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The heritage of glatiramer acetate and its use in multiple sclerosis

The heritage of glatiramer acetate and its use in multiple sclerosis Multiple sclerosis (MS) is a chronic and progressively debilitating disease of the central nervous system. Treatment of MS involves disease-modifying therapies (DMTs) to reduce the incidence of relapses and prevent disease progression. Glatiramer acetate (Copaxone®) was the first of the currently approved DMTs to be tested in human subjects, and it is still considered a standard choice for first-line treatment. The mechanism of action of glatiramer acetate appears to be relatively complex and has not been completely elucidated, but it is likely that it involves both immunomodulating and neuroprotective properties. The efficacy of glatiramer acetate 20 mg/mL once daily as first-line treatment in relapsing- remitting MS is well established, with ample evidence of efficacy from both placebo-controlled and active-comparator controlled clinical trials as well as real-world studies. There is also a considerable body of evidence indicating that the efficacy of glatiramer acetate is maintained in the long term. Clinical trial and real-world data have also consistently shown glatiramer acetate to be safe and well tolerated. Notably, glatiramer acetate has a good safety profile in women planning a pregnancy, and is not associated with foetal toxicity. Until recently, glatiramer acetate was only approved as 20 mg/mL once daily, but a new formulation with less frequent administration, 40 mg/mL three times weekly, has been developed and is now approved in many countries, including Italy. This review examines the mechanism of action, clinical efficacy, safety and tolerability of glatiramer acetate to provide suggestions for optimizing the use of this drug in the current MS therapeutic scenario. Keywords: Multiple sclerosis, Glatiramer acetate, Disease-modifying therapy, Pregnancy, Clinically isolated syndrome Background Several disease-modifying therapies (DMTs) are cur- Multiple sclerosis (MS) is a chronic, progressively debili- rently available to effectively treat MS, with the aim of tating disease affecting the central nervous system (CNS). abolishing/reducing the number of relapses and prevent- It is characterised by multifocal inflammation leading to ing disease progression [3]. Due to the chronic nature of demyelination, axonal damage and impaired nerve con- the disease, when assessing/exploring the profile of a puta- duction; MS is usually thought to be an inflammatory, tive treatment both efficacy and safety have to be exam- immune-mediated condition in the relapsing phase, but in ined in the long term [4]. the chronic progressive phase a neurodegenerative com- Glatiramer acetate (GA, Copaxone®) was the first of ponent is predominant [1]. The definition of clinically iso- the currently approved drugs to be tested in human sub- lated syndrome (CIS) [2] is used to recognize the first jects with MS [5, 6]. However, the approval of GA by the clinical presentation of a disease that could be MS, but European Medicines Agency (EMA), at the dose of 20 mg/ has yet to fulfil criteria of dissemination in time. mL once daily, subcutaneously administered, dates to 2001, when it joined interferon-beta (IFN-β)in the thera- peutic armamentarium. The therapeutic indications are * Correspondence: comi.giancarlo@hsr.it the following: first-line treatment of ambulatory patients Department of Neurology, INSPE, San Raffaele Scientific Institute, Via with RRMS according to McDonald criteria and treatment Olgettina 48, 20132 Milan, Italy of patients who have experienced a CIS and are considered Full list of author information is available at the end of the article © 2016 Comi et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 2 of 13 at high risk of developing clinically definite multiple scler- Mechanism of action osis (CDMS) [7]. The mechanism of action of GA in MS is complex, likely Very recently, with the availability of a new GA formula- involving an interplay of immunomodulating and neuro- tion (40 mg/mL, injected three times weekly), that was protective properties, with details still to be fully eluci- demonstrated to be equally effective as the 20 mg/mL dated [9–13] (Fig. 1). once daily dose in patients with RRMS [8] and was ap- GA was originally designed by researchers at the proved both by the EMA and the Food and Drug Admin- Weizmann Institute in Israel as a synthetic analogue istration (FDA), a substantial gain in patients’ quality of of myelin basic protein (MBP, an autoantigen implicated life has been achieved. The aim of this review is examining in the pathogenesis of MS), with the aim of using it as a the mechanism of action, clinical efficacy, safety and toler- molecular mimic of MBP to study the biology of experi- ability profiles of GA to provide suggestions for optimiz- mental autoimmune encephalomyelitis (EAE), an animal ing the use of this drug in the current MS therapeutic model of MS [14]. GA is a standardised mixture of poly- scenario. peptides randomly polymerized from four L-amino acids, Fig. 1 Immune-mediated pathological and modulatory pathways in multiple sclerosis (MS) and possible neuroprotective actions of glatiramer acetate (GA). GA has been shown to increase levels of neurotrophic factors (a), which are reduced in the serum and the cerebrospinal fluid of MS patients and whose actions include protection of neurons against pathological insults. By inducing specific populations of Th2 cells in the periphery, GA may promote neural growth and inhibit inflammatory demyelination resulting in loss of axons, neurons and oligodendrocytes (b). GA has also been shown to oppose glutamate excitotoxicity by restoring normal kinetic properties of glutamate-mediated synaptic transmission in the striatum (c). GA may produce this effect by blocking synaptic alterations due to TNF-alpha released by activated microglia (d). APC, antigen presenting cell; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; Treg, regulatory T cell (Modified with permission from [11]) Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 3 of 13 L-glutamic acid, L-lysine, L-alanine and L-tyrosine, in a Treg cells in RRMS may be associated with decreased ex- defined molar residue ratio of 0.14:0.34:0.43:0.09. The pression of scurfin, a product of the transcription factor same ratio is found in the amino acid sequence of MBP. forkhead box P3 (Foxp3) [35]. GA can increase Foxp3 ex- The molecular mass of the constituent polypeptides of pression, and in vitro studies have shown that exposure of GA ranges from 4.7 to 11 KDa. peripheral CD4+ T cells from healthy humans or GA- The researchers found that, surprisingly, the synthe- immunized mice to GA results in an increase in regula- sised analogue did not induce EAE, but instead sup- tory T cells, via activation of Foxp3 [36]. A similar finding pressed its development after exposure to crude myelin was reported in a small study in RRMS patients, in which preparations [15]. This finding encouraged studies focus- treatment with GA for up to 6 months increased total sing on potential competition between GA and MBP in Treg numbers and reversed the Treg defect [37]. various immune cell-related events, especially in binding Additionally, it has been demonstrated that GA may to major histocompatibility complex (MHC) molecules act to cause a switch in the B cell phenotype of patients and T-cell antigen receptors [16, 17]. However, it should with MS, leading to the development of low but signifi- be noted that these results were mostly obtained using cant titres of GA-reactive IgG4 antibodies [38]. Because in vitro test systems, and their relevance to the mechan- the isotype switch to IgG4 in B cells requires IL-4, an ism of action of GA in vivo is uncertain. Aharoni and important anti-inflammatory cytokine, this finding fur- colleagues also reported that GA can block the prolifera- ther supports the anti-inflammatory action of GA in tion of MBP-reactive T lymphocytes [18], but this find- treated patients. ing was not reliably reproduced in subsequent studies. There is also evidence to suggest that GA, in addition In fact, more recently, it has been shown that GA does to its action on the adaptive immune system, acts on not alter the proliferation of MBP-reactive T cells, but the innate immune system by directly modulating the some GA-reactive T cells (specifically the Th2 cells) can activity of myeloid cells, in particular monocytes and respond to MBP by secreting protective cytokines [19]. dendritic cells [39–42]. The properties of monocytes of GA-specific T cells, being able to cross the blood-brain RRMS patients undergoing treatment with GA have barrier (while the drug itself is not) mediate the activity of been compared with those of untreated patients and of GA in the central nervous system (CNS). Moreover GA- healthy controls, showing that monocyte reactivity was activated T cells are able to suppress EAE induced not inhibited in the treated patients. This study is import- only by MBP, but also by other encephalitogens, such as ant since it was the first to demonstrate this effect in proteolipid protein (PLP) and myelin oligodendrocyte human subjects treated with GA [43]. glycoprotein (MOG): this so-called “bystander suppression A number of studies have also addressed the question of mechanism” is considered an essential component of the the possible neuroprotective effects of GA. The results of mechanism of action of GA [20]. in vitro and animal model studies have shed some light on An important immunomodulatory effect of GA – and the possible mechanisms of these effects. In addition to in- possibly the primary mechanism behind its activity – is ducing an anti-inflammatory milieu in the CNS through the induction of a shift in the phenotype of reactive T cells the action of reactive T cells, GA has been shown to in- from a mostly pro-inflammatory Th1 pattern of cytokine crease levels of neurotrophic factors such as brain-derived secretion to a mostly anti-inflammatory Th2 pattern in- neurotrophic factor (BDNF), the actions of which include volving the production of IL-4, IL-5, IL-13, IL-10 and protection of neurons against pathological insults [11, 44]. TGF-β [19, 21–27]. However, even if this is probably the Another possible neuroprotective action of GA, against most important mechanism of action of GA, other bio- glutamate excitotoxicity, was recently reported in a mouse logical effects have been reported. model of MS [45]: GA was found to restore normal kinetic The role of Th17 cells (a subset of T cells that produce properties of glutamate-mediated synaptic transmission in a distinct profile of proinflammatory cytokines, including the striatum of treated animals, contrasting the excessive interleukin [IL]-17, IL-6, IL-9, IL-21, IL-22, IL-23, IL-26 glutamate action on postsynaptic receptors. GA produces and tumour necrosis factor-α [TNF-α]) in the immuno- this effect (independently of its immunomodulatory ac- pathogenesis of MS and EAE has recently been eluci- tion) possibly by blocking synaptic alterations induced by dated [28–30]. GA was found to reduce Th-17-related activated microglia-released TNF-α. neuroinflammation and levels of IL-17 and IL-6 in EAE The induction of specific populations of Th2 cells in the mice [31, 32]. periphery by GA may lead to an environment favouring Studies have shown that, in addition to Th17 cells, GA axonal protection, neural growth and remyelination, as re- acts on regulatory T (Treg) cells, whose role in suppress- ported in an in vitro and in vivo study by Skihar and col- ing autoimmunity is well recognized [33]. Patients with leagues [46]. Exposure of mouse embryonic forebrain cells RRMS have an impaired CD4+ CD25+ Treg cells-related in culture to GA-reactive T cells resulted in