CNS Drugs
`DOI 10.1007/s40263-015-0245-z
`
`ADIS DRUG EVA:C..UATIO.t~I
`
`Cross Mark
`
`Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple
`Sclerosis: A Review
`
`Kate McKeage1
`
`©Springer International Publishing Switzerland 2015
`
`Abstract Glatiramer acetate (Copaxone®) is a synthetic
`analogue of myelin basic protein, which is thought to be
`involved in the pathogenesis of multiple sclerosis (MS). The
`therapeutic effects of the drug in the treatment of MS are
`thought to be via immunomodulation and neuroprotection.
`Subcutaneous glatiramer acetate 20 mg/mL once daily is
`approved in several countries for the treatment of relapsing
`forms of MS. Recently, a high-concentration formulation of
`glatiramer acetate 40 mg/mL administered three
`times
`weekly was approved in the USA and several European
`countries in the same indication. This article reviews the
`efficacy and tolerability of the high-concentration regimen. In
`the randomized, phase III GALA study in patients with
`relapsing-remitting MS (RRMS), glatiramer acetate 40 mg/
`mL three times weekly reduced annualized relapse rates
`significantly more than placebo, and indirect comparisons
`indicate that the efficacy of the three-times-weekly regimen is
`similar to that of the 20 mg/mL once-daily regimen. Results of
`the randomized, phase IIIb GLACIER study in patients with
`
`The manuscript was reviewed by: R. Arnon, The Department of
`Immunology, The Weizmann Institute of Science, Rehovot, Israel;
`.J. L. Bainbridge, University of Colorado Anschutz Medical Campus,
`Skaggs School of Pharmacy and Pharmaceutical Sciences,
`Department of Clinical Phannacy and Neurology, Aurora, CO, USA;
`M. D. Kaufman, Knoxville Neurologic Clinic and University of
`Tennessee Medical Center, Knoxville, TN, USA; C. Zecca, Multiple
`Sclerosis Center, Neurocenter of Southern Switzerland, Lugano,
`Switzerland; R. Zivadinov, Buffalo Neuroimaging Analysis Center,
`Department of Neurology, State University of New York, Buffalo,
`NY, USA.
`
`RRMS demonstrated that the three-times-weekly regimen
`reduced the risk of injection-site reactions by 50 % and was
`associated with numerically greater patient convenience
`scores than the once-daily regimen. Thus, in the treatment of
`RRMS, glatiramer acetate 40 mg/mL three times weekly is
`effective and provides a better tolerated and possibly more
`convenient option than the once-daily regimen.
`
`Administered three times weekly
`
`Reduced annualized relapse rate more significantly
`than placebo in patients with RRMS
`
`Indirect comparisons suggest similar efficacy to that
`of the once-daily regimen (20 mg/mL)
`
`Reduced the incidence of injection-site reactions by
`50 % compared with the once-daily regimen
`
`May be more convenient than the once-daily
`regimen
`
`Associated with more favourable outcomes than
`placebo on brain magnetic resonance imaging
`assessments
`
`I Introduction
`
`C8J Kate McKeage
`demail @springer. com
`
`Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland,
`New Zealand
`
`Multiple sclerosis (MS) is a chronic, immune-mediated
`disease characterized by multifocal demyelination in the
`CNS with progressive neurodegeneration in genetically
`susceptible individuals [IJ. The disease is estimated to
`
`Published online: 24 April 2015
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`affect more than 2 million people worldwide [2]. MS
`phenotypes vary, but most patients ( ~ 80-85 %) are clas(cid:173)
`sified as having relapsing-remitting MS (RRMS), which
`presents with a clinically isolated syndrome (CIS) followed
`by episodes of acute worsening then recovery [I, 3]. Over a
`variable period and subsequent to the relapsing course,
`progressive accumulation of clinical disability may lead to
`progressive disease, termed secondary progressive MS
`[I, 3].
`Subcutaneous glatiramer acetate (Copaxone®) was ap(cid:173)
`proved in the USA for the treatment of RRMS almost two
`decades ago. More recently, with an improved under(cid:173)
`standing of the importance of early treatment, the drug was
`also approved in CIS. The glatiramer acetate dosage of
`20 mg/mL once daily, until recently, was the only regimen
`available and the
`and tolerability of this regimen is
`well proven [4].
