Patient Preference and Adherence
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`Two decades of subcutaneous glatiramer acetate
`injection: current role of the standard dose, and
`new high-dose low-frequency glatiramer acetate
`in relapsing–remitting multiple sclerosis treatment
`
`Matteo Caporro
`Giulio Disanto
`Claudio Gobbi
`Chiara Zecca
`Neurocenter of Southern Switzerland,
`Ospedale Regionale di Lugano, Lugano,
`Switzerland
`
`Correspondence: Chiara Zecca
`Neurocenter of Southern Switzerland,
`Ospedale Regionale di Lugano, 46 Via
`Tesserete, Lugano 6903, Switzerland
`Tel (cid:11)41 91 811 6921
`Fax (cid:11)41 91 811 6915
`Email chiara.zecca@eoc.ch
`
`Abstract: Glatiramer acetate, a synthetic amino acid polymer analog of myelin basic protein,
`is one of the first approved drugs for the treatment of relapsing–remitting multiple sclerosis.
`Several clinical trials have shown consistent and sustained efficacy of glatiramer acetate 20 mg
`subcutaneously daily in reducing relapses and new demyelinating lesions on magnetic resonance
`imaging in patients with relapsing–remitting multiple sclerosis, as well as comparable efficacy
`to high-dose interferon beta. Some preclinical and clinical data suggest a neuroprotective role
`for glatiramer acetate in multiple sclerosis. Glatiramer acetate is associated with a relatively
`favorable side-effect profile, and importantly this was confirmed also during long-term use.
`Glatiramer acetate is the only multiple sclerosis treatment compound that has gained the US
`Food and Drug Administration pregnancy category B. All these data support its current use as
`a first-line treatment option for patients with clinical isolated syndrome or relapsing–remitting
`multiple sclerosis. More recent data have shown that high-dose glatiramer acetate (ie, 40 mg)
`given three times weekly is effective, safe, and well tolerated in the treatment of relapsing–
`remitting multiple sclerosis, prompting the approval of this dosage in the US in early 2014.
`This high-dose, lower-frequency glatiramer acetate might represent a new, more convenient
`regimen of administration, and this might enhance patients’ adherence to the treatment, crucial
`for optimal disease control.
`Keywords: glatiramer acetate, disease modifying treatment, efficacy, safety
`
`Introduction
`Multiple sclerosis (MS) is a chronic immune-mediated disease involving the white and
`gray matter of the central nervous system (CNS), causing neurological dysfunction.1
`It affects predominantly females, and has a prevalence varying from five to 80 per
`100,000 persons worldwide.2 It is thought to be a multifactorial disease resulting from
`an autoimmune reaction to self-antigens in genetically predisposed individuals, and
`probably involving additionally several environmental factors, such as vitamin D
`deficiency, sun exposure, smoking, and infections. Evidence for a concomitant neuro-
`degenerative component has been highlighted to be present already at disease onset;3
`however, this prevails in the later phases of the disease.4,5
`Multifocal localized inflammation of the CNS leading to demyelination, axonal
`damage, and astrocytosis pathologically characterizes the disease and causes impaired
`nerve conduction,5 leading to MS symptoms commonly involving sensory, motor,
`visual, balance, sphincteric, and cognitive functions, as well as fatigue.
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`Patient Preference and Adherence 2014:8 1123–1134
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`Caporro et al
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`Relapsing–remitting (RR) is the most common (80%–85%)
`MS subtype, characterized by flares and remissions.6,7 The
`first MS relapse is currently referred to as clinically isolated
`syndrome (CIS), corresponding to a typical clinical and
`paraclinical early RRMS picture that cannot however fulfill
`current MS diagnostic criteria.8 Approximately 60%–70%
`of patients with RRMS evolve to secondary progressive
`MS over time, and around 10% of patients can be classified
`as having a primary progressive or progressive relapsing
`course.
`Though incurable, MS is currently treatable, with the
`aim of delaying as much as possible disability progression
`that may derive principally from unrecovered relapses and
`progressive neurological deterioration. To this end, several
`immunomodulating, immunosuppressive, and immunobio-
`logical agents have been developed to control inflammatory
`activity, prevent relapses, and possibly delay disability pro-
`gression, particularly in the early phase of the disease.