increased suppressive capacity [34], and functional alterations of levels of insulin-like growth factor-1 (IGF-1) and promoted Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 4 of 13 the formation of oligodendrocyte precursor cells (OPC). (56 % vs. 26 %; p = 0.045) [55]. The first pivotal trial, the Subsequently, mice subjected to induced demyelination of US Glatiramer Acetate phase III study, provided clear evi- the spinal cord were treated with GA; after 7 days, in- dence for the efficacy of GA, demonstrating a significant creased OPC generation and remyelination were observed, 29 % reduction favouring GA in annualised relapse rate associated with higher levels of IGF-1 and BDNF in the (ARR) (0.59 vs. 0.84 for placebo; p = 0.007), supported by spinal cord. trends in the proportion of relapse-free patients (33.6 % Some observations from clinical trials seem to support vs. 27.0 %, respectively), and the median time to first re- such effects. In a substudy of the PreCISe trial, patients lapse (287 vs. 198 days, respectively), after 2 years of treat- treated with GA had increased brain concentrations of ment [53] (Table 1). In this study MRI measures were not the neuronal integrity marker N-acetylaspartate, and an used. A second study, the European/Canadian MRI trial, improvement in brain neuronaxonal integrity, whereas was planned in order to better define the profile of efficacy patients receiving placebo did not [47]. Also, magnetic and safety of GA. It provided for the first time MRI resonance imaging (MRI) studies have demonstrated the evidence of the beneficial effect of GA; 9 months of ther- ability of GA to reduce the proportion of new T1 hypoin- apy resulted in significant differences favouring GA versus tense lesions evolving into permanent black holes (markers placebo for most endpoints: mean total number of enhan- of irreversible axonal loss), therefore supporting the neuro- cing lesions on T1-weighted images (primary endpoint; protective scenario [48, 49]. 25.96 vs. 36.80; p = 0.003), number of new enhancing lesions (17.4 vs. 26.0; p < 0.003) and their change of Clinical efficacy volume (p < 0.01), number of new lesions detected on T2- Subcutaneous GA has a long history of use for the treat- weighted images (9.4 vs. 13.5, respectively; p <0.003) and ment of RRMS. The initially approved dose, on the basis their change of volume (p = 0.001). Moreover, a significant of animal studies, is 20 mg/mL once daily; still widely con- reduction of the relapse rate was reported in the GA sidered as standard, it was a keystone for all later drug de- group versus placebo (33 %; p =0.012) (Table1). Alater velopment. Attempts to explore higher weekly doses (40 study that analysed MRI data from the European- mg/mL once daily) showed no additive benefit [50, 51]. Canadian trial using a fully automated, normalized Recent results of the GALA study [8] indicate that main- method also showed a significant (p = 0.037 at 18 months) taining a similar weekly dose, but with a different dosing reduction in the development of brain atrophy in the regimen (40 mg/mL three times a week), provides advan- GA group versus placebo [56]. A noteworthy finding tages in clinical use without impacting on efficacy. of the European/Canadian MRI study was a reduction The feasibility of oral administration of GA was tested in severity of tissue disruption in newly-formed le- in the placebo-controlled CORAL trial [52]. Patients with sions with GA [48]: the percentage of new lesions RRMS received 50 mg or 5 mg of GA or placebo daily for evolving into permanent black holes was significantly 14 months. Neither dose of GA affected the primary end- lower in patients treated with GA than in those point (relapse rate) or any other clinical and MRI end- receiving placebo at 7 months (18.9 % vs. 26.3 %, point. Thus, further development of oral administration respectively; p = 0.04) and at 8 months (15.6 % vs. 31.4 %, was discontinued. GA has been tested in progressive MS respectively; p = 0.002) after lesion appearance. with negative results. Active comparator-controlled trials GA has been com- Once-daily formulation pared head-to-head with high-dose subcutaneous IFN-β1a In relapsing-remitting multiple sclerosis or -1b in two double blind trials in patients with RRMS: The efficacy of GA 20 mg/mL once daily as first-line REGARD [57] and BECOME [58] (Table 1). Both showed treatment in RRMS is well established in many phase II, comparable efficacy between GA and IFN-β1a or -1b. III and IV studies. Moreover in the REGARD trial, GA was found to better protect against brain-volume loss (–1.07 % vs. –1.24 %; Placebo-controlled trials The efficacy of GA on clin- p = 0.018). These data were confirmed by two trials in ical and MRI-assessed outcomes has been demon- which GA was used as reference comparator. In the BE- strated in two major pivotal placebo-controlled trials – YOND trial [59], two arms receiving IFN-β1b (250 μgand the US Glatiramer Acetate trial [53] and the European/ 500 μg) were included, along with a third arm receiving Canadian MRI study [54], and supported by an initial GA: no significant differences were found between groups small study in 50 patients [55] (Table 1). This latter study either in the primary endpoint (ARR: 0.33 for IFN-β1b provided the first clinical evidence supporting GA in 500 μg, 0.36 for IFN-β1b 250 μg and 0.34 for GA; p =ns RRMS, with 2 years of treatment with GA 20 mg/mL daily for all comparisons) and in all other clinical outcomes resulting in a significant difference in the proportion (Table 1). The CONFIRM trial [60] compared two doses of patients experiencing no relapses versus placebo of dimethyl fumarate versus placebo, again with a third Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 5 of 13 Table 1 Clinical trials Study Number of patients Trial length Key outcomes Placebo-controlled trials Johnson et al. 1995 [53] 251 randomised 1:1 GA:PBO 2 years Mean relapse rate: GA 1.19 versus PBO 1.68; p = 0.007 (29 % reduction) (ARR: GA 0.59 versus PBO 0.84) Comi et al. 2001 [54] 239 randomised 1:1 GA:PBO 9 months Mean reduction in total enhancing lesions GA vs PBO -10.8 (95 % CI -18.0 to -3.7; p = 0.003); 29 % reduction. Bornstein et al. 1987 [55] 50 randomised 1:1 GA:PBO 2 years Proportion of relapse-free patients GA 56 % vs 26 % PBO; p = 0.045 Active comparator-controlled trials Mikol et al. 2008 [57] 764 randomised 1:1 GA:IFNβ-1a 96 weeks No between-group difference in time to first relapse (HR 0.94; 95 % CI (REGARD) 0.74–1.21; p = 0.64) th Cadavid et al. 2009 [58] 75 randomised 1:1 GA: INF-β1b 2 years Similar median (75 percentile) CAL count per scan in (BECOME) months 1–12, of 0.58 (2.45) vs 0.63 (2.76) O’Connor et al. 2009 [59] 2447 randomised 2:2:1 250 μg 3.5 years No between-group differences in relapse risk or EDSS progression (BEYOND) IFNβ-1b:500 μg IFNβ-1b:GA Fox et al. 2012 [60] Randomised 1:1:1:1 PBO: BG-12 96 weeks ARR significantly lower with twice-daily BG-12 (0.22), three times-daily (CONFIRM) twice daily:BG-12 three times BG-12 (0.20), and GA (0.29) than PBO (0.40) (RR GA 29 %, P = 0.01). daily:GA Combination trials Goodman et al. 2009 [85] 110 randomised 1:1 GA + NTZ 6 months Mean rate of development of new active lesions over the 24-week (GLANCE) versus GA alone study lower with combination therapy (0.03) vs GA alone (0.11; p = 0.031) Lindsey et al. 2012 [116] 1008 randomised 2:1:1 IFN + GA: 3 years No difference in ARR between combination group and GA group (CombiRx) IFN: GA (0.12 vs. 0.11). Both combination and GA alone superior to IFN group (0.16; p = 0.022 for combination group and p = 0.027 for GA group) Clinically isolated syndrome Comi et al. 2009 [86] 481 randomised 1:1 GA:PBO 36 months GA reduced risk of CDMS by 45 % versus PBO (HR 0.55, 95 % CI (PreCISe) 0.40–0.77; p = 0.0005) 95 % CI 95 % confidence interval, ARR Annualised relapse rate, CAL Combined active lesions, CDMS Clinically definite multiple sclerosis, EDSS Expanded disability status scale, GA Glatiramer acetate, HR Hazard ratio, IFN Interferon, NTZ natalizumab, PBO Placebo, RR Relative risk arm with GA as a reference comparator. Even if the discontinuation in extensions of clinical trials or post- design of the trial did not allow a comparison be- marketing studies [63, 70, 72, 73]. tween the two active treatments, both drugs proved The first follow-up of the US Glatiramer Acetate trial to be significantly superior to placebo in all clinical presented 15-year data [63]. Patients continuing in the and MRI outcomes (Table 1). In particular, GA sig- study (100 of the initial 232) showed a reduced ARR nificantly reduced the ARR versus placebo by 29 % (0.25 ± 0.34 per year vs. 1.12 ± 0.82 at baseline); 57 % (p = 0.01), thus confirming the results of the pivotal had stable or improved Expanded Disability Status Scale trials in a very large population sample (over 1400 (EDSS) scores (change ≤0.5 points) and 67 % showed patients). A post hoc subgroup analysis reported nu- stable disease, without transitioning to secondary pro- merically similar relapse-related outcomes between gressive MS. The most frequently reported reasons for the two dimethyl fumarate arms and the GA arm in treatment discontinuation were patient perception of most patient subgroups [61]. disease worsening (n = 29), a desire to switch or com- A systematic review summarising data from five ran- bine therapies (n = 26) and difficulty, inability, or un- domised studies comparing IFN-β with GA in patients willingness to adhere to the study protocol (n = 32). with RRMS confirmed a similar efficacy after 2 years of Twenty-year results are now available for the long- treatment [62]. term extension of this study [64]. Of the initial 232 patients, 74 remain in the trial and have been continu- Long-term and real-word data Even with all the limi- ously treated for a mean of 19.3 years. Very long-term tations of long-term extension studies, due to poten- use of GA appears to be associated with stable disease tial selection bias, available data suggest that the activity (cumulative ARR = 0.2; 24.3 % of patients efficacy of GA is maintained over time [63–71]. remained free of relapse for the entire period) and low Moreover, there have been no reports of rebound ef- levels of accumulated disability (mean EDSS score 3.1 fect or delayed disease reactivation after treatment vs. 2.4 at baseline). Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 6 of 13 The extension of the European/Canadian MRI study of- responding to first line therapies GA can be offered as fers serial long-term MRI data for a large cohort of an alternative to so-called second line medications if patients treated with GA [70]. After the 9-month double- there are concerns of tolerability/adverse events with the blind, placebo-controlled phase, all patients entered an latter therapies. Most studies describe switches from open-label, active treatment phase in which they received IFNβ-1a or -1b to GA, reporting reductions in mean GA 20 mg/mL once daily for a further 9 months, with a ARR after switching [81–83]. However, in those situa- long-term follow-up visit (LTFU) scheduled at least five tions when the shift is due to failure of the previous years after study entry. Overall, MRI results show that the treatment, results should be interpreted with caution be- effects of GA on MS activity are sustained (number of ac- cause the regression to the mean phenomenon is a tive lesions 0.9 at LTFU vs. 3.4 at baseline; percentage major concern. Therefore, randomised, controlled trials brain volume change –5.02 vs. baseline). Moreover, MRI are needed to confirm these results. results in the patients that were shifted from placebo to GA showed a significant reduction of MRI measures of Combination treatment trials Two important combin- disease activity, paralleling what was observed in the pa- ation therapy trials are the CombiRx trial [84] and the tients that received GA from the start. A notable finding is GLANCE trial [85] (Table 1). In CombiRx, patients were that the proportion of patients requiring walking aids at randomised to GA 20 mg/mL once daily plus IFN-β1a 30 the LTFU was significantly lower (p = 0.034) in the group μg once weekly or to monotherapy with one of these med- that received GA from the start of the study compared ications plus placebo for 3 years. For the primary outcome with delayed treatment, suggesting that early treat- of ARR, the combination therapy was significantly super- ment may have a positive impact on long-term disease ior to IFN-β, reducing the relapse rate by 25 % (p =0.022), outcomes. while there was no significant difference between the A 5-year brain MRI retrospective open study provides combination therapy and GA. It should be noted that the some evidence of the efficacy of GA in reducing brain study design allowed for the first time a comparison be- volume loss [74]: smaller reductions in brain volume tween intramuscular IFN-β and GA, with GA resulting were observed in patients with RRMS treated with sub- superior (relapse rate reduction by 31 % compared with cutaneous GA than with high-dose IFN-β regimens IFN-β; p = 0.027). The GLANCE study compared com- (percentage change in brain volume –2.27 % vs. –3.21 %; bination therapy with GA 20 mg/mL once daily plus p < 0.0001). intravenous natalizumab 300 mg every 4 weeks versus Various studies report real-world data for GA treat- monotherapy with GA 20 mg/mL once daily plus placebo ment in RRMS [72, 73, 75, 76], confirming the efficacy every 4 weeks. At 24 weeks, the combination therapy was profile of GA observed in the clinical studies. A signifi- superior on major MRI disease activity measures. cant impact of the treatment with GA on health-related quality of life has also been reported [77, 78], with bene- In clinically isolated syndrome ficial effects including significant reductions in fatigue Early treatment with GA in patients with CIS has been and in days of absence from work. shown to delay onset of CDMS in the placebo-controlled Controlled studies of MS treatments in children study PreCISe [86] (Table 1) and during its subsequent and adolescents are still lacking, but some published open-label extension period [87]. The study enrolled 481 evidence, albeit retrospective, points to the efficacy of patients with one unifocal neurological event and a posi- GA in this population. In an Italian cohort, 14 pa- tive MRI scan (defined as the presence of at least two tients with a mean age of 13.1 years were treated for cerebral lesions ≥6 mm in diameter on T2-weighted im- a mean of 5 years or more; these patients had a ages). Patients were randomised to GA 20 mg/mL once reduction in relapse rate, from about 3 per year be- daily or placebo for up to 36 months or until conversion fore treatment initiation to 0.2–0.4 per year during to MS. GA was associated with a 45 % reduction in risk of the treatment period [79]. A small study of seven patients conversion to MS (primary endpoint; p = 0.0005) and a with RRMS who had disease onset at 9–16 years of age delay in the time to conversion compared with placebo and began GA before 18 years of age showed that 24 (336 days vs. 722 days, respectively). GA was associated months of treatment resulted in two of seven patients with a 58 % reduction in number of new T2 lesions and a remaining relapse free over the study period, and three of smaller volume of T2 lesions. During the extension phase seven patients having stable disability scores as measured (total 5 years’ duration) the efficacy of GA was sustained, by the EDSS [80]. with a 41 % reduction in risk of conversion to MS in those treated with GA from the start compared with delayed Switching to glatiramer acetate Several trials have treatment; in the GA group, there was a delay of 972 days evaluated switching to GA from other MS therapies for before conversion to MS, a 42 % reduction in new T2 le- safety and efficacy reasons [81–83]. For patients not sions per year (p < 0.0001) and a 22 % reduction in T2- Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 7 of 13 lesion volume (p = 0.0005). In the extension phase pa- cumulative number of gadolinium-enhancing T1 le- tients treated with GA from study entry showed a signifi- sions (44.8 %; p < 0.0001) and new or enlarged T2 le- cant 28 % reduction (p = 0.0209) in brain volume loss sions (34.7 %; p < 0.0001) were reported; the numerical compared with patients initially randomised to placebo, values of these parameters were very similar to those confirming the neuroprotective effects of GA. This is observed in the pivotal studies with the 20 mg/mL once the first trial to demonstrate that early treatment with daily dose. Three-year results of the open-label extension GA reduces brain atrophy versus delayed treatment in of the GALA study demonstrated sustained efficacy on this setting. ARR and MRI parameters of disease activity [91]. Patients switched from placebo to GA after the double blind phase In progressive forms of multiple sclerosis reported significant gains in efficacy, but those treated GA was assessed in primary progressive forms of MS, with GA from study entry showed a significantly lower re- with negative results. The PROMiSe study [88] was a lapse rate (ARR 0.23 vs 0.30, respectively, p = 0.0052) and randomised, double-blind, placebo-controlled, multicen- significantly fewer enhancing T1 lesions and new or en- tre, international study that investigated the effect of GA larged T2 lesions (RR = 0.660, p = 0.0005 for T1; RR = on disability progression in 943 patients with progressive 0.680, p < 0.0001 for T2) compared with patients with MS. After 3 years of treatment, the time to sustained delayed treatment. accumulated disability was similar between GA- and An important finding from a recent post hoc MRI ana- placebo-treated patients (hazard ratio [HR] 0.87; 95 % lysis of data from the GALA study is that GA 40 mg/mL CI 0.71 to 1.07; p = 0.1753). A post hoc analysis showed three times weekly (cumulative weekly dose of 120 mg) a possible effect in slowing clinical progression in male shares the ability of the standard formulation (cumu- patients (HR 0.71; 95 % CI 0.53 to 0.95; p = 0.0193) [88], lative weekly dose of 140 mg) to reduce conversion of but a subsequent analysis of these results did not dem- new active lesions into black holes, markers of perman- onstrate an impact of gender on the efficacy of GA [89]. ent damage and disability progression, with a significant An additional study investigating metabolite ratios as de- 24 % reduction compared with placebo (p = 0.006) in termined by MRI in a subset of 58 patients from the the odds of conversion from new lesions at month 6 to PROMISe study showed no difference between the GA black holes at month 12 [49]. and placebo groups [90]. However, it should be noted In the absence of head-to-head studies comparing GA that the PROMISe study was terminated early due to 20 mg/mL once daily and 40 mg/mL three times weekly, lack of effect, and that the low rate of disability progres- indirect comparisons have also shown very similar effi- sion and the high rate of premature discontinuations led cacy of the two doses [92, 93]. to a decrease in power of the study, hampering the de- On the same lines, the GLACIER study, in which pa- termination of a treatment effect [88]. tients were asked to report the personal experience of shifting from the 20 mg/mL once daily dose to the 40 mg/ Three times weekly formulation mL three times weekly dose, demonstrated a favourable The first trial to evaluate a high-dose regimen of GA was convenience profile and patient satisfaction when convert- the phase III FORTE study [51] that compared the 40 mg/ ing from the once-daily formulation [94]. mL once daily dose with the standard 20 mg/mL once daily dose in patients with RRMS. Both doses showed Safety similar effects on efficacy measures and no difference in After 20 years’ continuous clinical use and more than 2 the safety profile. Post-hoc analyses revealed potential million patient-years’ exposure, the safety profile of GA benefits of the 40 mg/mL dose in some subgroups (for ex- is well established. No evidence of any association of GA ample, in the “frequent MRI cohort” patients treated with with immunosuppression or with malignant and auto- 40 mg/mL showed a slight numerical advantage in the re- immune disease has been reported after 10 and 15 years duction of the mean number of gadolinium-enhancing le- follow-up [63, 65]. GA was not associated with psychi- sions at various timepoints vs. baseline). After this study atric or mood disorders and in some studies a significant the development of the high-dose once daily regimen was improvement in fatigue was observed, even in patients discontinued, but it provided a starting point for subse- switching from other DMTs [78]. In a study of patients quent research on the high-dose, lower-frequency regimen with RRMS and spasticity, switching from IFN-β to GA (40 mg/mL three times weekly). improved spasm frequency, muscle tone and pain after 3 TheefficacyofsubcutaneousGA40mg/mL three times months of treatment; these improvements were main- weekly in patients with RRMS was shown in the 1-year, tained over 6 months of treatment with GA [95]. A few double blind, placebo-controlled GALA study, involving cases of hepatotoxicity during treatment with GA have about 1400 patients [8]. Significant reductions com- recently been reported [96–98], with no such cases re- pared with placebo in relapse rate (34.0 %; p < 0.0001), ported in clinical trials, hence it is unclear at present if Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 8 of 13 liver function monitoring is warranted. It should be treatment may be assessed on a case-by-case basis [104]. noted, though, that because some of the patients report- An Italian retrospective study showed that the mother’s ing this AE had concurrent autoimmune conditions, it is exposure to GA when the drug was suspended within 4 impossible to disentangle the potential contribution of weeks from conception was not associated with an in- GA treatment and the underlying condition to hepato- creased frequency of spontaneous abortion nor with toxicity. IgE-mediated allergic reactions have also been other negative pregnancy and foetal outcomes compared described [99, 100]. with women in whom the medication was suspended 4 Both formulations of GA appear equivalent from the weeks or more from conception, or who were untreated safety standpoint [64, 91, 94]. In the GALA study AEs as- [107]. These findings confirm those of a previous obser- sociated with administration of GA 40 mg/mL three times vational study [106] suggesting that GA and the IFNs do a week were found to be consistent with the known safety not represent a significant risk for prenatal developmen- profile of GA 20 mg/mL once daily. Moreover, no new tal toxicity. Relapse rate decreases during pregnancy, AEs emerged during treatment with high-dose GA [8, 91]. with a well-known increase in the first three months At present there are no controlled studies of DMTs in after childbirth [110] that sometimes requires second- children and adolescents with MS, but published evidence, line therapy to be controlled [103–105]. mostly retrospective studies, support a similar safety pro- file of GA in this population [79, 80]. GA, along with IFN- Tolerability β, has been recommended as the standard treatment for The tolerability of GA 20 mg/mL once daily has con- paediatric RRMS in two position papers, one produced by sistently been reported as good versus both placebo European experts [101] and the other one by the Inter- and active treatment in the previously mentioned clin- national paediatric MS Study [102]. Since paediatric onset ical trials [54, 57, 59, 86], and the nature