`This article focuses on the efficacy and tolerability of a
`new dosage regimen comprising high-concentration sub(cid:173)
`cutaneous glatiramer acetate 40 mg/mL administered three
`times weekly.
`
`2 Pharmacodynamic Properties
`
`The pharmacodynamic properties of glatiramer acetate
`have been reviewed in detail previously [4-6]. Briefly, the
`drug is a synthetic analogue of myelin basic protein, an
`antigen believed to be involved in the pathogenesis of MS
`[4-7]. The drug's mechanism of action in the treatment of
`MS is not fully understood, but is thought to involve
`
`K. McKeage
`
`immunomodulation and neuroprotection [7]. Table l pro(cid:173)
`vides a summary of selected pharmacodynamic properties.
`Although glatiramer acetate is rapidly degraded in the
`periphery and does not cross the blood-brain barrier,
`glatiramer acetate-induced T helper-2 cells migrate into the
`CNS, leading to the subsequent downregulation of CNS(cid:173)
`based inflammation associated with MS (Table 1) [4, 6, 8].
`Glatiramer acetate-reactive antibodies produced in re(cid:173)
`sponse to treatment are of the IgG subtype and do not affect
`the clinical efficacy of the drug [4].
`
`3 Pharmacokinetic Properties
`
`The pharmacokinetic properties of subcutaneous glatiramer
`acetate (reviewed previously [4, 9]) have not been fully
`characterized in patients. Limited data are available from
`preclinical studies and healthy controls. The drug is rapidly
`absorbed and most of the dose is rapidly hydrolysed in
`subcutaneous tissue [10, II]. Some of the injected drug,
`either intact or partially hydrolysed, reaches regional
`lymph nodes (presumably via the lymphatic circulation)
`and some may enter the systemic circulation intact [I 0, J I].
`Fragments of glatiramer acetate can be detected as glati(cid:173)
`ramer acetate-reactive antibodies [10].
`In radiolabelling studies in animals, the major elimina(cid:173)
`tion pathway of glatiramer acetate was urinary excretion,
`and only trace amounts of the drug were detected in the
`faeces [4].
`Drug interaction studies with glatiramer acetate and
`other drugs, including interferon (IFN)-j3, have not been
`
`Table I Summary of selected pharmacodynamic properties of glatiramer acetate
`
`Immunomodulatory effects
`Rapidly and competitively binds to MHC class II molecules on MBP-specific APCs in the periphery with high affinity, preventing MBP
`from binding to and stimulating these cells [4, 6, 71
`Induces shift in phenotype of GA-reactive T -cells from Th I pattern of cytokine secretion (IL-2, IL-12, IFNy, TNF) to a Th2 pattern (fL-4,
`IL-5, IL-10, TGF-~) [4, 6, 7)
`GA-specific Th2 cells cross the BBB and secrete anti-inflammatory cytokines [6, 8]
`Induces T-regulatory cells such as CD4+, CDS+ and CD4+CD25+ T-cells, which are associated with disease suppression [4, 6, 37]
`Downregulates Thl7 cells, which are associated with MS exacerbations [4, 6, 37]
`Acts on APCs, such as monocytes, dendritic cells and microglia, leading to preferential stimulation of anti-inflammatory responses [4, 6, 38,
`391
`Decreases level of platelet activation, possibly leading to suppression of neurointlammation [401
`Neuroprotective and neuroregenerative effects
`Induces increased levels of neurotrophic factors such as BDNF, which is important for neuronal and glial cell survival [4, 6, 8]
`Enhances myelin repair and neurogenesis [ 6, 8]
`Leads to a reduction in the number of new Tl hypointense lesions transforn1ing into black holes [4, 24]
`Genetic factors
`May normalize deregulated miRNA expression [41]
`
`APC antigen-presenting cells, BBB blood-brain barrier, BDNF brain-derived neurotrophic factor, GA glatiramer acetate, IfN interferon. IL
`interleukin, MBP myelin basic protein, MHC major histocompatibility complex, miRNA microRNA, MS multiple sclerosis, Th T helper, TGF
`transfonning growth factor, TNF tumour necrosis factor
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`Glatiramer Acetate 40 mg/mL: A Review
`
`formally conducted (I 0, II]. However, no significant in(cid:173)
`teractions have been observed in clinical trials in which
`glatiramer acetate was coadministered with other drugs
`commonly used
`in MS,
`including corticosteroids and
`IFNP-la [10, 12]. Glatiramer acetate is highly bound to
`plasma proteins, but is not thought to displace or be dis(cid:173)
`placed by phenytoin or carbamazepine [4]. No well con(cid:173)
`trolled studies have been performed with glatiramer acetate
`in pregnant women [10, II).