`Glatiramer acetate (GA; Copaxone®; Teva Pharmaceutical
`Industries, Petah Tikva, Israel) and beta-interferons (IFN(cid:66)s)
`have been traditionally considered first-line treatments of
`RRMS, and represent the cornerstone in MS therapy.9 Until
`recently, these two drug types were the only immunomodula-
`tory therapies available for the treatment of RRMS. However,
`these drugs are not always sufficiently efficacious to suppress
`inflammatory activity in all MS patients. Moreover, they may
`not be well tolerated due to side effects or frequent injections,
`which sometimes preclude adequate adherence.10 The advent
`of second-line drugs, such as natalizumab,11 fingolimod,12
`teriflunomide,13 and dimethyl fumarate,14 as well as alem-
`tuzumab15 in some countries, is promising both for possible
`higher anti-inflammatory efficacy and a more convenient way
`of administration (ie, either intravenous injections or oral).
`These advantages have, however, the price of a variable but
`overall less favorable safety and side-effect profile.16 Never-
`theless, the approval of these new compounds changed the
`MS therapeutic landscape and the first-line drug-decision
`process in a newly diagnosed MS patient.
`This paper reviews relevant data concerning the mecha-
`nism of action, efficacy, and safety of GA administered at
`the licensed (20 mg daily) dose, summarizes more recent
`data concerning the administration of GA at higher doses
`with lower frequency, and aims to define its current role as
`a treatment option in MS.
`PubMed was searched for abstracts using the terms
`“glatiramer acetate AND multiple sclerosis” and “glatiramer
`acetate AND adherence”. Only articles written in English
`were considered, and there was no time-period restriction.
`
`The references of the resulting studies were used to identify
`additional articles to be included in the review (Table 1).
`
`Glatiramer acetate
`GA (Copaxone) is a synthetic amino acid polymer analog of
`myelin basic protein (MBP), an antigen thought to be involved
`in the pathogenesis of MS.17–21 It consists of a standardized
`combination of four amino acids (L-alanine, L-glutamic acid,
`L-lysine and L-tyrosine) randomly combined to form a poly-
`mer with an average length of 40–100 amino acids.17–20
`It has been empirically found to suppress autoimmune
`encephalomyelitis in mice,22 possibly due to a displacement
`of immune cells targeting native myelin components. Clinical
`results consistent with this rationale have also been shown in
`humans, leading to its licensing for MS treatment in 1997 in
`the US and 2000 in Europe. Initially, GA was approved as
`first-line treatment in RRMS at a dose of 20 mg subcutane-
`ous (SC) injection daily. More recently, further approval was
`obtained for the treatment of CIS patients.23
`
`Mechanism of action
`It is believed that GA has a multifaceted mechanism of
`action, involving both immunomodulation and neuropro-
`tection (Figure 1). It is basically an immunomodulator
`capable of modifying the immune responses that drive MS
`pathogenesis.17–20,24 It binds to major histocompatibility
`complex (MHC) class II molecules on MBP-specific antigen-
`presenting cells, preventing MBP itself from binding to and
`stimulating these cells.18,20,24 A body of preclinical and clinical
`data support a role of GA in inducing a T-helper (Th)-1 to
`Th2-cell phenotype shift. In other words, GA-reactive
`T cells predominantly secrete anti-inflammatory cytokines,
`such as IL-1, IL-4, and IL-10, characterizing Th2 regulatory
`cells instead of typical Th1, and proinflammatory cytokines,
`such as IL-2 and IL-12.18,20,24 It has to be underlined that GA
`per se is not able to penetrate the CNS blood–brain barrier.
`Its immunomodulatory function is carried out by peripheral
`GA-induced Th2 cells that enter the CNS, recognize myelin
`antigens, and are thus reactivated, ultimately reducing inflam-
`mation associated with MS.24–26 This mechanism of action is
`known as “bystander suppression”.27
`In addition, several studies have suggested further effects
`on the immune system mediated by GA.17,24 GA induces
`T-regulatory cells, such as CD4+, CD8+, and CD4+CD25+
`T cells, while it downregulates Th17 cells that have been
`associated with MS disease activity. Moreover, GA drives
`monocytes, dendritic cells, and microglia to preferential
`anti-inflammatory responses.24,25,28–34
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`Glatiramer acetate: standard and new treatment regimens
`
`GdE, gadolinium-enhancing; IFN(cid:66), interferon beta; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging.