and frequency MS is characterized by high disease burden, early treat- of treatment-related AEs were similar between short- ment, although off-label, should be promptly started after and long-term treatment periods [63–65, 67]. The most confirmation of the diagnosis. The favourable tolerability common (>1/10) treatment-related AEs are transient profile of GA should be considered when making a thera- injection-site reactions, occurring occasionally in about peutic choice [101, 102]. two thirds of patients [7]. These include injection site No limitations to concomitant administration of GA bruising, erythema, pain, pruritus and induration. Rarer and other drugs have been identified; the medication is cases of localized lipoatrophy and skin necrosis at injection not linked to blood test abnormalities that require sites have been reported during post-marketing [111, 112]. monitoring. One peculiar injection-related tolerability issue with GA is the occurrence of immediate post-injection reactions Pregnancy (IPIR) that present immediately or a few minutes after the Animal reproduction studies have failed to demonstrate a injection, consisting in flushing, chest tightness, palpita- risk of GA treatment to the foetus, and post-marketing tion, dyspnoea and intense anxiety. The crisis resolves studies support the absence of foetal toxicity [103–108]. spontaneously in a few minutes [53]. These reactions are For these reasons GA has been classified as FDA Class B unpredictable, affecting about 15 % of patients and seldom during pregnancy [109]. Most of the other drugs approved recurring more than once. The intensity of the reaction is for the treatment of MS are categorized by the FDA as not connected to any real risk to patients. Class C, with the exception of mitoxantrone, classified as The tolerability of GA 40 mg/mL three times weekly Class D (positive evidence of human foetal risk), and teri- has been shown to be similar to that of the 20 mg/mL flunomide, classified as Class X (foetal toxicity) [104, 109]. once-daily formulation [8, 91]. Importantly, in the GLA- GA can be continued right up until conception, unlike CIER study [94], three times weekly GA was found to be other DMTs for which a washout period is recommended better tolerated than the once-daily formulation in terms prior to trying to conceive [104]. GA may also be used as of injection-related adverse events (IRAEs): the adjusted bridging therapy in women planning a pregnancy who are mean annualized rate of IRAEs was reduced by 50 % in receiving treatments requiring a washout period, if it patients receiving the new formulation (35.3 events per exposes women to the risk of MS reactivation, and of- year vs. 70.4 events per year, respectively; p = 0.0006), fers some advantages in women risking unplanned while the rate of moderate/severe events was reduced by pregnancies. 60 % (0.9 events per year vs. 2.2 events per year, respect- While it is currently recommended that, as for any ively; p = 0.0021). Furthermore, treatment convenience, other DMT, GA should be discontinued after confirmed as measured by the Treatment Satisfaction Question- evidence of pregnancy and until childbirth, available evi- naire for Medication-9 (TSQM-9) convenience subscale, dence suggests GA could be continued at least through- was improved for patients switching from GA 20 mg/ out the first trimester, while further continuation of GA mL once daily to the three times weekly formulation Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 9 of 13 [94]. Recently, results from the extension phase of the clinical trials demonstrating the efficacy of GA in these pa- GLACIER study confirm the safety profile of the 40 mg/ tients are currently lacking. mL three times weekly formulation, in terms of both We anticipate that the new 40 mg/mL three times IRAEs and convenience [113]. weekly regimen might increase compliance and adher- ence. Therefore it is recommended that, in all consenting patients currently treated with the once daily formulation, Conclusions the switch to the new formulation should be considered. The availability of multiple drugs has totally changed the An early start of GA treatment should be considered in scenario of MS treatment. Treatment choices became the light of data on brain atrophy from the PreCISe study much more complicated and decisions should be based [87]: there was a significant (–28 %; p = 0.0209) difference on the combination of the efficacy and safety profiles. when comparing early GA treatment versus delayed GA From this point of view GA associates a favourable effi- treatment. cacy profile, confirmed by more than 20 years of clinical In conclusion, clinical trials and real-life studies have use, with an excellent safety and tolerability profile. The consistently shown the efficacy and safety of both for- burden of daily injections has been recently reduced by mulations of GA in the first-line treatment of patients the availability of the new 40 mg/mL three times a week with RRMS and for delaying the onset of clinically defin- formulation, which has been shown to share the same effi- ite MS in patients with CIS. Overall, data suggest that cacy of the 20 mg/mL once daily formulation, but with while many types of patients can be expected to benefit obvious advantages in terms of patient convenience. from GA, the “ideal” subject would be one with RR dis- GA has been classified as a first-line drug for the treat- ease or newly-diagnosed, young and active, wanting to ment of RRMS in Europe, with a clear indication both in lead a normal life. The use of GA for more than two naïve patients and in patients who discontinue other ther- decades shows a reassuring safety profile and optimal apies for safety or tolerability issues. The recent evidence of tolerability. The major concern may be the frequency of the importance of personalized treatment implies that the administration, an issue that the new formulation can assessment of the individual prognostic profile should drive be expected to minimize, contributing to the use of this treatment decisions, at the same time considering also pa- drug. Besides patient convenience, the fact that no tients’ preference and convenience. Patients with a good complex clinical monitoring is required during treat- prognostic profile as indicated by low disease activity – re- ment clearly represents another strong point of the vealed by low brain lesion burden and few or absent active clinical use of GA. lesions at the time of treatment onset – may haveahigh probability of responding to first-line therapies, including Abbreviations ARR: Annualized relapse rate; BDNF: Brain derived neurotrophic factor; GA. On the contrary, patients with very active disease in CDMS: Clinically definite multiple sclerosis; CIS: Clinically isolated syndrome; the early phases tend to require an induction approach to CNS: Central nervous system; DMTs: Disease-modifying therapies; obtain a positive response to treatment. EDSS: Expanded disability status scale; GA: Glatiramer acetate; IFN: Interferon; IRAEs: Injection-related adverse events; LTFU: Long-term follow up; Considering the choice among first-line therapies, GA MBP: Myelin basic protein; MHC: Major histocompatibility complex; offers an obvious advantage in young, potentially fertile MRI: Magnetic resonance imaging; MS: Multiple sclerosis; RRMS: Relapsing- women for the favourable safety profile in this popula- remitting multiple sclerosis; TNF: Tumour necrosis factor; TSQM-9: Treatment satisfaction questionnaire for medication-9. tion, as discussed above [107]. Patients with CIS are also expected to benefit from GA, given the evidence of effi- Competing interests cacy in such patients, supported by extension studies GC has received honoraria as a consultant and for lecturing at scientific showing clear protection from brain atrophy [86, 87]. meetings from Novartis, Teva, Sanofi-Aventis, Genzyme, Merck Serono, Another possible use of GA is as maintenance treatment Biogen, Bayer, Serono Symposia International Foundation, Excemed, Roche, Almirall, Chugai, Receptos and Forward Pharma. in patients who start with an induction approach be- AB has received honoraria for serving in the scientific advisory boards of cause of a negative prognostic profile. Induction therapy Almirall, Bayer, Biogen, Genzyme, with approval by the Director of AOU San has often the advantage of “reshaping” the immune sys- Luigi University Hospital, and has received speaker honoraria from Biogen, Genzyme, Novartis, Teva; his institution has received grant support from tem, which can then be maintained by GA [114, 115]. Bayer, Biogen, Merck, Novartis, Teva, from the Italian Multiple Sclerosis The classification of MS clinical courses [2] defines the Society, Fondazione Ricerca Biomedica ONLUS and San Luigi ONLUS. importance of disease activity not only in RRMS, but also DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Teva and received in patients with a progressive disease course. The presence honoraria for speaking or consultation fees from Almirall, Bayer Schering, of disease activity represents a clear target for DMTs. Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi- Among them, the use of GA should be considered because Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and the principal investigator in clinical trials for of the long-term safety and absence of negative impact on Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, spasticity, a frequent AE of IFN-β treatment in this popula- Sanofi-Aventis, Teva. His preclinical and clinical research was supported by tion. It should be noted, however, that conclusive data from grants from Bayer, Biogen, Merck Serono, Novartis and Teva. Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 10 of 13 NDS has received honoraria or consultation fees from Novartis, Merck and Advanced Technologies, G.F. Ingrassia, Multiple Sclerosis Center, Serono, Biogen Idec, La Roche; has been member of Advisory Boards for University of Catania, Catania, Italy. Department of Neurology and Novartis, Merck Serono, Biogen Idec; has participated in company-sponsored Psychiatry, Sapienza University of Rome, Rome, Italy. Department of speaker’s bureau for Novartis, Merck Serono, Biogen Idec; has received travel Experimental and Clinical Medicine, 1 Neurological Clinic, Marche Polytechnic reimbursements from Novartis, Merck Serono and Biogen Idec. University, Ancona, Italy. Centre for Experimental Neurological Therapies CF has received grants and personal fees from Teva, and grants from Merck (CENTERS), S. Andrea Hospital Site, Sapienza University of Rome, Rome, Italy. Serono, Novartis and Fondazione Italiana Sclerosi Multipla. Department of Medical, Surgical, Neurological, Metabolic and Aging AG serves on scientific advisory boards or as consultant for Merck Serono, Sciences, Second University of Naples, Naples, Italy. Department of Basic Teva, Novartis, Biogen Idec; he has received honoraria for lecturing from Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Merck Serono, Biogen Idec, Novartis, Teva, Genzyme, Almirall. Italy. PG is an Advisory Board member of Almirall, Biogen Italy, Sanofi-Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Teva and received honoraria for Received: 2 November 2015 Accepted: 11 April 2016 speaking or consultation fees from Almirall, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and has been the principal investigator in clinical trials for Biogen Idec, Merck References Serono, Novartis, Roche, Sanofi-Aventis, Teva, Almirall. His preclinical and 1. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4):1180–8. clinical research was supported by grants from Bayer-Shering, Biogen-Idec, doi:10.1172/JCI58649. 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The heritage of glatiramer acetate and its use in multiple sclerosis