`
`4 Therapeutic Efficacy
`
`The efficacy of subcutaneous glatiramer acetate 20 mg/mL
`once daily is well established and was reviewed in this
`journal previously [4]. Briefly, in clinical trials in patients
`with RRMS, once-daily glatiramer acetate 20 mg/mL re(cid:173)
`duced annualized relapse rates (ARRs) and the burden and
`activity of disease on magnetic resonance imaging (MRI)
`more effectively than placebo (p ::=: 0.01) [13, 14] and
`demonstrated generally similar efficacy, with regard to
`these endpoints, to subcutaneous IFNP-1 a 44 ).lg three
`times weekly and subcutaneous IFN P-1 b 250 or 500 ).lg
`every other day [15-17]. However, in a combination
`therapy trial in patients with RRMS, glatiramer acetate
`20 mg/mL once daily plus intramuscular IFNP-la 30 ).lg
`once weekly was no more effective than glatiramer acetate
`plus placebo, but was more effective than IFNP-la plus
`placebo, in terms of reducing ARRs [12]. Long-term ex(cid:173)
`tension studies have shown that the beneficial effects of
`glatiramer acetate 20 mg/mL once daily are sustained over
`the long term, including up to 20 years of treatment [ 18,
`19]. Furthermore, in patients with CIS, glatiramer acetate
`20 mg/mL once daily significantly reduced the risk of de(cid:173)
`veloping clinically definite MS compared with placebo
`(p = 0.0005) [20]. Results of a phase III dose-comparison
`study in patients with RRMS demonstrated that there was
`no gain in efficacy with glatiramer acetate 40 mg once
`daily compared with 20 mg once daily (21 ]. However, less
`frequent administration (of a high-concentration 40 mg/mL
`formulation) may be associated with fewer localized in(cid:173)
`jection-site reactions than once-daily administration.
`This section focuses on the efficacy of subcutaneous
`glatiramer acetate 40 mg/mL three times weekly in adults
`(aged :0::18 years) with RRMS in the randomized, phase III,
`double-blind, placebo-controlled, multinational GALA
`(Glatiramer Acetate Low-frequency Administration) study
`[22].
`
`4.1 GALA Study
`
`Patients with a confirmed diagnosis of RRMS and an Ex(cid:173)
`panded Disability Status Scale (EDSS) score of ::=:5.5 who
`
`were relapse free for :0::30 days were eligible for inclusion
`[22]. Patients were also required to have had ::=:I relapse in
`the previous 12 months,
`:0::2 relapses in
`the previous
`24 months, or I relapse between 12 and 24 months previ(cid:173)
`ously with ::=:I Tl gadolinium-enhancing (GdE) lesion on
`MRI in the previous 12 months. MS phenotypes other than
`RRMS, and recent treatment with immunomodulators or
`immunosuppressive agents were among exclusion criteria
`[22].
`Patients received glatiramer acetate 40 mg/mL or
`placebo three times weekly for 12 months, and the primary
`endpoint was the total number of confirmed relapses
`(Table 2) [22]. Brain MRI parameters were evaluated in
`secondary analyses. Patients underwent a complete neu(cid:173)
`rological assessment,
`including Kurtzke' s EDSS and
`functional system assessment, at screening, baseline and
`months 3, 6, 9 and 12 [22]. If a relapse was suspected,
`patients were assessed within 7 days. Brain MRI studies
`were performed at baseline and months 6 and 12.
`The mean age of patients was
`::::::; 38 years, and most
`(68 %of patients) were female [22). At baseline, the mean
`time from the onset of MS symptoms was ::::::; 8 years in
`both groups, and the mean volume of T2 lesions in the
`glatiramer acetate and placebo groups was 19.7 and
`17.4 mL, respectively. The number of exacerbations ex(cid:173)
`perienced over the 12 months prior to the study was 1.3 in
`both groups [22].