`Abbreviations: RRMS, relapsing–remitting multiple sclerosis; CIS, clinically isolated syndrome; CDMS, clinically definite multiple sclerosis; GA, glatiramer acetate; SC, subcutaneously; HR, hazard ratio; CI, confidence interval;
`
`34% reduction of annual relapse rate compared to placebo (P(cid:12)0.0001)
`No difference in relapse rate between the two groups (P(cid:29)0.49)
`P(cid:29)0.089)
`Trend to lower number of GdE lesions in the 40 mg group (38% reduction,
`
`12 months
`12 months
`
`Placebo (n(cid:29)461)
`GA 20 mg/day SC (n(cid:29)586)
`
`9 months
`
`GA 20 mg/day SC (n(cid:29)44)
`
`(n(cid:29)943)
`GA 40 mg 3 times/week SC
`GA 40 mg/day SC (n(cid:29)569)
`
`RRMS
`RRMS
`
`Khan et al62
`Comi et al59
`
`GA 40 mg/day SC (n(cid:29)46)
`
`Cohen et al58
`Studies with high-dose GA
`
`RRMS
`
`two groups
`No significant difference in combined active lesions (P(cid:29)0.58) between the
`
`No difference in relapse risk (P(cid:29)0.48 and P(cid:29)0.74) between the groups
`between the two groups
`No difference in time to first relapse (HR 0.94, 95% CI 0.74–1.21; P(cid:29)0.64)
`
`Up to 2 years
`
`GA 20 mg/day SC (n(cid:29)39)
`
`2.0–3.5 years
`
`GA 20 mg/day SC (n(cid:29)445)
`
`96 weeks
`
`GA 20 mg/day SC (n(cid:29)378)
`
`IFN(cid:66)-1b 250 (cid:77)g/2 days SC (n(cid:29)36)
`and 500 (cid:77)g/2 days SC (n(cid:29)887)
`IFN(cid:66)-1b 250 (cid:77)g/2 days SC (n(cid:29)888)
`(n(cid:29)386)
`IFN(cid:66)-1a 44 (cid:77)g 3 times/week SC
`
`No difference in MRI measures between the two groups
`
`54% reduction in mean number of GdE lesions in patients switching to GA
`57% stable/improved EDSS
`Decreased relapse rate from 1.12/year prestudy to 0.25/year during study
`during study
`Decreased relapse rate from 1.18/year prestudy to approximately 1/5 years
`
`to a mean of 5.8 years
`Comi et al59 extended
`for additional 9 months
`Comi et al59 extended
`to 15 years
`Johnson et al39 extended
`to 10 years
`Johnson et al39 extended
`
`patients’ switch to GA
`No difference in relapse rate between the two groups after placebo-treated
`
`to 8 years
`Johnson et al39 extended
`
`patients’ switch to GA
`No difference in relapse rate between the two groups after placebo-treated
`
`32% reduction in relapse rate compared to placebo (P(cid:29)0.002)
`
`to 6 years
`Johnson et al39 extended
`for additional 1–11 months
`Johnson et al39 extended
`
`(n(cid:29)69)
`after placebo for 9 months
`GA or other/no treatment
`placebo for 9 months (n(cid:29)113)
`GA 20 mg/day SC after
`
`–
`
`–
`
`end of 8th year)
`placebo for 30 months (n(cid:29)70,
`GA 20 mg/day SC after
`end of 6th year)
`placebo for 30 months (n(cid:29)86,
`GA 20 mg/day SC after
`initiation
`Placebo (n(cid:29)104) since study
`
`study initiation
`GA 20 mg/day SC (n(cid:29)73) since
`study initiation
`GA 20 mg/day SC (n(cid:29)111) since
`of 15th year) since study initiation
`GA 20 mg/day SC (n(cid:29)100, end
`SC (n(cid:29)232)
`At least one dose of GA 20 mg/day
`
`of 8th year) since study initiation
`GA 20 mg/day SC (n(cid:29)72, end
`
`of 6th year) since study initiation
`GA 20 mg/day SC (n(cid:29)83, end
`study initiation
`GA 20 mg/day SC (n(cid:29)99) since
`
`CIS
`
`Cadavid et al50RRMS or
`et al49
`O’Connor
`
`RRMS
`
`Mikol et al48
`RRMS
`Head-to-head trials
`
`Rovaris et al47RRMS
`et al46
`Wolinsky
`
`RRMS
`
`RRMS
`
`Ford et al44
`
`RRMS
`
`Ford et al43
`
`Johnson et al42RRMS
`
`Johnson et al41RRMS
`
`Johnson et al40RRMS
`Extension studies
`