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Psychology; Neuropsychology; Clinical Psychology
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Abstract

Multiple sclerosis (MS) is a chronic and progressively debilitating disease of the central nervous system. Treatment of MS involves disease-modifying therapies (DMTs) to reduce the incidence of relapses and prevent disease progression. Glatiramer acetate (Copaxone®) was the first of the currently approved DMTs to be tested in human subjects, and it is still considered a standard choice for first-line treatment. The mechanism of action of glatiramer acetate appears to be relatively complex and has not been completely elucidated, but it is likely that it involves both immunomodulating and neuroprotective properties. The efficacy of glatiramer acetate 20 mg/mL once daily as first-line treatment in relapsing- remitting MS is well established, with ample evidence of efficacy from both placebo-controlled and active-comparator controlled clinical trials as well as real-world studies. There is also a considerable body of evidence indicating that the efficacy of glatiramer acetate is maintained in the long term. Clinical trial and real-world data have also consistently shown glatiramer acetate to be safe and well tolerated. Notably, glatiramer acetate has a good safety profile in women planning a pregnancy, and is not associated with foetal toxicity. Until recently, glatiramer acetate was only approved as 20 mg/mL once daily, but a new formulation with less frequent administration, 40 mg/mL three times weekly, has been developed and is now approved in many countries, including Italy. This review examines the mechanism of action, clinical efficacy, safety and tolerability of glatiramer acetate to provide suggestions for optimizing the use of this drug in the current MS therapeutic scenario. Keywords: Multiple sclerosis, Glatiramer acetate, Disease-modifying therapy, Pregnancy, Clinically isolated syndrome Background Several disease-modifying therapies (DMTs) are cur- Multiple sclerosis (MS) is a chronic, progressively debili- rently available to effectively treat MS, with the aim of tating disease affecting the central nervous system (CNS). abolishing/reducing the number of relapses and prevent- It is characterised by multifocal inflammation leading to ing disease progression [3]. Due to the chronic nature of demyelination, axonal damage and impaired nerve con- the disease, when assessing/exploring the profile of a puta- duction; MS is usually thought to be an inflammatory, tive treatment both efficacy and safety have to be exam- immune-mediated condition in the relapsing phase, but in ined in the long term [4]. the chronic progressive phase a neurodegenerative com- Glatiramer acetate (GA, Copaxone®) was the first of ponent is predominant [1]. The definition of clinically iso- the currently approved drugs to be tested in human sub- lated syndrome (CIS) [2] is used to recognize the first jects with MS [5, 6]. However, the approval of GA by the clinical presentation of a disease that could be MS, but European Medicines Agency (EMA), at the dose of 20 mg/ has yet to fulfil criteria of dissemination in time. mL once daily, subcutaneously administered, dates to 2001, when it joined interferon-beta (IFN-β)in the thera- peutic armamentarium. The therapeutic indications are * Correspondence: comi.giancarlo@hsr.it the following: first-line treatment of ambulatory patients Department of Neurology, INSPE, San Raffaele Scientific Institute, Via with RRMS according to McDonald criteria and treatment Olgettina 48, 20132 Milan, Italy of patients who have experienced a CIS and are considered Full list of author information is available at the end of the article © 2016 Comi et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 2 of 13 at high risk of developing clinically definite multiple scler- Mechanism of action osis (CDMS) [7]. The mechanism of action of GA in MS is complex, likely Very recently, with the availability of a new GA formula- involving an interplay of immunomodulating and neuro- tion (40 mg/mL, injected three times weekly), that was protective properties, with details still to be fully eluci- demonstrated to be equally effective as the 20 mg/mL dated [9–13] (Fig. 1). once daily dose in patients with RRMS [8] and was ap- GA was originally designed by researchers at the proved both by the EMA and the Food and Drug Admin- Weizmann Institute in Israel as a synthetic analogue istration (FDA), a substantial gain in patients’ quality of of myelin basic protein (MBP, an autoantigen implicated life has been achieved. The aim of this review is examining in the pathogenesis of MS), with the aim of using it as a the mechanism of action, clinical efficacy, safety and toler- molecular mimic of MBP to study the biology of experi- ability profiles of GA to provide suggestions for optimiz- mental autoimmune encephalomyelitis (EAE), an animal ing the use of this drug in the current MS therapeutic model of MS [14]. GA is a standardised mixture of poly- scenario. peptides randomly polymerized from four L-amino acids, Fig. 1 Immune-mediated pathological and modulatory pathways in multiple sclerosis (MS) and possible neuroprotective actions of glatiramer acetate (GA). GA has been shown to increase levels of neurotrophic factors (a), which are reduced in the serum and the cerebrospinal fluid of MS patients and whose actions include protection of neurons against pathological insults. By inducing specific populations of Th2 cells in the periphery, GA may promote neural growth and inhibit inflammatory demyelination resulting in loss of axons, neurons and oligodendrocytes (b). GA has also been shown to oppose glutamate excitotoxicity by restoring normal kinetic properties of glutamate-mediated synaptic transmission in the striatum (c). GA may produce this effect by blocking synaptic alterations due to TNF-alpha released by activated microglia (d). APC, antigen presenting cell; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; Treg, regulatory T cell (Modified with permission from [11]) Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 3 of 13 L-glutamic acid, L-lysine, L-alanine and L-tyrosine, in a Treg cells in RRMS may be associated with decreased ex- defined molar residue ratio of 0.14:0.34:0.43:0.09. The pression of scurfin, a product of the transcription factor same ratio is found in the amino acid sequence of MBP. forkhead box P3 (Foxp3) [35]. GA can increase Foxp3 ex- The molecular mass of the constituent polypeptides of pression, and in vitro studies have shown that exposure of GA ranges from 4.7 to 11 KDa. peripheral CD4+ T cells from healthy humans or GA- The researchers found that, surprisingly, the synthe- immunized mice to GA results in an increase in regula- sised analogue did not induce EAE, but instead sup- tory T cells, via activation of Foxp3 [36]. A similar finding pressed its development after exposure to crude myelin was reported in a small study in RRMS patients, in which preparations [15]. This finding encouraged studies focus- treatment with GA for up to 6 months increased total sing on potential competition between GA and MBP in Treg numbers and reversed the Treg defect [37]. various immune cell-related events, especially in binding Additionally, it has been demonstrated that GA may to major histocompatibility complex (MHC) molecules act to cause a switch in the B cell phenotype of patients and T-cell antigen receptors [16, 17]. However, it should with MS, leading to the development of low but signifi- be noted that these results were mostly obtained using cant titres of GA-reactive IgG4 antibodies [38]. Because in vitro test systems, and their relevance to the mechan- the isotype switch to IgG4 in B cells requires IL-4, an ism of action of GA in vivo is uncertain. Aharoni and important anti-inflammatory cytokine, this finding fur- colleagues also reported that GA can block the prolifera- ther supports the anti-inflammatory action of GA in tion of MBP-reactive T lymphocytes [18], but this find- treated patients. ing was not reliably reproduced in subsequent studies. There is also evidence to suggest that GA, in addition In fact, more recently, it has been shown that GA does to its action on the adaptive immune system, acts on not alter the proliferation of MBP-reactive T cells, but the innate immune system by directly modulating the some GA-reactive T cells (specifically the Th2 cells) can activity of myeloid cells, in particular monocytes and respond to MBP by secreting protective cytokines [19]. dendritic cells [39–42]. The properties of monocytes of GA-specific T cells, being able to cross the blood-brain RRMS patients undergoing treatment with GA have barrier (while the drug itself is not) mediate the activity of been compared with those of untreated patients and of GA in the central nervous system (CNS). Moreover GA- healthy controls, showing that monocyte reactivity was activated T cells are able to suppress EAE induced not inhibited in the treated patients. This study is import- only by MBP, but also by other encephalitogens, such as ant since it was the first to demonstrate this effect in proteolipid protein (PLP) and myelin oligodendrocyte human subjects treated with GA [43]. glycoprotein (MOG): this so-called “bystander suppression A number of studies have also addressed the question of mechanism” is considered an essential component of the the possible neuroprotective effects of GA. The results of mechanism of action of GA [20]. in vitro and animal model studies have shed some light on An important immunomodulatory effect of GA – and the possible mechanisms of these effects. In addition to in- possibly the primary mechanism behind its activity – is ducing an anti-inflammatory milieu in the CNS through the induction of a shift in the phenotype of reactive T cells the action of reactive T cells, GA has been shown to in- from a mostly pro-inflammatory Th1 pattern of cytokine crease levels of neurotrophic factors such as brain-derived secretion to a mostly anti-inflammatory Th2 pattern in- neurotrophic factor (BDNF), the actions of which include volving the production of IL-4, IL-5, IL-13, IL-10 and protection of neurons against pathological insults [11, 44]. TGF-β [19, 21–27]. However, even if this is probably the Another possible neuroprotective action of GA, against most important mechanism of action of GA, other bio- glutamate excitotoxicity, was recently reported in a mouse logical effects have been reported. model of MS [45]: GA was found to restore normal kinetic The role of Th17 cells (a subset of T cells that produce properties of glutamate-mediated synaptic transmission in a distinct profile of proinflammatory cytokines, including the striatum of treated animals, contrasting the excessive interleukin [IL]-17, IL-6, IL-9, IL-21, IL-22, IL-23, IL-26 glutamate action on postsynaptic receptors. GA produces and tumour necrosis factor-α [TNF-α]) in the immuno- this effect (independently of its immunomodulatory ac- pathogenesis of MS and EAE has recently been eluci- tion) possibly by blocking synaptic alterations induced by dated [28–30]. GA was found to reduce Th-17-related activated microglia-released TNF-α. neuroinflammation and levels of IL-17 and IL-6 in EAE The induction of specific populations of Th2 cells in the mice [31, 32]. periphery by GA may lead to an environment favouring Studies have shown that, in addition to Th17 cells, GA axonal protection, neural growth and remyelination, as re- acts on regulatory T (Treg) cells, whose role in suppress- ported in an in vitro and in vivo study by Skihar and col- ing autoimmunity is well recognized [33]. Patients with leagues [46]. Exposure of mouse embryonic forebrain cells RRMS have an impaired CD4+ CD25+ Treg cells-related in culture to GA-reactive T cells resulted in increased suppressive capacity [34], and functional