`
`4.1.1 Relapse Rate
`
`Patients receiving glatiramer acetate 40 mg/mL three
`times weekly experienced significantly fewer relapses
`than patients receiving placebo, equating to a mean ARR
`risk reduction of 34% (p < 0.0001) (Table 2) [22]. With
`regard to exploratory endpoints, the mean annualized
`severe relapse rate was significantly lower and the time to
`first relapse significantly longer in the glatiramer acetate
`group than in the placebo group (Table 2). Moreover,
`more patients remained relapse free following glatiramer
`acetate versus placebo (77.0 vs. 65.5 %, respectively;
`p < 0.0001). EDSS progression was similar in the two
`groups [22].
`Initiating treatment with glatiramer acetate early was
`associated with a lower risk of relapse than delayed ini(cid:173)
`tiation in an open-label extension of the GALA study (re(cid:173)
`ported in an abstract) [23J. Patients continued to receive
`glatiramer acetate 40 mg/mL three times weekly (n = 716;
`early initiation group) or switched from placebo to glati(cid:173)
`ramer acetate 40 mg/mL three times weekly (n = 325;
`delayed initiation group) for a further 2 years. The adjusted
`mean ARR from baseline to month 36 was significantly
`lower in the early than the delayed initiation group (0.23
`vs. 0.30; p = 0.0052) [23].
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`Table 2 Clinical efficacy of glatiramer acetate 40 mg/mL three times weekly in the treatment of adults with relapsing-remitting multiple
`sclerosis. Results of the randomized, double-blind, 12-month GALA study [22]
`
`Treatment
`
`No. of ptsa Relapse endpoints
`
`MRI endpoints
`
`Mean
`ARRb
`
`RR (95% CI)
`
`Mean ASRRc Time to first
`relapsec (days)
`
`Cum. GdE Tl lesions Cum. newc T2 lesions
`at 6 and 12 months 0
`at 6 and 12 monthsct
`
`GLA 40 mg tiw 943
`PL
`461
`
`0.331 * 0.656 (0.539-0.799) 0.301*
`0.505
`0.466
`
`393*
`377
`
`0.905*
`1.639
`
`3.650*
`5.592
`
`ARR annualized relapse rate, ASRR annualized severe relapse rate, Cum cumulative, GdE gadolinium enhancing, GIA glatiramer acetate, MRI
`magnetic resonance imaging, PL placebo, pts patients, RR risk ratio, riw three times weekly
`* p < 0.0001 VS. PL
`a Intent-to-treat population, used for primary analysis
`h Primary endpoint Relapse was defined as the appearance of::: I new neurological abnormality or the reappearance of::: I previously observed
`neurological abnormality lasting :::48 h and subsequent to an improved neurological state of :::30 days from the onset of previous relapse
`c Exploratory endpoint
`d Secondary endpoint
`e New or newly enlarging
`
`4.1.2 MRI-Assessed Outcomes
`
`With regard to MRI endpoints, results were also sig(cid:173)
`nificantly more favourable in the glatiramer acetate group
`than in the placebo group, with a 45 % reduction in the
`cumulative number of GdE Tl lesions and a 35 % re(cid:173)
`duction in the cumulative number of new or newly en(cid:173)
`larging T2 lesions (Table 2) [22]. There was no difference
`between the respective groups in the percentage change
`in normalized brain volume at 12 months ( -0.706 and
`-0.645).
`Treatment with glatiramer acetate 40 mg/mL three
`times weekly was associated with a significantly lower rate
`of new active MRl lesions converting to black holes than
`placebo in an analysis of GALA data [24]. Among 1292
`patients in the GALA study with complete MRI data
`available at baseline and months 6 and 12, the adjusted
`mean number of GdE Tl or new T2 lesions at month 6 that
`were not present at baseline and that had converted to black
`holes at month 12 was 0.31 in the glatiramer acetate group
`compared with 0.45 in the placebo group [risk ratio 0.70
`(95 % CI 0.51-0.96); p = 0.0258]. In corresponding
`groups, among 680 patients with new active lesions at
`month 6, the adjusted proportion of lesions converting to
`black holes at month 12 was 15.8 versus 19.8% [adjusted
`odd ratio (OR) 0.76; p = 0.006].
`Furthermore, preliminary results from the open-label
`extension study report that at month 36, there were sig(cid:173)
`nificantly fewer GdE Tl and new or enlarging T2 lesions
`in patients who initiated glatiramer acetate 40 mg/mL
`three
`times weekly early (i.e. 36 months'
`treatment
`completed) than those who initiated glatiramer acetate
`after
`the placebo-controlled period (i.e. 24 months'
`treatment completed) [p = 0.0005 for Tl and p < 0.0001
`for T2] [23].
