Hindawi
`.
`Multiple Sclerosis International
`Volume 2019, Article ID 7151685, 19 pages
`https:lldoi.orgl [0.1155l2019l7i51685
`
`Review Article
`
`
`
`Hindawi
`
`Enduring Clinical Value of Copaxone® (Glatiramer Acetate) in
`Multiple Sclerosis after 20 Years of Use
`
`Daniel R. Wyn-111%
`
`Director, Clinical Research; Consultants in Neurology, Multiple Sclerosis Center, Northbrook, IL, USA
`
`Correspondence should be addressed to Daniel R. Wynn; dwynnmd®gmaiLcom
`
`Received 9 January 2018; Revised 29 June 2018; Accepted 29 November 2018; Published 15 January 2019
`
`Academic Editor: Bruno Brochet
`
`
`
`Copyright © 2019 Daniel R. Wynn. This is an open access article distributed under the Creative Commons Attribution License,
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Multiple sclerosis (MS) is a chronic progressive neurodegenerative demyelinating disease affecting the central nervous system.
`Glatiramer acetate (GA; Copaxone‘b) was die first disease~modifying treatment (DMT) for MS successfully tested in humans (1977)
`and was approved by the US Food and Drug Administration in December 1996. Since then, there have been numerous developments
`in the MS field: advances in neuroimaging allowing more rapid and accurate diagnosis; the availability of a range of DMTs including
`immunosuppressant monoclonal antibodies and oral agents; a more holistic approach to treatment by multidisciplinary teams; and
`an improved awareness ofthe need to consider a patient's preferences and patient-reported outcomes such as quality of iife. The use
`of GA has endured throughout these advances. The purpose of this article is to provide an overview of the important developments
`in the MS field during the 30 years since GA was approved and to review clinical data for GA in MS, with the aim of understanding
`the continued and widespread use of GA. Both drug-related (efficacy versus side-effect profile and monitoring requirements) and
`patient factors (preferences regarding mode of administration and possible pregnancy) will be explored.
`
`I. Introduction
`
`Multiple sclerosis (MS) is a chronic progressive neurodegen-
`erative demyelinating disease alfecting the central nervous
`system (CNS). Symptoms of MS include fatigue, visual
`impairment, spasticity, ataxia,
`tremor, bladderlbowel dys-
`function, sexual dysfunction, pain, and cognitive impair-
`ment. These symptoms have a negative impact on patients’
`quality of life (QOL) as a consequence of reduced inde—
`pendence, ability to work, and participation in sociallleisure
`activities [1]. MS is a highly individual disease with a different
`course in each patient.
`Interferon beta—1b (Betaseron‘F’) was the first Food and
`Drug Administration (FDA)—approved disease-modifying
`treatment (DMT) for MS in 1993, followed by Avonex®
`(interferon beta-la) in May 1996, and Copaxone‘i’ (glatiramer
`acetate [GA]) in December 1996. Generic versions of GA are
`now available; however, throughout this article, “GA” will be
`used to refer to Copaxone®. A discussion of the development
`of generic versions is beyond the scope of this article and the
`reader is referred elsewhere [2—4].
`
`GA was the first subsequently approved DMT success-
`fully tested in humans [5, 6] and it has been studied for
`over 40 years. GA has a complex mechanism of action
`that is not fully understood; however, both neuroprotective
`and immunomodulatory effects are thought to be involved
`(reviewed by Comi et al. [7}). Since the introduction of the
`interferon betas and GA, a wide variety of DMTs have been
`approved,
`including the immunosuppressant monoclonal
`antibodies natalizumab, alemtuzumab, daclizumab {subse-
`quently withdrawn, March 2013), and ocrelizumab (Figure 1).
`Despite this, use of GA has endured. indeed, GA has been
`the most commonly prescribed DMT for relapsing MS in the
`USA since 2008 (40 mg and 20 mg combined prescriptions;
`based on prescriptions for the market definition of DMT for
`relapsing forms of MS in the US [8]). Interestingly, in a study
`of 102 predominantly US neurologists, although efficacy
`was considered the most important attribute of a DMT by
`neurologists, GA was the most commonly prescribed [9]. It
`should also be noted that the development of multiple generic
`versions of GA provides further support for the continued
`clinical value of GA in MS.
`
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`Multiple Sclerosis International
`
`'
`
`Interferon
`
`beta- lba
`I
`; (Betaseron‘)
`
`.