alterations of levels of insulin-like growth factor-1 (IGF-1) and promoted Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 4 of 13 the formation of oligodendrocyte precursor cells (OPC). (56 % vs. 26 %; p = 0.045) [55]. The first pivotal trial, the Subsequently, mice subjected to induced demyelination of US Glatiramer Acetate phase III study, provided clear evi- the spinal cord were treated with GA; after 7 days, in- dence for the efficacy of GA, demonstrating a significant creased OPC generation and remyelination were observed, 29 % reduction favouring GA in annualised relapse rate associated with higher levels of IGF-1 and BDNF in the (ARR) (0.59 vs. 0.84 for placebo; p = 0.007), supported by spinal cord. trends in the proportion of relapse-free patients (33.6 % Some observations from clinical trials seem to support vs. 27.0 %, respectively), and the median time to first re- such effects. In a substudy of the PreCISe trial, patients lapse (287 vs. 198 days, respectively), after 2 years of treat- treated with GA had increased brain concentrations of ment [53] (Table 1). In this study MRI measures were not the neuronal integrity marker N-acetylaspartate, and an used. A second study, the European/Canadian MRI trial, improvement in brain neuronaxonal integrity, whereas was planned in order to better define the profile of efficacy patients receiving placebo did not [47]. Also, magnetic and safety of GA. It provided for the first time MRI resonance imaging (MRI) studies have demonstrated the evidence of the beneficial effect of GA; 9 months of ther- ability of GA to reduce the proportion of new T1 hypoin- apy resulted in significant differences favouring GA versus tense lesions evolving into permanent black holes (markers placebo for most endpoints: mean total number of enhan- of irreversible axonal loss), therefore supporting the neuro- cing lesions on T1-weighted images (primary endpoint; protective scenario [48, 49]. 25.96 vs. 36.80; p = 0.003), number of new enhancing lesions (17.4 vs. 26.0; p < 0.003) and their change of Clinical efficacy volume (p < 0.01), number of new lesions detected on T2- Subcutaneous GA has a long history of use for the treat- weighted images (9.4 vs. 13.5, respectively; p <0.003) and ment of RRMS. The initially approved dose, on the basis their change of volume (p = 0.001). Moreover, a significant of animal studies, is 20 mg/mL once daily; still widely con- reduction of the relapse rate was reported in the GA sidered as standard, it was a keystone for all later drug de- group versus placebo (33 %; p =0.012) (Table1). Alater velopment. Attempts to explore higher weekly doses (40 study that analysed MRI data from the European- mg/mL once daily) showed no additive benefit [50, 51]. Canadian trial using a fully automated, normalized Recent results of the GALA study [8] indicate that main- method also showed a significant (p = 0.037 at 18 months) taining a similar weekly dose, but with a different dosing reduction in the development of brain atrophy in the regimen (40 mg/mL three times a week), provides advan- GA group versus placebo [56]. A noteworthy finding tages in clinical use without impacting on efficacy. of the European/Canadian MRI study was a reduction The feasibility of oral administration of GA was tested in severity of tissue disruption in newly-formed le- in the placebo-controlled CORAL trial [52]. Patients with sions with GA [48]: the percentage of new lesions RRMS received 50 mg or 5 mg of GA or placebo daily for evolving into permanent black holes was significantly 14 months. Neither dose of GA affected the primary end- lower in patients treated with GA than in those point (relapse rate) or any other clinical and MRI end- receiving placebo at 7 months (18.9 % vs. 26.3 %, point. Thus, further development of oral administration respectively; p = 0.04) and at 8 months (15.6 % vs. 31.4 %, was discontinued. GA has been tested in progressive MS respectively; p = 0.002) after lesion appearance. with negative results. Active comparator-controlled trials GA has been com- Once-daily formulation pared head-to-head with high-dose subcutaneous IFN-β1a In relapsing-remitting multiple sclerosis or -1b in two double blind trials in patients with RRMS: The efficacy of GA 20 mg/mL once daily as first-line REGARD [57] and BECOME [58] (Table 1). Both showed treatment in RRMS is well established in many phase II, comparable efficacy between GA and IFN-β1a or -1b. III and IV studies. Moreover in the REGARD trial, GA was found to better protect against brain-volume loss (–1.07 % vs. –1.24 %; Placebo-controlled trials The efficacy of GA on clin- p = 0.018). These data were confirmed by two trials in ical and MRI-assessed outcomes has been demon- which GA was used as reference comparator. In the BE- strated in two major pivotal placebo-controlled trials – YOND trial [59], two arms receiving IFN-β1b (250 μgand the US Glatiramer Acetate trial [53] and the European/ 500 μg) were included, along with a third arm receiving Canadian MRI study [54], and supported by an initial GA: no significant differences were found between groups small study in 50 patients [55] (Table 1). This latter study either in the primary endpoint (ARR: 0.33 for IFN-β1b provided the first clinical evidence supporting GA in 500 μg, 0.36 for IFN-β1b 250 μg and 0.34 for GA; p =ns RRMS, with 2 years of treatment with GA 20 mg/mL daily for all comparisons) and in all other clinical outcomes resulting in a significant difference in the proportion (Table 1). The CONFIRM trial [60] compared two doses of patients experiencing no relapses versus placebo of dimethyl fumarate versus placebo, again with a third Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 5 of 13 Table 1 Clinical trials Study Number of patients Trial length Key outcomes Placebo-controlled trials Johnson et al. 1995 [53] 251 randomised 1:1 GA:PBO 2 years Mean relapse rate: GA 1.19 versus PBO 1.68; p = 0.007 (29 % reduction) (ARR: GA 0.59 versus PBO 0.84) Comi et al. 2001 [54] 239 randomised 1:1 GA:PBO 9 months Mean reduction in total enhancing lesions GA vs PBO -10.8 (95 % CI -18.0 to -3.7; p = 0.003); 29 % reduction. Bornstein et al. 1987 [55] 50 randomised 1:1 GA:PBO 2 years Proportion of relapse-free patients GA 56 % vs 26 % PBO; p = 0.045 Active comparator-controlled trials Mikol et al. 2008 [57] 764 randomised 1:1 GA:IFNβ-1a 96 weeks No between-group difference in time to first relapse (HR 0.94; 95 % CI (REGARD) 0.74–1.21; p = 0.64) th Cadavid et al. 2009 [58] 75 randomised 1:1 GA: INF-β1b 2 years Similar median (75 percentile) CAL count per scan in (BECOME) months 1–12, of 0.58 (2.45) vs 0.63 (2.76) O’Connor et al. 2009 [59] 2447 randomised 2:2:1 250 μg 3.5 years No between-group differences in relapse risk or EDSS progression (BEYOND) IFNβ-1b:500 μg IFNβ-1b:GA Fox et al. 2012 [60] Randomised 1:1:1:1 PBO: BG-12 96 weeks ARR significantly lower with twice-daily BG-12 (0.22), three times-daily (CONFIRM) twice daily:BG-12 three times BG-12 (0.20), and GA (0.29) than PBO (0.40) (RR GA 29 %, P = 0.01). daily:GA Combination trials Goodman et al. 2009 [85] 110 randomised 1:1 GA + NTZ 6 months Mean rate of development of new active lesions over the 24-week (GLANCE) versus GA alone study lower with combination therapy (0.03) vs GA alone (0.11; p = 0.031) Lindsey et al. 2012 [116] 1008 randomised 2:1:1 IFN + GA: 3 years No difference in ARR between combination group and GA group (CombiRx) IFN: GA (0.12 vs. 0.11). Both combination and GA alone superior to IFN group (0.16; p = 0.022 for combination group and p = 0.027 for GA group) Clinically isolated syndrome Comi et al. 2009 [86] 481 randomised 1:1 GA:PBO 36 months GA reduced risk of CDMS by 45 % versus PBO (HR 0.55, 95 % CI (PreCISe) 0.40–0.77; p = 0.0005) 95 % CI 95 % confidence interval, ARR Annualised relapse rate, CAL Combined active lesions, CDMS Clinically definite multiple sclerosis, EDSS Expanded disability status scale, GA Glatiramer acetate, HR Hazard ratio, IFN Interferon, NTZ natalizumab, PBO Placebo, RR Relative risk arm with GA as a reference comparator. Even if the discontinuation in extensions of clinical trials or post- design of the trial did not allow a comparison be- marketing studies [63, 70, 72, 73]. tween the two active treatments, both drugs proved The first follow-up of the US Glatiramer Acetate trial to be significantly superior to placebo in all clinical presented 15-year data [63]. Patients continuing in the and MRI outcomes (Table 1). In particular, GA sig- study (100 of the initial 232) showed a reduced ARR nificantly reduced the ARR versus placebo by 29 % (0.25 ± 0.34 per year vs. 1.12 ± 0.82 at baseline); 57 % (p = 0.01), thus confirming the results of the pivotal had stable or improved Expanded Disability Status Scale trials in a very large population sample (over 1400 (EDSS) scores (change ≤0.5 points) and 67 % showed patients). A post hoc subgroup analysis reported nu- stable disease, without transitioning to secondary pro- merically similar relapse-related outcomes between gressive MS. The most frequently reported reasons for the two dimethyl fumarate arms and the GA arm in treatment discontinuation were patient perception of most patient subgroups [61]. disease worsening (n = 29), a desire to switch or com- A systematic review summarising data from five ran- bine therapies (n = 26) and difficulty, inability, or un- domised studies comparing IFN-β with GA in patients willingness to adhere to the study protocol (n = 32). with RRMS confirmed a similar efficacy after 2 years of Twenty-year results are now available for the long- treatment [62]. term extension of this study [64]. Of the initial 232 patients, 74 remain in the trial and have been continu- Long-term and real-word data Even with all the limi- ously treated for a mean of 19.3 years. Very long-term tations of long-term extension studies, due to poten- use of GA appears to be associated with stable disease tial selection bias, available data suggest that the activity (cumulative ARR = 0.2; 24.3 % of patients efficacy of GA is maintained over time [63–71]. remained free of relapse for the entire period) and low Moreover, there have been no reports of rebound ef- levels of accumulated disability (mean EDSS score 3.1 fect or delayed disease reactivation after treatment vs. 2.4 at baseline). Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 6 of 13 The extension of the European/Canadian MRI study of- responding to first line therapies GA can be offered as fers serial long-term MRI data for a large cohort of an alternative to so-called second line medications if patients treated with GA [70]. After the 9-month double- there are concerns of tolerability/adverse events with the blind, placebo-controlled phase, all patients entered an latter therapies. Most studies describe switches from open-label, active treatment phase in which they received IFNβ-1a or -1b to GA, reporting reductions in mean GA 20 mg/mL once daily for a further 9 months, with a ARR after switching [81–83]. However, in those situa- long-term follow-up visit (LTFU) scheduled at least five tions when the shift is due to failure of the previous years after study entry. Overall, MRI results show that the treatment, results should be interpreted with caution be- effects of GA on MS activity are sustained (number of ac- cause the regression to the mean phenomenon is a tive lesions 0.9 at LTFU vs. 3.4 at baseline; percentage major concern. Therefore, randomised, controlled trials brain volume change –5.02 vs. baseline). Moreover, MRI are needed to confirm these results. results in the patients that were shifted from placebo to GA showed a significant reduction of MRI measures of Combination treatment trials Two important combin- disease activity, paralleling what was observed in the pa- ation therapy trials are the CombiRx trial [84] and the tients that received GA from the start. A notable finding is GLANCE trial [85] (Table 1). In CombiRx, patients were that the proportion of patients requiring walking aids at randomised to GA 20 mg/mL once daily plus IFN-β1a 30 the LTFU was significantly lower (p = 0.034) in the group μg once weekly or to monotherapy with one of these med- that received GA from the start of the study compared ications plus placebo for 3 years. For the primary outcome with delayed treatment, suggesting that early treat- of ARR, the combination therapy was significantly super- ment may have a positive impact on long-term disease ior to IFN-β, reducing the relapse rate by 25 % (p =0.022), outcomes. while there was no significant difference between the A 5-year brain MRI retrospective open study provides combination therapy and GA. It should be noted that the some evidence of the efficacy of GA in reducing brain study design allowed for the first time a comparison be- volume loss [74]: smaller reductions in brain volume tween intramuscular IFN-β and GA, with GA resulting were observed in patients with RRMS treated with sub- superior (relapse rate reduction by 31 % compared with cutaneous GA than with high-dose IFN-β regimens IFN-β; p = 0.027). The GLANCE study compared com- (percentage change in brain volume –2.27 % vs. –3.21 %; bination therapy with GA 20 mg/mL once daily plus p < 0.0001). intravenous natalizumab 300 mg every 4 weeks versus Various studies report real-world data for GA treat- monotherapy with GA 20 mg/mL once daily plus placebo ment in RRMS [72, 73, 75, 76], confirming the efficacy every 4 weeks. At 24 weeks, the combination therapy was profile of GA observed in the clinical studies. A signifi- superior on major MRI disease activity measures. cant impact of the treatment with GA on health-related quality of life has also been reported [77, 78], with bene- In clinically isolated syndrome ficial effects including significant reductions in fatigue Early treatment with GA in patients with CIS has been and in days of absence from work. shown to delay onset of CDMS in the placebo-controlled Controlled studies of MS treatments in children study PreCISe [86] (Table 1) and during its subsequent and adolescents are still lacking, but some published open-label extension period [87]. The study enrolled 481 evidence, albeit retrospective, points to the efficacy of patients with one unifocal neurological event and a posi- GA in this population. In an Italian cohort, 14 pa- tive MRI scan (defined as the presence of at least two tients with a mean age of 13.1 years were treated for cerebral lesions ≥6 mm in diameter on T2-weighted im- a mean of 5 years or more; these patients had a ages). Patients were randomised to GA 20 mg/mL once reduction in relapse rate, from about 3 per year be- daily or placebo for up to 36 months or until conversion fore treatment initiation to 0.2–0.4 per year during to MS. GA was associated with a 45 % reduction in risk of the treatment period [79]. A small study of seven patients conversion to MS (primary endpoint; p = 0.0005) and a with RRMS who had disease onset at 9–16 years of age delay in the time to conversion compared with placebo and began GA before 18 years of age showed that 24 (336 days vs. 722 days, respectively). GA was associated months of treatment resulted in two of seven patients with a 58 % reduction in number of new T2 lesions and a remaining relapse free over the study period, and three of smaller volume of T2 lesions. During the extension phase seven patients having stable disability scores as measured (total 5 years’ duration) the efficacy of GA was sustained, by the EDSS [80]. with a 41 % reduction in risk of conversion to MS in those treated with GA from the start compared with delayed Switching to glatiramer acetate Several trials have treatment; in the GA group, there was a delay of 972 days evaluated switching to GA from other MS therapies for before conversion to MS, a 42 % reduction in new T2 le- safety and efficacy reasons [81–83]. For patients not sions per year (p < 0.0001) and a 22 % reduction in T2- Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 7 of 13 lesion volume (p = 0.0005). In the extension phase pa- cumulative number of gadolinium-enhancing T1 le- tients treated with GA from study entry showed a signifi- sions (44.8 %; p < 0.0001) and new or enlarged T2 le- cant 28 % reduction (p = 0.0209) in brain volume loss sions (34.7 %; p < 0.0001) were reported; the numerical compared with patients initially randomised to placebo, values of these parameters were very similar to those confirming the neuroprotective effects of GA. This is observed in the pivotal studies with the 20 mg/mL once the first trial to demonstrate that early treatment with daily dose. Three-year results of the open-label extension GA reduces brain atrophy versus delayed treatment in of the GALA study demonstrated sustained efficacy on this setting. ARR and MRI parameters of disease activity [91]. Patients switched from placebo to GA after the double blind phase In progressive forms of multiple sclerosis reported significant gains in efficacy, but those treated GA was assessed in primary progressive forms of MS, with GA from study entry showed a significantly lower re- with negative results. The PROMiSe study [88] was a lapse rate (ARR 0.23 vs 0.30, respectively, p = 0.0052) and randomised, double-blind, placebo-controlled, multicen- significantly fewer enhancing T1 lesions and new or en- tre, international study that investigated the effect of GA larged T2 lesions (RR = 0.660, p = 0.0005 for T1; RR = on disability progression in 943 patients with progressive 0.680, p < 0.0001 for T2) compared with patients with MS. After 3 years of treatment, the time to sustained delayed treatment. accumulated disability was similar between GA- and An important finding from a recent post hoc MRI ana- placebo-treated patients (hazard ratio [HR] 0.87; 95 % lysis of data from the GALA study is that GA 40 mg/mL CI 0.71 to 1.07; p = 0.1753). A post hoc analysis showed three times weekly (cumulative weekly dose of 120 mg) a possible effect in slowing clinical progression in male shares the ability of the standard formulation (cumu- patients (HR 0.71; 95 % CI 0.53 to 0.95; p = 0.0193) [88], lative weekly dose of 140 mg) to reduce conversion of but a subsequent analysis of these results did not dem- new active lesions into black holes, markers of perman- onstrate an impact of gender on the efficacy of GA [89]. ent damage and disability progression, with a significant An additional study investigating metabolite ratios as de- 24 % reduction compared with placebo (p = 0.006) in termined by MRI in a subset of 58 patients from the the odds of conversion from new lesions at month 6 to PROMISe study showed no difference between the GA black holes at month 12 [49]. and placebo groups [90]. However, it should be noted In the absence of head-to-head studies comparing GA that the PROMISe study was terminated early due to 20 mg/mL once daily and 40 mg/mL three times weekly, lack of effect, and that the low rate of disability progres- indirect comparisons have also shown very similar effi- sion and the high rate of premature discontinuations led cacy of the two doses [92, 93]. to a decrease in power of the study, hampering the de- On the same lines, the GLACIER study, in which pa- termination of a treatment effect [88]. tients were asked to report the personal experience of shifting from the 20 mg/mL once daily dose to the 40 mg/ Three times weekly formulation mL three times weekly dose, demonstrated a favourable The first trial to evaluate a high-dose regimen of GA was convenience profile and patient satisfaction when convert- the phase III FORTE study [51] that compared the 40 mg/ ing from the once-daily formulation [94]. mL once daily dose with the standard 20 mg/mL once daily dose in patients with RRMS. Both doses showed Safety similar effects on efficacy measures and no difference in After 20 years’ continuous clinical use and more than 2 the safety profile. Post-hoc analyses revealed potential million patient-years’ exposure, the safety profile of GA benefits of the 40 mg/mL dose in some subgroups (for ex- is well established. No evidence of any association of GA ample, in the “frequent MRI cohort” patients treated with with immunosuppression or with malignant and auto- 40 mg/mL showed a slight numerical advantage in the re- immune disease has been reported after 10 and 15 years duction of the mean number of gadolinium-enhancing le- follow-up [63, 65]. GA was not associated with psychi- sions at various timepoints vs. baseline). After this study atric or mood disorders and in some studies a significant the development of the high-dose once daily regimen was improvement in fatigue was observed, even in patients discontinued, but it provided a starting point for subse- switching from other DMTs [78]. In a study of patients quent research on the high-dose, lower-frequency regimen with RRMS and spasticity, switching from IFN-β to GA (40 mg/mL three times weekly). improved spasm frequency, muscle tone and pain after 3 TheefficacyofsubcutaneousGA40mg/mL three times months of treatment; these improvements were main- weekly in patients with RRMS was shown in the 1-year, tained over 6 months of treatment with GA [95]. A few double blind, placebo-controlled GALA study, involving cases of hepatotoxicity during treatment with GA have about 1400 patients [8]. Significant reductions com- recently been reported [96–98], with no such cases re- pared with placebo in relapse rate (34.0 %; p < 0.0001), ported in clinical trials, hence it is unclear at present if Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 8 of 13 liver function monitoring is warranted. It should be treatment may be assessed on a case-by-case basis [104]. noted, though, that because some of the patients report- An Italian retrospective study showed that the mother’s ing this AE had concurrent autoimmune conditions, it is exposure to GA when the drug was suspended within 4 impossible to disentangle the potential contribution of weeks from conception was not associated with an in- GA treatment and the underlying condition to hepato- creased frequency of spontaneous abortion nor with toxicity. IgE-mediated allergic reactions have also been other negative pregnancy and foetal outcomes compared described [99, 100]. with women in whom the medication was suspended 4 Both formulations of GA appear equivalent from the weeks or more from conception, or who were untreated safety standpoint [64, 91, 94]. In the GALA study AEs as- [107]. These findings confirm those of a previous obser- sociated with administration of GA 40 mg/mL three times vational study [106] suggesting that GA and the IFNs do a week were found to be consistent with the known safety not represent a significant risk for prenatal developmen- profile of GA 20 mg/mL once daily. Moreover, no new tal toxicity. Relapse rate decreases during pregnancy, AEs emerged during treatment with high-dose GA [8, 91]. with a well-known increase in the first three months At present there are no controlled studies of DMTs in after childbirth [110] that sometimes requires second- children and adolescents with MS, but published evidence, line therapy to be controlled [103–105]. mostly retrospective studies, support a similar safety pro- file of GA in this population [79, 80]. GA, along with IFN- Tolerability β, has been recommended as the standard treatment for The tolerability of GA 20 mg/mL once daily has con- paediatric RRMS in two position papers, one produced by sistently been reported as good versus both placebo European experts [101] and the other one by the Inter- and active treatment in the previously mentioned clin- national paediatric MS Study [102]. Since paediatric onset ical trials [54, 57, 59, 86], and the nature and frequency MS is characterized by high disease