)
` — The low-frequency GA40 regimen was shown to have an efficacy and safety profile
`similar to that of the established daily GA20 regimen9
` — The new GA40 dosing regimen provides the convenience of fewer injections per week
`• The randomized, open-label GLACIER (GLatiramer Acetate low frequenCy safety and
`patIent ExpeRience) study evaluated the clinical value of GA40 by analyzing safety,
`tolerability, and patient experience endpoints in a cohort of RRMS patients converting
`from GA20 to GA40
` — In the 4-month core study, patients converting to GA40 had a 50% lower rate of
`injection-related adverse events (IRAEs) compared with those randomized to continue
`GA20 (Figure 1)10
` — Patient expectations that GA40 would be more convenient than GA20 were
`confirmed, as the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)
`convenience subscale score showed positive changes for GA40-treated patients soon
`after conversion11
`• At the end of the 4-month core study, GA20 completers were invited to convert to
`GA40, and GA40 completers were invited to continue on GA40, for an extension phase
`of the GLACIER study
` — The current study evaluates patient-centric outcomes and, more specifically, the
`perceived convenience of GA40 among all participants in the extension phase
` — This study also evaluates the primary endpoint of IRAE rate during the extension phase
`
`Figure 1. Adjusted Mean Annualized Rate of IRAEs during Core Phase
`
`RR=0.50
`95% CI: 0.34–0.74
`P=0.0006
`
`70.4
`
`GA20
`(n=101)
`
`35.3
`
`GA40
`(n=108)
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`(Events per Year)
`
`Adjusted Mean Annualized IRAE Rate
`
`Error bars represent standard error.
`CI, confidence interval; GA20, glatiramer acetate 20 mg/mL administered daily by subcutaneous injection; GA40, glatiramer acetate
`40 mg/mL administered three-times weekly by subcutaneous injection; IRAE, injection-related adverse event; RR, relative risk.
`
`Core Phase
`
`218 screened for eligibility
`
`209 enrolled and randomized
`
`METHODS
`
`Study Design
`• GLACIER was an open-label, randomized, parallel-group study conducted at 31 sites in
`the United States and consisting of a core phase and an extension phase
` — As described previously,10 the eligibility criteria identified a neurologically stable
`population of RRMS patients who had been treated with GA20 for at least 6 months
`prior to screening
` — During the core phase, eligible patients were randomly assigned in equal proportions
`(1:1) to continue with GA20 or convert to GA40
`• Patients from either treatment group in the core phase (GA20 and GA40) were eligible
`for participation in the extension study if they completed the core study according to the
`protocol
`• All patients participating in the extension phase received GA40 treatment and were
`identified as follows:
` — Converters: patients converting from GA20 during the core phase to GA40 in the
`extension phase
` — Non-converters: patients continuing with GA40 treatment from the core phase to the
`extension phase
`• Site visits and patient evaluations occurred during the extension phase at the extension
`phase baseline (Month 4 visit of the core phase) and every 4 months until GA40 became
`commercially available for the treatment of patients with RRMS or when a participant
`terminated the study early (termination/early termination [ET] visit of the extension phase)
`Study Endpoints
`• The primary endpoint was the annualized rate of IRAEs, i.e. the total number of IRAE
`events occurring during the extension phase per patient-year of drug exposure during
`the extension phase
` — Assessments of IRAEs (including all local injection-site reactions [ISRs] and symptoms
`or events related to immediate post-injection reaction) were performed throughout
`the extension phase based on the patient’s diary card recordings of IRAE occurrence
`and severity
` — Severity was defined as shown in Box 1
` — All IRAEs occurring in the active treatment phase were coded to MedDRA 16.0
`preferred terms
`• The secondary endpoint was change in assessment of patient perceptions of
`convenience, using the convenience-specific subscale (items 4–6) of the validated TSQM-9,
`as measured every 4 months from extension phase baseline (Box 2)
` — Higher scores represented more positive perceptions of treatment
`• Additional endpoints included the rate of ISRs, subject-reported impact on physical and
`psychological well-being using the Multiple Sclerosis Impact Scale-29 questionnaire (MSIS-29),
`and subject perceptions of overall satisfaction using the TSQM-9 subscale (items 7–9)
`Study Methodology
`• The last observed post-baseline data were used for endpoint visit analysis in the
`extension phase
` — For patients who withdrew from the study, data at the ET visit were included in the
`endpoint visit analysis, with the exception of MSIS-29 and TSQM-9 questionnaire data,
`for which the ET visit was considered as the next scheduled visit
`
`101 assigned to GA20
`
`108 assigned to GA40
`
`3 discontinued
`
`7 discontinued
`
` 98 completed 4 months
`
`101 completed 4 months
`
`Extension Phase
`
`97 continued to GA40
`extension phase
`
`101 continued to GA40
`extension phase
`
`6 discontinued
`3 had an adverse event
`2 withdrew consent
`1 was lost to follow-up
`
`4 discontinued
`2 had an adverse event
`1 withdrew consent
`1 had a protocol violation
`
`91 converters
`completed studya
`
`97 non-converters
`completed studya
`
`Extent of Exposure to GA40 during the Extension Phase
`Time Treated, n (%)
`Converters (n=97)
`≤4 months
`44 (45.4)
`>4 months
`53 (54.6)
`
`Non-converters (n=101)
`43 (42.6)
`58 (57.4)
`
`aPatients participating in the GLACIER extension were exposed to GA40 for varying lengths of time during the extension phase.