`
`'
`
`3 Natalizumab
`.
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`Mimxnmrone‘
`(Novantmne‘)
`
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`
`_, 2010
`Fingolimod
`(orienya‘)
`
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`
`2014
`Peginterferon
`
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`
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`(Ottevusn')
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`
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`Interferon
`beta-la (1M)
`(Avonexn)
`
`2002
`
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`
`Interferon
`bola-1a (SC)
`
`2013
`Dimethyl
`fumarate
`
`{Tecfidera‘};
`
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`2016
`Daelizumab“l
`(Zinbryta‘)
`
`I
`
`FIGURE 1: Timeline of approval by the FDA of disease-modifying therapies for multiple sclerosis. FDA: Food and Drug Administration; IM:
`intramuscular; SC: subcutaneous. aInterferon beta-1b was also approved in 2009 as Extavia°a (which is the Novartis—branded version of the
`Bayer product Betaseron‘”). bVarious generic versions of glatiramer acetate are in development. GlatopaTM [10] was approved in 2015 by the
`FDA. Other generic versions were approved in the EU in 2016 and by the FDA in 2017 [11, 12]. cBioequivalent generic mitoxantrone was
`approved in 2.006. dSubsequently withdrawn (March 2018).
`
`The purpose ofthis article is to explore the reasons behind
`the enduring use of GA through narrative review of the
`important developments in the MS field during the 20 years
`since GA was approved and a summary of the key data for
`GA in MS.
`
`2. Developments in the MS Field Over the Last
`Two Decades
`
`There have been significant developments in the field of MS
`during the two decades since the approval of GA, which
`are summarized below. Before discussing this, however, it is
`relevant to loolc further back in history. The study of currently
`available DMTs for MS began 40 years ago, with the first
`clinical investigation of GA [5], which led to the develop-
`ment of modern—day MS trial design. This first GA study
`[5] initiated a cascade of research, which resulted in both
`improved study design and treatment options for patients
`with MS. In parallel during this period, the evolution of
`magnetic resonance imaging (MRI) technology has allowed
`the dynamic inflammatory processes in MS to be viewed
`in viva. Over this period, assessments of MS developed
`considerably, from focusing on number and severity of
`relapses, to also considering disability worsening, through
`to use of MRI endpoints such as number of new brain
`lesions, whole brain volume, and brain atrophy, and finally
`to determining segmental brain volume changes (reviewed
`in detail elsewhere [13]). There has also been a growing
`appreciation that changes in CNS gray matter occur in MS
`[i4] , which has permitted a more in-depth understanding and
`prediction of the course of MS in an individual.
`
`In the 19705, the average time to diagnosis was 7 years
`[15]; a definite diagnosis by an MS specialist is now usually
`provided within 6 months of referral
`[16]. This has been
`facilitated by refinement in MRI technology and the con-
`sequent changes to the MS diagnostic criteria (2010 and
`2017 Revisions to the McDonald criteria [17, 18]). The 2017
`revisions to the McDonald criteria allow for a diagnosis (and
`therefore treatment) of MS in patients with a typical clinically
`isolated syndrome and clinical or MRI demonstration of
`dissemination in space and presence of cerebrospinal fluid-
`specific oligoclonal bands [18]. However, given the low symp—
`tom burden in these patients, consideration ofthe tolerability
`of a DMT is particularly important during decision-making.
`An understanding of the critical role played by B cells
`(reviewed by von Biidingen et al. [19]) is another important
`advance in the MS field. This, together with initial reports of
`the efficacy of the CDZO-targeting B-cell—depieting agent rit-
`uximab in MS [20, 21], has paved the way for the development
`of anti-B—ceil therapies, such as ocrelizumab, which is FDA
`approved for both relapsing MS and primary progressive
`M8, for which it was the first FDA-approved therapy (March
`2017). Additional agents, e.g., ofatumurnab and ublituximab,
`are currently in Phase 3 clinical trials. To date, however,
`there is no universally accepted treatment algorithm for
`MS [22].
`Together, the improvements in diagnosis and availability
`of eifective treatment options have allowed earlier treatment
`of patients. The consensus of opinion supports initiation of
`DMTs early in the course of MS [22, 23] with the goal of
`preventing accumulation of irreversible neurological damage
`and worsening to secondary progressive MS. Attention has
`now turned to consideration of personalized therapy, with
`
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`Multiple Sclerosis International
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`a goal of establishing the most effective and safe treatment
`outcomes.