burden, early treat- of treatment-related AEs were similar between short- ment, although off-label, should be promptly started after and long-term treatment periods [63–65, 67]. The most confirmation of the diagnosis. The favourable tolerability common (>1/10) treatment-related AEs are transient profile of GA should be considered when making a thera- injection-site reactions, occurring occasionally in about peutic choice [101, 102]. two thirds of patients [7]. These include injection site No limitations to concomitant administration of GA bruising, erythema, pain, pruritus and induration. Rarer and other drugs have been identified; the medication is cases of localized lipoatrophy and skin necrosis at injection not linked to blood test abnormalities that require sites have been reported during post-marketing [111, 112]. monitoring. One peculiar injection-related tolerability issue with GA is the occurrence of immediate post-injection reactions Pregnancy (IPIR) that present immediately or a few minutes after the Animal reproduction studies have failed to demonstrate a injection, consisting in flushing, chest tightness, palpita- risk of GA treatment to the foetus, and post-marketing tion, dyspnoea and intense anxiety. The crisis resolves studies support the absence of foetal toxicity [103–108]. spontaneously in a few minutes [53]. These reactions are For these reasons GA has been classified as FDA Class B unpredictable, affecting about 15 % of patients and seldom during pregnancy [109]. Most of the other drugs approved recurring more than once. The intensity of the reaction is for the treatment of MS are categorized by the FDA as not connected to any real risk to patients. Class C, with the exception of mitoxantrone, classified as The tolerability of GA 40 mg/mL three times weekly Class D (positive evidence of human foetal risk), and teri- has been shown to be similar to that of the 20 mg/mL flunomide, classified as Class X (foetal toxicity) [104, 109]. once-daily formulation [8, 91]. Importantly, in the GLA- GA can be continued right up until conception, unlike CIER study [94], three times weekly GA was found to be other DMTs for which a washout period is recommended better tolerated than the once-daily formulation in terms prior to trying to conceive [104]. GA may also be used as of injection-related adverse events (IRAEs): the adjusted bridging therapy in women planning a pregnancy who are mean annualized rate of IRAEs was reduced by 50 % in receiving treatments requiring a washout period, if it patients receiving the new formulation (35.3 events per exposes women to the risk of MS reactivation, and of- year vs. 70.4 events per year, respectively; p = 0.0006), fers some advantages in women risking unplanned while the rate of moderate/severe events was reduced by pregnancies. 60 % (0.9 events per year vs. 2.2 events per year, respect- While it is currently recommended that, as for any ively; p = 0.0021). Furthermore, treatment convenience, other DMT, GA should be discontinued after confirmed as measured by the Treatment Satisfaction Question- evidence of pregnancy and until childbirth, available evi- naire for Medication-9 (TSQM-9) convenience subscale, dence suggests GA could be continued at least through- was improved for patients switching from GA 20 mg/ out the first trimester, while further continuation of GA mL once daily to the three times weekly formulation Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 9 of 13 [94]. Recently, results from the extension phase of the clinical trials demonstrating the efficacy of GA in these pa- GLACIER study confirm the safety profile of the 40 mg/ tients are currently lacking. mL three times weekly formulation, in terms of both We anticipate that the new 40 mg/mL three times IRAEs and convenience [113]. weekly regimen might increase compliance and adher- ence. Therefore it is recommended that, in all consenting patients currently treated with the once daily formulation, Conclusions the switch to the new formulation should be considered. The availability of multiple drugs has totally changed the An early start of GA treatment should be considered in scenario of MS treatment. Treatment choices became the light of data on brain atrophy from the PreCISe study much more complicated and decisions should be based [87]: there was a significant (–28 %; p = 0.0209) difference on the combination of the efficacy and safety profiles. when comparing early GA treatment versus delayed GA From this point of view GA associates a favourable effi- treatment. cacy profile, confirmed by more than 20 years of clinical In conclusion, clinical trials and real-life studies have use, with an excellent safety and tolerability profile. The consistently shown the efficacy and safety of both for- burden of daily injections has been recently reduced by mulations of GA in the first-line treatment of patients the availability of the new 40 mg/mL three times a week with RRMS and for delaying the onset of clinically defin- formulation, which has been shown to share the same effi- ite MS in patients with CIS. Overall, data suggest that cacy of the 20 mg/mL once daily formulation, but with while many types of patients can be expected to benefit obvious advantages in terms of patient convenience. from GA, the “ideal” subject would be one with RR dis- GA has been classified as a first-line drug for the treat- ease or newly-diagnosed, young and active, wanting to ment of RRMS in Europe, with a clear indication both in lead a normal life. The use of GA for more than two naïve patients and in patients who discontinue other ther- decades shows a reassuring safety profile and optimal apies for safety or tolerability issues. The recent evidence of tolerability. The major concern may be the frequency of the importance of personalized treatment implies that the administration, an issue that the new formulation can assessment of the individual prognostic profile should drive be expected to minimize, contributing to the use of this treatment decisions, at the same time considering also pa- drug. Besides patient convenience, the fact that no tients’ preference and convenience. Patients with a good complex clinical monitoring is required during treat- prognostic profile as indicated by low disease activity – re- ment clearly represents another strong point of the vealed by low brain lesion burden and few or absent active clinical use of GA. lesions at the time of treatment onset – may haveahigh probability of responding to first-line therapies, including Abbreviations ARR: Annualized relapse rate; BDNF: Brain derived neurotrophic factor; GA. On the contrary, patients with very active disease in CDMS: Clinically definite multiple sclerosis; CIS: Clinically isolated syndrome; the early phases tend to require an induction approach to CNS: Central nervous system; DMTs: Disease-modifying therapies; obtain a positive response to treatment. EDSS: Expanded disability status scale; GA: Glatiramer acetate; IFN: Interferon; IRAEs: Injection-related adverse events; LTFU: Long-term follow up; Considering the choice among first-line therapies, GA MBP: Myelin basic protein; MHC: Major histocompatibility complex; offers an obvious advantage in young, potentially fertile MRI: Magnetic resonance imaging; MS: Multiple sclerosis; RRMS: Relapsing- women for the favourable safety profile in this popula- remitting multiple sclerosis; TNF: Tumour necrosis factor; TSQM-9: Treatment satisfaction questionnaire for medication-9. tion, as discussed above [107]. Patients with CIS are also expected to benefit from GA, given the evidence of effi- Competing interests cacy in such patients, supported by extension studies GC has received honoraria as a consultant and for lecturing at scientific showing clear protection from brain atrophy [86, 87]. meetings from Novartis, Teva, Sanofi-Aventis, Genzyme, Merck Serono, Another possible use of GA is as maintenance treatment Biogen, Bayer, Serono Symposia International Foundation, Excemed, Roche, Almirall, Chugai, Receptos and Forward Pharma. in patients who start with an induction approach be- AB has received honoraria for serving in the scientific advisory boards of cause of a negative prognostic profile. Induction therapy Almirall, Bayer, Biogen, Genzyme, with approval by the Director of AOU San has often the advantage of “reshaping” the immune sys- Luigi University Hospital, and has received speaker honoraria from Biogen, Genzyme, Novartis, Teva; his institution has received grant support from tem, which can then be maintained by GA [114, 115]. Bayer, Biogen, Merck, Novartis, Teva, from the Italian Multiple Sclerosis The classification of MS clinical courses [2] defines the Society, Fondazione Ricerca Biomedica ONLUS and San Luigi ONLUS. importance of disease activity not only in RRMS, but also DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Teva and received in patients with a progressive disease course. The presence honoraria for speaking or consultation fees from Almirall, Bayer Schering, of disease activity represents a clear target for DMTs. Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi- Among them, the use of GA should be considered because Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and the principal investigator in clinical trials for of the long-term safety and absence of negative impact on Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, spasticity, a frequent AE of IFN-β treatment in this popula- Sanofi-Aventis, Teva. His preclinical and clinical research was supported by tion. It should be noted, however, that conclusive data from grants from Bayer, Biogen, Merck Serono, Novartis and Teva. Comi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:6 Page 10 of 13 NDS has received honoraria or consultation fees from Novartis, Merck and Advanced Technologies, G.F. Ingrassia, Multiple Sclerosis Center, Serono, Biogen Idec, La Roche; has been member of Advisory Boards for University of Catania, Catania, Italy. Department of Neurology and Novartis, Merck Serono, Biogen Idec; has participated in company-sponsored Psychiatry, Sapienza University of Rome, Rome, Italy. Department of speaker’s bureau for Novartis, Merck Serono, Biogen Idec; has received travel Experimental and Clinical Medicine, 1 Neurological Clinic, Marche Polytechnic reimbursements from Novartis, Merck Serono and Biogen Idec. University, Ancona, Italy. Centre for Experimental Neurological Therapies CF has received grants and personal fees from Teva, and grants from Merck (CENTERS), S. Andrea Hospital Site, Sapienza University of Rome, Rome, Italy. Serono, Novartis and Fondazione Italiana Sclerosi Multipla. Department of Medical, Surgical, Neurological, Metabolic and Aging AG serves on scientific advisory boards or as consultant for Merck Serono, Sciences, Second University of Naples, Naples, Italy. Department of Basic Teva, Novartis, Biogen Idec; he has received honoraria for lecturing from Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Merck Serono, Biogen Idec, Novartis, Teva, Genzyme, Almirall. Italy. PG is an Advisory Board member of Almirall, Biogen Italy, Sanofi-Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Teva and received honoraria for Received: 2 November 2015 Accepted: 11 April 2016 speaking or consultation fees from Almirall, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and has been the principal investigator in clinical trials for Biogen Idec, Merck References Serono, Novartis, Roche, Sanofi-Aventis, Teva, Almirall. His preclinical and 1. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4):1180–8. clinical research was supported by grants from Bayer-Shering, Biogen-Idec, doi:10.1172/JCI58649. 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Multiple Sclerosis and Demyelinating Disorders – Springer Journals

Published: Jul 4, 2016

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