`GA 20 mg/day SC (n(cid:29)243)
`GA 20 mg/day SC (n(cid:29)119)
`GA 20 mg/day SC (n(cid:29)125)
`
`95% CI 0.40–0.77; P(cid:29)0.0005)
`45% reduced risk of conversion to CDMS compared to placebo (HR 0.55,
`Reduced number of GdE lesions compared to placebo (P(cid:29)0.003)
`29% reduction in relapse rate compared to placebo (P(cid:29)0.007)
`
`Up to 36 months
`9 months
`2 years
`
`Placebo (n(cid:29)238)
`Placebo (n(cid:29)120)
`Placebo (n(cid:29)126)
`
`No relapse in 56% of GA-treated subjects versus 26% in placebo (P(cid:29)0.045)
`
`2 years
`
`Placebo (n(cid:29)23)
`
`Main outcome
`
`Length of follow-up
`
`Comparison
`
`GA 20 mg/day SC (n(cid:29)25)
`
`RRMS
`
`PatientsTreatment arm
`
`Comi et al23
`CIS
`RRMS
`Comi et al45
`Johnson et al39RRMS
`et al38
`Bornstein
`Pivotal trials
`Article
`Table 1 Reviewed studies
`
`Patient Preference and Adherence 2014:8
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`Anti-inflammatory
`cytokines
`
`Neurotrophic
`factors
`
`APC
`
`TGA
`
`APC
`
`TMyelin
`
`Blood–brain barrier
`
`Treg
`
`APC
`
`APC
`
`MHC
`
`TCR
`
`GA
`
`TGA
`
`MHC
`
`TCR
`
`GA
`
`TGA
`
`APC
`
`MHC
`
`TCR
`
`GA
`
`GA
`
`TMyelin
`
`Figure 1 Mechanisms of action of glatiramer acetate (GA) in multiple sclerosis. GA exhibits competitive binding at the MHC-II complex and T-cell receptor (TCR) antagonism.
`GA is able to displace myelin basic protein from the binding site on MHC-II molecules. Treatment with GA leads to the induction of antigen-specific TH2 T cells in the periphery (1).
`In addition CD8+ and CD4+CD25+ regulatory T cells are induced by GA therapy (2). The constant activation seems to have an important impact on the induction and
`maintenance of the regulatory/suppressive immune cells (3). Because of the daily activation, GA T cells are believed to be able to cross the blood–brain barrier (4). Inside
`the central nervous system, some GA-specific T cells cross-react with products of local myelin turnover presented by local antigen-presenting cells (APCs) (5). In response,
`anti-inflammatory cytokines are secreted, which dampen the local inflammatory process (bystander suppression) (6). Furthermore, GA-specific T cells secrete neurotrophic
`factors that might favor remyelination and axonal protection (7). Reprinted from Autoimmun Rev. 2007;6(7). Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of
`action in multiple sclerosis. 469–475. Copyright © 2007, with permission from Elsevier.78
`
`Finally, GA seems to induce neuroprotective and/or
`neuroregenerative effects at the preclinical level.17,18,24,25 For
`instance, it increases neurotrophic factors like brain-derived
`neurotrophic factor, involved in neuronal and glial cell
`survival, and may mediate neuroprotection. There is also
`evidence that GA induces remyelination and enhances
`neurogenesis.17,18,21,24,25
`The majority of patients treated with GA develop GA-
`reactive IgG antibodies. However, these do not appear to be
`related to clinical or radiological clinical course measures
`of efficacy.35–37
`
`Clinical efficacy: data from clinical trials
`Pivotal trials
`Pivotal trials have shown consistent efficacy of GA in the
`treatment of RRMS patients. The first study assessing the
`efficacy of GA in RRMS was published more than 25 years
`ago.38 It was a double-blind, randomized, placebo-controlled
`
`pilot trial involving 50 RRMS patients who were treated
`either with daily GA 20 mg or daily placebo over 2 years.