`
`4.2 Indirect Comparison of Glatiramer Acetate
`40 mg/mL Three Times Weekly and 20 mg/mL
`Once Daily
`
`Results of a systematic review and meta-analysis [25], and
`a predictive statistical model [26] (both reported
`in
`abstracts) indicate that, based on indirect comparisons,
`glatiramer acetate 40 mg/mL three times weekly has
`similar efficacy to that of glatiramer acetate 20 mg/mL
`once daily. In the meta-analysis, statistical adjustments and
`weighting were used to account for differences in study
`design, patients numbers and drug exposure [25]. Pooled
`individual data
`from
`four placebo-controlled studies
`showed an ARR reduction of 28 % with glatiramer acetate
`20 mg/mL once daily versus placebo (p = 0.01 12), com(cid:173)
`pared with an ARR reduction of 34 % with glatiramer
`acetate 40 mg/mL three times weekly versus placebo
`(p < 0.000 I) in the GALA study. Compared with placebo,
`new T2 lesions were reduced by 43 % (p = 0.002) and
`35 % (p < 0.0001) with each active regimen, respectively.
`Confidence intervals for the calculated risk ratios for each
`endpoint indicated a similar treatment effect on these
`endpoints with each regimen [25].
`The predictive model (validated using baseline covariates
`and actual data from clinical trials) found that predicted
`ARRs with the three-times-weekly or once-daily regimen
`were generally similar to those likely to be achieved if the
`patients had received the alternate regimen [26].
`
`5 Tolerability and Convenience
`
`Results from numerous clinical trials and real world stud(cid:173)
`ies, including treatment periods of up to 20 years, show
`that once-daily glatiramer acetate 20 mg/mL is generally
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`Glatiramer Acetate 40 mg/mL: A Review
`
`well tolerated [4, 19]. The most common treatment-emer(cid:173)
`gent adverse events are injection-site reactions and va(cid:173)
`sodilation, with most events being mild in severity. The
`theory that fewer injections would lead to fewer injection(cid:173)
`site reactions was evaluated in the randomized, open-label,
`phase Illb, multicentre GLACIER study that compared the
`tolerability of glatiramer acetate 40 mg/mL three times
`weekly with that of 20 mg/mL once daily in patients with
`RRMS [27].
`
`5.1 GLACIER Study
`
`Adults with an EDSS score of ::::5.5 who had been re(cid:173)
`ceiving glatiramer acetate 20 mg/mL once daily for
`::=::6 months were randomized to continue the same treat(cid:173)
`ment or switch to glatiramer acetate 40 mg/mL three times
`weekly for 4 months [27]. Patients were assessed at base(cid:173)
`line and at months I, 2 and 4; to date, all data are available
`in abstracts and/or posters.
`The primary endpoint was the annualized rate of injec(cid:173)
`tion-related adverse events (i.e. including localized reac(cid:173)
`tions and generalized symptoms), based on patients' diary
`cards [27]. Convenience was assessed with the validated
`Treatment Satisfaction Questionnaire for Medication-9
`(TSQM-9). Most (82 %) patients were female, the average
`age was approximately 51 years, and the mean time since
`MS diagnosis was 11.5 years [27, 28].
`
`5.1.1 Injection-Related Adverse Events
`
`At 4 months, there was a significantly lower mean annu(cid:173)
`alized rate of injection-related adverse events in the 40 mgl
`mL three-times-weekly group than in the 20 mg/mL once(cid:173)
`daily group, equating to a 50 % rate reduction (Table 3)
`[27]. Similarly, there was a 60 % reduction in the mean
`annualized rate of moderate or severe injection-related
`adverse events with glatiramer acetate three times weekly
`compared with once daily (Table 3) [27].
`
`With regard to local injection-site reactions only, the
`mean annualized event rates with glatiramer acetate
`40 mg/mL three times weekly and 20 mg/mL once daily
`[35.2 vs. 70.4; risk ratio (RR) 0.50; p = 0.0006] were
`almost identical to the event rates in the respective
`groups for all injection-related adverse events (Table 3)
`[28]. The proportion of patients reporting moderate or
`severe local injection-site reactions was 9.2 % in the
`three-times-weekly group compared with 15.4 % in the
`once-daily group. When common injection-site reactions
`were compared based on MedDRA preferred
`terms
`(version 16.0), annualized rates for pain, erythema, mass,
`swelling and pruritus were numerically lower in the
`three-times-weekly group than in the once-daily group,
`and moderate or severe rates of these events were either
`similar in both groups (pain, erythema, mass) or nu(cid:173)
`merically lower in the three-times-weekly group (swel(cid:173)
`ling and pruritus) [28].