`Converters, patients converting from GA20 during the core phase to GA40 in the extension phase; GA20, glatiramer acetate 20 mg/mL daily;
`GA40, glatiramer acetate 40 mg/mL three-times weekly; non-converters, patients continuing with GA40 treatment from the core phase to
`the extension phase.
`
`Table 1. Extension Phase Baseline Patient Demographics and Disease Characteristics
`Converters
`Non-converters
`(n=97)
`(n=101)
`50.3±9.4
`50.6±11.2
`79 (81.4)
`84 (83.2)
`
`Age, years, mean ± SD
`Female gender, n (%)
`Race, n (%)
`94 (93.1)
`92 (94.8)
`White
`5 (5.0)
`5 (5.2)
`Black/African American
`2 (2.0)
`0 (0.0)
`Asian
`0 (0.0)
`0 (0.0)
`Native American/Alaskan Native
`27.9±6.2
`29.3±6.5
`Body mass index, mean ± SD
`2.4±1.3
`2.4±1.4
`EDSS, mean ± SD
`15.4±11.0
`16.1±11.0
`Years from onset of first MS symptoms, mean ± SD
`10.4±8.3
`12.2±10.1
`Years from MS diagnosis, mean ± SD
`Converters, patients converting from GA20 during the core phase to GA40 in the extension phase; EDSS, Expanded Disability Status
`Scale; MS, multiple sclerosis; non-converters, patients continuing with GA40 treatment from the core phase to the extension phase;
`SD, standard deviation.
`Patient-Reported Perceptions of Convenience Using the TSQM-9
`• Converters demonstrated an improvement in mean convenience score, from 78.0
`following GA20 treatment to 82.2 at last observation following conversion to GA40;
`non-converters had a mean convenience score of 85.1 at the beginning of the extension
`phase and a score of 84.9 at last observation (Figure 3)
`• Patients continuing on GA40 in the extension phase maintained the improved
`convenience scores that were observed as early as the first month of treatment during
`the core phase (Figure 3)
` — During the core phase, patients receiving GA40 had a nominally greater increase in
`the TSQM-9 convenience score from baseline to Month 4 versus those receiving
`GA20 (treatment effect, 7.0)
`
`Acknowledgments This study was funded by Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel. We thank the patients and site personnel involved with this
`study; Robin Everts (of Teva Pharmaceuticals) for assistance with study conduct and statistical analyses; and Rhonda Charles, PhD (Chameleon Communications International
`with funding from Teva Pharmaceutical Industries) and Peter Feldman, PhD (Teva Pharmaceuticals) for editorial assistance.
`Disclosures Daniel Wynn has received compensation for speaking and/or consulting from Acorda Therapeutics, Avanir Pharmaceuticals, EMD Serono,
`GlaxoSmithKline, Pfizer, Sanofi/Genzyme, Teva, and Xenoport, and has received research support from Acorda Therapeutics, Avanir Pharmaceuticals, Chugai Pharma, EMD
`Serono, GlaxoSmithKline, Novartis, Ono, Osmotica, Receptos, Roche, Sanofi/Genzyme, Xenoport, Teva, and the National MS Society.
`Scott Kolodny, Svetlana Rubinchick, Joshua R. Steinerman, and Augusto Grinspan are employees of Teva Pharmaceutical Industries.
`Jerry S. Wolinsky has received compensation for service on steering committees or data monitoring boards for Novartis, Roche, Sanofi, and Teva, and for consulting from
`Athersys, Genzyme, Novartis, Roche, RND, Teva, and XenoPort; has received royalty payments through the University of Texas Health Science Center at Houston for
`monoclonal antibodies out-licensed to Chemicon International; and has received research support from Genzyme, Sanofi, and the National Institutes of Health through the
`University of Texas Health Science Center at Houston.
`
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`Medscape J Med 2008;10:225. 2. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol 2009;256:568-576.
`3. Al-Sabbagh A, Bennet R, Kozma C, Dickson M, Meletiche DM. Medication gaps in disease-modifying therapy for multiple sclerosis are associated with an increased risk
`of relapse: Findings from a national managed care database. J Neurol 2008;255:S79. 4. Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S. Impact of adherence to disease-
`modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther 2011;28:51-61. 5. Remington G, Rodriguez Y, Logan D,
`Williamson C, Treadaway K. Facilitating medication adherence in patients with multiple sclerosis. Int J MS Care 2013;15:36-45. 6. Copaxone® [package insert] North Wales,
`PA: Teva Pharmaceuticals USA, Inc., 2014. 7. Boster A, Bartoszek MP, O’Connell C, Pitt D, Racke M. Efficacy, safety, and cost-effectiveness of glatiramer acetate in the
`treatment of relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord 2011;4:319-332. 8. Data on file. Copaxone exposure (June 30, 2014). Teva Pharmaceutical Industries
`Ltd. 9. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013;73:705-713.
`10. Wolinsky JS, Dietrich DW, Borresen TE, et al. GLACIER: open-label, randomized safety/tolerability study of glatiramer acetate 40mg/mL three times weekly versus 20mg/
`mL daily in RRMS. Mult Scler 2014;20(suppl 1):14-66. Abstract FC3.2. 11. Wolinsky JS, Borresen TE, Dietrich DW, et al. Convenience of glatiramer acetate 40mg/mL three
`times weekly: evidence from the GLACIER study. Mult Scler 2014; 20(suppl 1):67-284. Abstract P080.
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`YEDA EXHIBIT NO. 2096
`MYLAN PHARM. v YEDA
`IPR2015-00644