`
`Two treatment approaches are currently used for initial
`treatment of MS: lower- versus higher~efficacy DMTs from
`the time of disease diagnosis. Administration of lower-
`efficacy therapies at disease diagnosis is more common and
`is suitable for patients who present with MS with favor-
`able prognostic factors. It involves initial use of therapies
`such as GA and interferon betas, followed by newer agents
`(dimethyl fumarate, fingolimod, teriflunomide, natalizumab,
`alemtuzumab, ocrelizumab, etc.) if the patient’s response to
`first-line treatment is suboptimal. In contrast, administration
`of highweflicacy therapies from the time of MS diagnosis
`is used for patients with aggressive MS where the risk of
`early permanent disability from active disease may outweigh
`the risk of drug-related safety issues (detailed later). This
`approach involves early use of immunosuppressive therapy
`to achieve disease control, after which patients may switch to
`another agent ifthere is either lack ofefficacy, or tolerability or
`safety concerns. The best approach for early treatment is the
`topic of considerable debate and is beyond the scope of this
`article; the subject has been extensively reviewed elsewhere
`[24—26]. Key points of the debate are the differences in
`riskzbenefit for the disease versus adverse drug effects.
`Such has been the progress in treatment of MS that it is
`now possible to contemplate the target of "no evident disease
`activity” (NEDA), i.e., the absence of clinical disease activ-
`ity (relapse, disease progression, and radiographic lesions
`determined by MRI). Although this is currently a topic of
`much debate, a discussion on the applicability of NEDA is
`beyond the scope of this review. In the author’s opinion,
`the issues with NEDA at present {27} limit its usefulness in
`clinical practice. Furthermore, repeatedly switching DMTs in
`an attempt to achieve NEDA, in the absence of a cure for MS,
`may result in both unknown safety consequences and unclear
`benefits in preventing long-term disability.
`Implementation ofthe management ofMS by multidisci-
`plinary teams has resulted in substantial improvements in the
`experience of patients with MS [28, 29]. Care is now delivered
`by teams of clinicians including a wide range of specialists.
`A further positive development in MS management is mul-
`tidisciplinary pharmacological management of the disabling
`symptoms of MS (reviewed by Toosy et al. [30]).
`Although not unique to MS, consideration of patients’
`views on disease management has contributed to improved
`patient care. Shared decision-making between the patient
`and physician is now considered best practice [31] and is
`thought to improve treatment satisfaction and adherence
`[32]. Associated with the importance of patients’ views is the
`recognition of the importance of patient-reported outcomes
`in MS [1]. In the absence of a curative therapy, and given
`the different safety profiles ofDMTs, shared decision-making
`and patient—reported outcomes are particularly important
`for the treatment of MS and affect treatment adherence
`(discussed later). Obtaining patient-reported outcome data is
`new standard in MS clinical trials.
`
`Further areas of interest in the field of MS that are beyond
`the scope of this review but are attracting a considerable
`degree of attention include the potential involvement of the
`
`gut microbiome [33]; ongoing efforts to identify pharmacoge-
`netic markers for treatment response [34]; and the possibility
`of cell-based therapies for MS (particularly neuroprotection
`and/or repair of MS~related damage to the CNS) [35].
`Although progress has been made across the MS field dur—
`ing the past 20 years, a range of treatment issues remain to be
`addressed. No targeted DMT is approved for secondary pro—
`gressive MS, although the Phase 3 EXPAND study reported
`that siponimod reduced the risk of disability progression in
`patients with secondary progressive MS [36]. Furthermore,
`as a consequence of the availability of numerous DMTs,
`treatment decisions are now more complex. However, reliable
`biological markers for predicting future disease course and
`response to treatment are not yet available.
`
`3. The Clinical Value of Glatirarner Acetate in
`the Treatment of MS
`
`GA (also known as copolymer—l) was designed as a synthetic
`analog of myelin basic protein, a presumptive autoanti-
`gen associated with MS. GA is a standardized mixture of
`polypeptides randomly polymerized from four L-amino acids
`found in myelin basic protein: nglutamic acid, L-lysine, L-
`alanine, and L-tyrosine, in a defined molar residue ratio of
`0.14:0.34:0.43:0.09 [7]. The average molecular mass of GA
`is 5—9 ltDa [37]. GA was initially approved as a 20 mg
`subcutaneous (SC) once-daily formulation;
`it is now also
`available as a 40 mg three-times weekly formulation. Possible
`reasons for the long-standing use of GA in the treatment of
`MS will be explored through review ofthe clinical data for GA
`and factors (relating to both the drug and patient) affecting
`the choice of DMTs for MS.