`In an extension of the GLACIER study, in which all
`patients (n
`198) received glatiramer acetate 40 mg/mL
`three times weekly for a further I 8 weeks, the mean an(cid:173)
`nualized event rate was generally similar in the group that
`received the three-times-weekly regimen from the start of
`the GLACIER study and the group that switched to the
`three-times-weekly regimen at the start of the extension
`study (23.1 vs. 28.0 events/year) [29].
`
`5.1.2 Patient Well-Being and Convenience
`
`An assessment of patient-reported physical and psycho(cid:173)
`logical well-being in the GLACIER study using the MS
`Impact Scale-29 questionnaire found no difference be(cid:173)
`tween the glatiramer acetate 40 mg/mL three-times-weekly
`and 20 mg/mL once-daily treatment regimens at month 4
`with regard to this endpoint [30]. Therefore, because of the
`predefined statistical testing hierarchy, treatment differ(cid:173)
`ences for subsequent secondary endpoints (including the
`TSQM-9) could not be tested for significance.
`
`Table 3 Injection reactions associated with glatiramer acetate 40 mg/mL three times weekly or 20 mg/mL once daily in adults with relapsing(cid:173)
`remitting multiple sclerosis. Results of the randomized, open-label, 4-month GLACIER study (reported in an abstract) [27]
`
`Treatment (mg/mL)
`
`No. of pts"
`
`Mean annualized rates of injection reactionsb
`
`IRAEC
`
`RR (95% CI)
`
`Moderate to severed IRAE
`
`RR (95% Cl)
`
`GLA 40 tiw
`GLA 20 od
`
`108
`101
`
`35.3
`70.4
`
`0.50 (0.34-0.74)**
`
`0.88
`2.20
`
`0.40 (0.23-0.72)*
`
`GlA glatiramer acetate, !RAE injection-related adverse event, od once daily, pts patients, RR risk ratio, tiw three times weekly
`* p < 0.0021, ** p < 0.0006 vs. GLA 20 od
`" All randomized patients who received at least one dose of GLA
`b Includes local injection-site reactions and symptoms relating to immediate post-injection reactions, such as flushing, palpitations, anxiety and
`dyspnoea. Based on patients' diary cards
`c Primary endpoint
`d Moderate (interferes with nonnal daily activities) and severe (prevents normal daily activities) IRAEs were assessed in a post hoc analysis
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`Glatiramer acetate 40 mg/mL three times weekly was
`associated with numerically greater improvements in pa(cid:173)
`tient convenience scores than 20 mg/mL once daily [30].
`The perception that the three-times-weekly regimen would
`be more convenient than the once-daily regimen was
`indicated by 87 % of 209 patients at baseline [30]. The
`TSQM-9 unadjusted convenience score increased (im(cid:173)
`proved) from 75.6 at baseline to 85.9 at month I and 84.7
`at month 4 in the three-times-weekly group [30], and this
`score was maintained in an 18-week extension (84.9 at last
`observation) [29]. In contrast, there was a minimal increase
`from baseline to months I and 4 in the unadjusted TSQM-9
`score (75.9, 76.9 and 77.6) in the once-daily group [30], but
`after switching to glatiramer acetate 40 mg/mL three times
`weekly in the extension study, the score at last observation
`had increased to 82.2
`
`6 Dosage and Administration
`
`Subcutaneous glatiramer acetate 40 mg/mL three times
`weekly is approved in the USA [I 0] and several European
`countries (including the UK [II]) for the treatment of pa(cid:173)
`tients with relapsing forms of MS. The 40 mg/mL formu(cid:173)
`lation is not interchangeable with the once-daily 20 mg/mL
`formulation. Injections of glatiramer acetate 40 mg/mL
`should not be administered less than 48 h apart. To assist in
`minimizing the risk of lipoatrophy or skin necrosis, correct
`subcutaneous injection techniques should be followed and
`the injection site rotated at each injection [10, 11].
`Glatiramer acetate 40 mg/mL is contraindicated in
`pregnant women in the UK [ 11 ], whereas the US pre(cid:173)
`scribing information states that it should only be used in
`pregnant women if clearly needed (Sect. 3) [10].