`Twenty-six percent of placebo- and 56% of GA-treated
`patients experienced no relapses over the study period
`(P(cid:29)0.045). Among less disabled patients (Kurtzke disability
`score 0–2), those taking GA improved ((cid:11)1.2 Kurtzke units),
`while placebo-treated patients worsened ((cid:13)0.5 Kurtzke units,
`P(cid:29)0.012). In contrast, more disabled patients in both groups
`showed an increase in Kurtzke disability score. Limited by
`the small sample size, this pivotal trial provided the first
`clinical evidence for a role of GA in the treatment of RRMS.
`A number of subsequent larger multicenter trials confirmed
`these results.
`The first large Phase III double-blind, placebo-controlled
`study included 251 RRMS subjects 18–45 years old, with an
`Expanded Disability Status Scale (EDSS) score of 0–5.0, a
`history of at least two relapses in the 2 years prior to study
`entry, and a disease duration of at least 1 year. Participants were
`
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`Glatiramer acetate: standard and new treatment regimens
`
`randomized to receive GA or placebo by daily SC injection for
`2 years, with a reduction of 29% in the annualized relapse rate
`(ARR; primary end point) in favor of the GA group (0.59 ver-
`sus 0.84, respectively; P(cid:29)0.0007).39 Among secondary clinical
`outcomes, median time to first relapse from baseline and the
`proportion of relapse-free patients over 2 years showed a trend
`favoring GA over placebo (287 versus 198 days, P(cid:29)0.097;
`33.6% versus 27.0%, P(cid:29)0.098; respectively). Overall, param-
`eters of disability change also favored GA over placebo (EDSS
`change from baseline (cid:13)0.05 versus 0.21, P(cid:29)0.023), though the
`proportion of patients who were free from disability progres-
`sion was similar between groups (78.4% versus 75.4%, not
`significant). The main limitation of this trial was the absence
`of magnetic resonance imaging (MRI) monitoring.
`A pivotal GA study by Johnson et al was followed by a
`prospective, open-label study replicating the benefits of early
`versus delayed GA at 3, 6 and 8 years.41,42 Further 10-year
`extension data were obtained from 47% of the original
`cohort,43 and showed that continuous GA treatment led to
`more than 80% decline in relapse rate (from 1.18 relapses/year
`prestudy to one relapse/5 years), with no significant disabil-
`ity progression, evaluated using the EDSS score. Recently,
`data concerning 15-year extension were published.44 Of the
`initially randomized subjects, 43% were still on GA treat-
`ment, and had received only this immunomodulator during
`the disease course. Of those, two-thirds had not reached
`secondary progression, 57% had stable or improved EDSS,
`and 82% of patients could still walk. The comparator cohort
`that had interrupted GA obtained fairly good results as well;
`however, the mean disease duration in these patients was
`much shorter (13 versus 22 years).
`The clinical efficacy of GA was replicated in a European/
`Canadian trial45 involving 239 RRMS subjects, and extended
`results toward a benefit on MRI disease activity. Main inclu-
`sion criteria were age between 18 and 50 years, a disease
`duration of at least 1 year, an EDSS score up to 5.0, and
`documented disease activity (at least one relapse in the pre-
`ceding 2 years, and at least one gadolinium-enhanced [GdE]
`lesion on their screening brain MRI). Patients were random-
`ized to either daily injections of GA 20 mg or placebo and
`treated for 9 months, and were followed with monthly brain
`MRIs. GA-treated patients showed a significant reduction
`in total GdE lesions (primary end point (cid:13)10.8 versus (cid:13)18.0,
`P(cid:29)0.003), number and volume of new T2 lesions, and brain-
`atrophy progression, as well as clinical efficacy measured by
`reduction of mean relapse rate. Interestingly, the treatment
`effect of GA on the mean number of GdE lesions per patient
`per month, as well as mean number of relapses per patient,
`consistently appeared only from month 6 after GA start.