`
`3.1. Clinical Datafor Glatimmer Acetate
`
`3.1.1. Pivotal Clinical Studies and Long~Term Data. GA was
`initially investigated in a case series [5], followed by two small
`pilot studies [6, 38]. Two pivotal placebo-controlled studies
`subsequently demonstrated the efficacy of GA in patients
`with relapsing MS (US Glatiramer Acetate Trial [39] and the
`EuropeanlCanadian MRI study [40]; see Table 1).
`The 2-year US Glatiramer Acetate Trial was the US
`registration study and reported a 29% reduction in the
`annualized relapse rate (ARR) for GA treatment compared
`with placebo. Similarly,
`the 9-month EuropeanlCanadian
`MRI study reported a 33% reduction in the relapse rate
`[40]. These short-term studies did not report significant
`improvements in disability progression as assessed by the
`Expanded Disability Status Scale (EDSS). However, the US
`Glatiramer Acetate Trial open-label extension study reported
`consistently low ARRs (15 years: 0.25; 20 years: 0.2) with
`more than three-quarters of patients being ambulatory with-
`out mobility aids (EDSS score <6) at 15 years (82%) and
`20 years (79.5%) [41, 42]. Furthermore, 65% and 53% had
`not progressed to secondary progressive MS at the 15- and
`20-year timepoints, respectively [41, 42]. These data are for
`patients who continued in the study (n=100 at 15 years;
`n=74 at 20 years); as with all long~terrn extension studies,
`
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`
`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 6
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`
`
`

`

`Multiple Sclerosis International
`
`the issue of selection bias owing to drop-outs of patients
`with more aggressive disease should be borne in mind when
`considering these data. Overall, the two long-term extension
`studies (Table 1) demonstrated that the efficacy of GA is
`maintained over time {41—44]. Furthermore, there are no
`reports of a rebound effect or delayed reactivation following
`discontinuation [41, 44, 48, 49]. As detailed in Table 1, real—
`world data from a variety of sources (retrospective studies,
`US claims database analysis, and propensity score-matched
`analysis of the MSBase registry) support the efficacy data
`reported in clinical studies [46—49].
`Lower-frequency dosing regimens have been investigated
`for GA. A large Phase 3 placebo-controlled trial (GALA study
`{581) in GA—nai've patients reported similar safety and efficacy
`profiles for GA 40 mg three-times weekly compared with the
`earlier pivotal controlled trials of a 20 mg once-daily dose.
`This trial led to FDA approval in January 2014 of the GA
`threeutimes weekly SC formulation (40 mg). A further study
`(GLACIER) demonstrated the efficacy, safety, and tolerability
`of switching from GA 20 mg SC once daily (after >6 months’
`therapy) to 40 mg three-times weekly [59].
`in both pivotal trials of GA 20 mg, injection-site reaction
`was the most common adverse event associated with GA
`treatment [39, 40] and safety in the extension studies was
`consistent with the placebo-controlled phases, with no long-
`term safety issues identified [41-44]. The three-times weekly
`formulation was noted to be associated with a 50% reduction
`in the annualized risk of injection-site reactions compared
`with the once—daily formulation (GLACIER study [59]). To
`date, GA is the only DMT with more than 10 years of
`continuously monitored safety data, with follow-up data for
`up to 20 years also avaiiable (US Glatiramer Acetate Trial
`[41, 42]; see Tabie 1). It is interesting to note that patients
`in the extension study were committed to self-administering
`daily SC injections of GA, thus emphasizing the iong-term
`tolerability and patient acceptance of GA and its route of
`administration [41].