`Local prescribing information should be consulted for
`further details regarding contraindications, warnings and
`precautions, and recommendations for use in special pa(cid:173)
`tient populations.
`
`7 Current Status of Glatiramer Acetate 40 mg/mL
`in Relapsing-Remitting Multiple Sclerosis
`
`The main goal for the use of disease-modifying therapy
`(DMT) in MS is to reduce early clinical and subclinical
`disease activity that is thought to contribute to long-term
`disability [2]. While no currently available therapies ef(cid:173)
`fectively stop disease progression, early treatment can de(cid:173)
`lay conversion to clinically definite MS, and treatment of
`relapsing MS can improve relapse rates and disability
`progression. Furthermore, the use of DMT is associated
`with improvements in health-related quality of life (2].
`
`L\ Adis
`
`K. McKeage
`
`Subcutaneous glatiramer acetate is among recommend(cid:173)
`ed options for DMT in MS, and its place in disease man(cid:173)
`agement, along with other recommended agents (i.e. IFN~­
`lb, IFN~-la, mitoxantrone and natalizumab), and other
`approved therapies (e.g. dimethyl fumarate, alemtuzumab,
`fingolimod and teriftunomide) was previously reviewed in
`detail in this journal [4] and elsewhere [31, 32].
`The efficacy and good tolerability of glatiramer acetate
`20 mg/mLoncedaily is well established [4]. However, the use
`of daily injections is a disadvantage for some patients, with
`frequent injections being associated with high rates of injec(cid:173)
`tion-site reactions [33] and a potential barrier to adherence
`[34]. Therefore, providing treatment strategies that improve
`patient experience is an important aspect of care [35, 36].
`The phase III GALA study demonstrated that high(cid:173)
`concentration
`acetate 40 mg/mL three times
`weekly effectively reduced relapse rates in patients with
`RRMS (Sect. 4.1.1 ). Furthermore, the three-times-weekly
`regimen was associated with more favourable MRI out(cid:173)
`comes than placebo, including a reduction in the number of
`new active MRI lesions converting to black holes (a
`manifestation that is associated with disability progres(cid:173)
`sion). In the phase IIIb GLACIER study in patients with
`RRMS, the three-times-weekly regimen reduced the inci(cid:173)
`dence of injection-site reactions significantly more than the
`once-daily regimen (Sect. 5.1.1 ), and appeared to be as(cid:173)
`sociated with greater patient convenience (Sect. 5.1.2).
`Although, the efficacy of glatiramer acetate 40 mg/mL
`three times weekly has not been directly compared with the
`20 mg/mL once-daily regimen, results of indirect com(cid:173)
`parisons suggest that the two regimens have similar effi(cid:173)
`cacy (Sect. 4.2).
`In conclusion, glatiramer acetate 40 mg/mL three times
`weekly provides an effective treatment for patients with re(cid:173)
`lapsing forms of MS, with a significantly lower risk of in(cid:173)
`jection-site reactions than the 20 mg/mL once-daily regimen.
`
`Data selection sources: Relevant medical literature (including
`published and unpublished data) on glatiramer acetate was iden(cid:173)
`tified by searching databases including MEDLINE (from 1946)
`and EMBASE (from 1996) [searches last updated 14 April],
`bibliographies from published literature, clinical
`trial reg(cid:173)
`istries/databases and websites. Additional information was also
`requested from the company developing the drug.
`Search terms: Glatiramer, glatiramer acetate, Copaxone, re(cid:173)
`lapsing-remitting multiple sclerosis.
`Study selection: Studies in patients with relapsing-remitting
`multiple sclerosis who received glatiramer acetate, When avail(cid:173)
`able, large, well designed, comparative trials with appropriate
`statistical methodology were preferred. Relevant pharmacody(cid:173)
`namic and phannacokinetic data are also included.
`
`Disclosure The preparation of this review was not supported by any
`external funding. During the peer review process, the manufacturer of
`
`Page 6 of 8
`
`YEDA EXHIBIT NO. 2025
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`Glatiramer Acetate 40 mg/mL: A Review
`
`the agent under review was offered an opportunity to comment on this
`article. Changes resulting from comments received were made by the
`author on the basis of scientific and editorial merit. Kate McKeage is
`a salaried employee of Adis/Springer.
`
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