`
`Patient Preference and Adherence 2014:8
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`However, the short duration of the study prevented assess-
`ment of treatment effects on disability progression, especially
`in light of the delayed onset of GA action.
`In the 9-month, open-label phase of the European/
`Canadian study45 involving 94% of the original cohort, the
`effect of GA treatment was sustained: a 54% reduction in
`the mean number of GdE lesions for those switching from
`placebo to GA and a further 24.6% reduction for those
`remaining on GA were observed.46 A 5.8-year extension
`phase47 involving 63.4% of the original cohort showed that
`66% of the patients were still on GA and had the highest
`relapse-free period, compared either to IFN switchers or to
`untreated patients (3.5 versus 1.3 versus 2.9, respectively).
`No significant differences for any MRI parameters were
`found at 5 years between originally GA- or placebo-treated
`subjects. However, the proportion of patients not requiring
`walking aids was lower in the first group (P(cid:29)0.034), suggest-
`ing that an earlier initiation of GA might have a favorable
`impact on long-term disease evolution.
`In conclusion, between the late 1980s and early 2000s, the
`results of three pivotal trials were published, which consis-
`tently assessed the efficacy of GA in the treatment of patients
`with RRMS, showing an approximately 30% reduction in
`relapse rate and consistent benefits on MRI for surrogates of
`disease activity compared to placebo. Open-label extension
`studies consistently showed a sustained efficacy of GA up to
`15 years in a subgroup of patients participating in pivotal trials,
`though these were limited by several factors, including absence
`of a placebo arm and positive selection of responders.
`
`CIS trial
`GA has been recently labeled for CIS based on the favorable
`results of the PreCISe (Evaluate Early Glatiramer Acetate
`Treatment in Delaying Conversion to Clinically Definite
`Multiple Sclerosis of Subjects Presenting with Clinically Iso-
`lated Syndrome) trial.23 This involved 481 subjects present-
`ing with a monofocal CIS and two or more T2 brain lesions
`((cid:4)6 mm), that were randomly assigned to either SC GA
`20 mg per day or placebo. A significant delay in conversion
`to clinically definite MS (722 versus 336 days in the treat-
`ment versus placebo groups, P(cid:29)0.0005), as well as consistent
`benefits on radiological parameters (number/volume of new
`T2, number of new T1 GdE and T1 hypointense lesions) were
`observed after approximately 2.4 years of treatment. The
`study included only a restricted subgroup of CIS subjects,
`and did not provide information concerning the impact of
`GA on disability progression. In conclusion, the PreCISe trial
`provided substantial information in favor of the effectiveness
`of GA in the treatment of early forms of MS.
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`Head-to-head trials
`Three head-to-head trials48–50 assessed the efficacy of GA
`compared to high-dose IFNs. REGARD48 (REbif vs Glati-
`ramer Acetate in Relapsing MS Disease) was a randomized,
`open-label trial comparing SC IFN(cid:66)-1a 44 (cid:77)g three times
`per week (Rebif®; EMD Millipore, Billerica, MA, USA)
`to daily SC GA 20 mg in 764 RRMS patients. Main inclu-
`sion criteria were 18–60 years of age, EDSS score between
`0 and 5.5, and at least one relapse in the year prior to study
`entry. After 96 weeks, there were no differences between
`the two treatment groups in the time to relapse (primary
`outcome, P(cid:29)0.64) or in the number or volume of active
`T2 lesion load on MRI. However, the IFN group showed
`significantly fewer GdE lesions, and the GA-group had
`less pronounced brain-volume loss (1.073% versus 1.24%,
`P(cid:29)0.018). The main limitations of the study were a lack of
`patient blinding to treatment (although the assessor was
`blinded) and a low on-study relapse rate, which could have
`prevented the capturing of differences between the two
`active compounds.