`Importantly, results from a comprehensive database anal-
`ysis [60] of the long-term safety and tolerability of GA in
`all patients with MS who have ever been exposed to GA
`(20 mg SC daily) in clinical trials are consistent with the long-
`term extension studies. In brief, the total exposure to GA was
`10 017 patient—years and treatment duration ranged from 0
`to 23.1 years (median 1.8 years). Injection-site—reiated events
`were the most common adverse events, affecting 49% of
`patients; erythema at the injection site was the most common
`effect (29%). Such local injection-site reactions are generally
`transient, resolving within hours to days and decreasing in
`frequency over time [61]. An acute and transient immediate
`systemic postinjection reaction including at ieast one of the
`following symptoms: flushing, chest tightness, palpitations,
`and dyspnea, is also common; the database analysis found
`an incidence of 24%, with dyspnea being the most common
`manifestation (12%). Other common adverse events were
`rash (i596), headache (14%), infection (12%), and vasodilation
`(11%) {60]. No unexpected adverse events were recorded [60].
`The prescribing information for GA includes a warning that
`localized lipoatrophy and, rarely, injection-site necrosis may
`occur with GA treatment [37]. Lipoatrophy (loss of fat tissue
`
`resuiting in depressions in the skin) at injection sites may
`occur up to several months after treatment initiation and
`persist after treatment cessation [62]. Although some studies
`suggest that it occurs in up to 64% of patients treated with
`GA [62], the database analysis found it to be reported as an
`adverse event in 0.3% ofGA—treated patients [60]. Patients are
`advised to rotate injection sites daily to assist in minimizing
`such effects [37}.
`
`3.1.2. MRI Data. The EuropeaniCanadian Glatiramer
`Acetate MRI study was designed to evaluate the effect of GA
`on MRI-monitored features of MS and inciuded monthly
`MRI scans. This study reported a 29% reduction in the
`number ofgadoliniumnenhancing iesions with GA treatment
`and treatment eifects
`favoring GA across other MRI
`endpoints [40]. Although MR1 endpoints were not included
`in the initial placebo«controlled phase of the US Glatiramer
`Acetate Study [39], MRI evaluation was added during the
`open-label
`long-term foliow-up [63]. GA treatment had
`modest but consistent effects in reducing brain atrophy
`metrics compared with placebo [63]. Overall, available
`MRI data suggest that GA treatment reduces brain axonal
`metabolic injury, tissue damage, atrophy, and brain volume
`loss {45, 64—67].
`
`3.1.3. Comparator Studies. Few head-to-head studies have
`compared GA 20 mg with other DMTs (Table 2). In gen-
`eral, similar clinical eflicacy has been observed to that of
`interferon beta-1a and interferon beta—1b (Table 2). In short-
`term studies, there are conflicting data on brain volume loss
`with GA versus interferons [51, 53] (see Table 2). A long-
`term study of brain volume changes reported that patients
`receiving GA experienced a significantly lower reduction in
`brain volume over 5 years compared with those receiving low-
`dose interferon beta-1a or high-dose interferon beta-lb [45].
`However, these data should be interpreted with caution as
`MRI parameters were not standardized across studies.
`A systematic Cochrane review comparing GA with
`interferon treatments for MS reported similar efficacy at
`24 months for clinical endpoints (number of patients with
`relapse,
`interferon versus GA: risk ratio [RR] 1.04, 95%
`confidence interval {CI} 0.87 to 1.24; and worsening [EDSS
`progression]: RR 13.1, 95% Ci 0.91 to 1.35; both moderate-
`grade evidence) and some MRI endpoints (new gadolinium-
`enhancing T1 lesions: mean difference [MD] interferon ver-
`sus GA -0.l4, 95% CI -0.30 to 0.02; moderate—grade evidence);
`however, long—term data (>3 years) were not included [68].
`In contrast, when MRI lesion ioad accrual was analyzed,
`interferon treatments were found to limit the increase in
`lesion burden to a greater extent than GA (total T2-weighted
`lesion volume MD -0.58, 95% CI -0.99 to ~0.18, p=0.004; total
`Tl—weighted iesion volume MD «0.20, 95% CI -0.33 to -0.07,
`p=0.003; moderate-grade evidence) [68].
`A 2-year Phase 3 study designed to compare GA 20 mg
`and dimethyl fumarate (240 mg two- [FDA-approved dose]
`or three-times daily) with placebo reported that estimated
`treatment effects for clinical and MRI outcomes were numeri-
`cally similar for the active comparators or greater for dimethyl
`fumarate [54]. Although of limited value, a post hoc direct
`
`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 7
`
`

`

`
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`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 8
`
`MYLAN PHARMS. INC. EXHIBIT 1064 PAGE 8
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`
`
`
`
`
`
`

`

`Multiple Sclerosis International
`
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