`BEYOND (Betaferon Efficacy Yielding Outcomes
`of a New Dose) was a large randomized trial49 involving
`2,244 RRMS patients randomized to either 250 (cid:77)g SC or
`500 IFN(cid:66)-1b (Betaseron®; Bayer, Leverkusen, Germany)
`every other day or daily 20 mg GA SC over a minimum of
`2 years. Main inclusion criteria were 18–55 years of age,
`EDSS score between 0 and 5.0, and at least one relapse
`in the year prior to study entry. Results demonstrated no
`statistically significant differences in the ARR (0.33, 0.36,
`and 0.34, respectively), disability progression measured by
`EDSS, the majority of MRI-monitoring parameters (GdE
`lesions, T1 lesions, normalized brain volume) among groups.
`Partial blinding was a major limitation.
`The BECOME (Betaseron vs Copaxone in Multiple Scle-
`rosis with Triple-Dose Gadolinium and 3-Tesla MRI End-
`points) study50 compared primarily radiological efficacy of
`SC IFN(cid:66)-1b 250 (cid:77)g every other day and daily SC 20 mg GA
`over 2 years in 75 RRMS and CIS patients. Main inclusion
`criteria were 18–55 years of age and EDSS score (cid:12)5.5. The
`study was performed using a 3 T MRI machine and adminis-
`tering triple-dose Gd combined with delayed imaging, which
`is known to more than double lesion detection compared to
`standard techniques. Treatment arms showed similar results
`in the number of combined active lesions (overall GdE plus
`new nonenhancing fluid-attenuated inversion-recovery
`lesions) per patient per scan at year 1, obtained by monthly
`brain MRI monitoring. The main limitations of this study
`were the relatively small sample size, lack of patient blind-
`ing, and the monocentric design.
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`It has to be underlined that in all these head-to-head trials,
`the on-study relapse rate was much lower than the rates
`reported in the pivotal trials (0.29–0.34 in head-to-head stud-
`ies versus 0.59 in the Johnson et al trial),39 mainly reflecting
`a change in study populations over two decades. Increasing
`treatment options and changes in MS diagnostic criteria
`probably account for this phenomenon.
`Among the novel therapeutic compounds for MS, only
`the Phase III CONFIRM (Comparator and an Oral Fumarate
`in Relapsing–Remitting Multiple Sclerosis) trial51 testing
`BG-12 included a treatment arm with GA monotherapy.
`This was a multicenter, placebo-controlled, randomized
`trial involving 1,417 RRMS patients from 18 to 55 years of
`age, having an EDSS score up to 5.0, who had experienced
`at least one clinical relapse in the past year or showed one
`GdE brain lesion at baseline. Enrolled subjects were random-
`ized either to BG-12 240 mg twice a day, BG-12 240 mg
`three times a day, GA 20 mg SC daily, or placebo, and were
`treated for 2 years. Compared to placebo, relapse risk was
`reduced by 29%, 34%, and 45% by GA (P(cid:29)0.01), twice-
`daily (P(cid:29)0.002) and three-times-daily (P(cid:12)0.001) BG-12,
`respectively (primary end point). Secondary end points,
`including disability progression and several radiological
`surrogates of disease activity, showed consistent results.
`Although the study was not powered to test the superiority
`or inferiority of BG-12 versus GA, both BG-12 doses were
`associated with results numerically similar or superior to GA
`across all study end points. A post hoc analysis with direct
`comparisons indicated a trend of superiority of BG-12 over
`GA (ARR – twice-daily BG-12 versus GA, P(cid:29)0.10, thrice-
`daily BG-12 versus GA, P(cid:29)0.02; new or enlarging T2
`lesions – twice-daily BG-12 versus GA, P(cid:29)0.007, thrice-
`daily BG-12 versus GA, P(cid:29)0.002). The limitations of this
`study were the partial blinding to treatment assignment, the
`late modification of the trial design with the inclusion of an
`additional comparative arm with GA required by healthy
`authorities, and the insufficient power for assessing direct
`efficacy comparisons between GA and BG-12.
`In conclusion, three head-to-head trials showed com-
`parable efficacy between GA and high-dose IFN(cid:66)s in the
`treatment of RRMS, both from a clinical and radiological
`perspective. Notably, some results suggest that GA better
`protects against brain-volume loss, while high dose IFN(cid:66)s
`are associated with fewer GdE lesions.
`
`Evidence for neuroprotection
`from clinical trials
`Besides preventing new MS-lesion formation, treatment
`with GA was also found to reduce the accumulation of
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`Patient Preference and Adherence 2014:8
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`Glatiramer acetate: standard and new treatment regimens
`
`permanent black holes, namely persistently hypointense
`T1 lesions, which are indicative of irreversible tissue damage
`and correlate with disability.20 Indeed, compared to placebo,
`the proportion of new T1 lesions that evolved into chronic
`black holes in RRMS patients participating in the European/
`Canadian trial52 was statistically significantly lower (18.9% ver-
`sus 26.3%, P(cid:29)0.04). However, it should be stressed that under
`GA treatment, a similar (BEYOND trial, IFN(cid:66) 21.6% versus
`GA 23.5%; P(cid:14)0.20)53 or smaller (BECOME trial, IFN(cid:66) 9.8%
`versus GA 15.2%; P(cid:29)0.20)54 proportion of acute black holes
`turned into persistent black holes compared to IFN(cid:66).
`MS is characterized by a more rapid rate of brain-volume
`decrease compared to the general population, which argues
`in favor of a mechanism of neurodegeneration behind the
`disease. In an MRI subgroup analysis of the pivotal trial by
`Johnson et al,39 GA significantly reduced the loss of brain
`volume compared to placebo (mean annual brain- volume
`change: (cid:13)0.6% and (cid:13)1.8%, respectively; P(cid:29)0.0078).55 This
`finding was, however, not confirmed by the European/
`Canadian trial.45 Notably, the REGARD study48 showed that
`GA better protects from brain-volume loss, while high-dose
`IFN(cid:66) is associated with fewer GdE lesions, which might sup-
`port a neuroprotective property of GA partially independent
`of anti-inflammatory activity.
`The integrity of axons in MS can be assessed in vivo
`by assessing levels of N-acetylaspartate, a neuronal marker
`compound.56 A spectroscopy analysis of a subgroup
`of 34 subjects participating in the Phase III PreCISe
`trial23 showed that treatment with GA was associated with
`an improvement, whereas placebo was associated with a
`decline in brain neuroaxonal integrity, as indicated by an
`increase and decrease in the ratio between N-acetylaspartate
`and creatine, respectively.56
`In conclusion, several clinical studies suggest a possible
`neuroprotective effect of GA in MS. However, it has not yet
`been clarified if this effect is peculiar to GA or a general con-
`sequence of any efficacious anti-inflammatory compound.
`
`High-dose GA and different
`regimens
`GA is currently approved as a 20 mg daily SC injection.
`However, some experimental data have suggested that higher
`doses were associated with greater efficacy.57
`
`High-dose GA
`A Phase II clinical trial was performed to evaluate differ-
`ences in efficacy, safety, and tolerability between 40 mg
`and 20 mg daily doses of SC GA in 38 RRMS patients for
`9 months.58 The primary efficacy end point was the total
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`Patient Preference and Adherence 2014:8
`
` number of GdE lesions on MRI at 7, 8, and 9 months of
` follow-up. Results showed a trend for increased efficacy in the
`higher compared to the lower dose (number of GdE lesions
`3.62 versus 2.26, respectively, rate ratio 0.62; P(cid:29)0.09). The
`decrease in GdE lesions occurred earlier in the 40 mg group
`(from month 3) than in the 20 mg group. Safety profiles were
`comparable between the two doses, with a mild increase of
`local injection-site manifestations with the 40 mg dose. The
`main limitation of this trial was the small sample size.
`A more recent Phase III, randomized, double-blind,
`parallel-group trial compared daily administration of SC
`40 mg or 20 mg GA over 1 year.59 This study was conducted
`in 136 sites across 20 different countries worldwide. A total
`of 1,262 p