Glatiramer Acetate in Multiple Sclerosis: A Review - NCBI

CNS Drug ReviewsVol. 13, No. 2, pp. 178–191C© 2007 The AuthorsJournal compilation C© 2007 Blackwell Publishing Inc.

Glatiramer Acetate in Multiple Sclerosis: A Review

Maddalena Ruggieri1, Carlo Avolio2, Paolo Livrea1, and Maria Trojano1

1Department of Neurological and Psychiatric sciences, University of Bari, Bari, Italy2Department of Medical and Occupational Sciences University of Foggia, Foggia, Italy

Keywords: Antiinflammatory drugs — EAE — Experimental allergic encephalomyelitis —Glatiramer acetate — Multiple sclerosis — Neuroprotection.

ABSTRACT

Multiple sclerosis (MS) is considered to be primarily an inflammatory autoimmune dis-ease. Over the last 5 years, our view of the pathogenesis of MS has evolved considerably. Theaxonal damage was recognized as an early event in the disease process and as an importantdeterminant of long-term disability. Therefore, the antiinflammatory and neuroprotectivestrategies are thought to represent promising approach to the therapy of MS. The thera-peutic potential of glatiramer acetate (GA), a synthetic amino acid polymer composed ofa mixture of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine in defined proportions, inMS has been apparent for many years. GA has been shown to be effective in preventingand suppressing experimental allergic encephalomyelitis (EAE), the animal model of MS.GA has been, therefore, evaluated in several clinical studies and found to alter the naturalhistory of relapsing-remitting (RR)MS by reducing the relapse rate and affecting disability.These findings were confirmed in open-label follow-up trials covering more than 10 yearsof treatment. The trials demonstrated sustained efficacy for GA in slowing the progressionof disability. The clinical therapeutic effect of GA is consistent with the results of magneticresonance imaging (MRI) findings from various clinical centers. At a daily standard dose of20 mg, s.c., GA was generally well tolerated. The induction of GA-reactive T-helper 2-likeregulatory suppressor cells is thought to be the main mechanism of the therapeutic action ofthis drug. In addition, it was recently shown that GA-reactive T cells produce neurotrophicfactors (e.g., brain-derived neurotrophic factor [BDNF]) that protect neurons and axons inthe area of injury.

Address correspondence and reprint requests to: Dr. Maddalena Ruggieri, Dept. of Neurological and PsychiatricSciences, University of Bari – Policlinico, Piazza Giulio Cesare, 11, 70124 BARI Italy. Tel.: +390805478518;Fax: +390805478532; E-mail: [email protected] of Interest: The authors have no conflicts of interest.

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GLATIRAMER ACETATE IN MULTIPLE SCLEROSIS 179

INTRODUCTION

Multiple sclerosis (MS) is an immunopathological, presumably autoimmune disease thatis clearly influenced by genetic and environmental factors and is one of the commonest causeof neurological disability in young adults (Compston and Coles 2000; Noseworthy et al.2000).

Genetic and environmental factors (e.g., viral infection, bacterial lipopolysaccharides,superantigens, reactive metabolites, and metabolic stress) may disrupt the blood–brain bar-rier and facilitate the movement of autoreactive T cells and demyelinating antibodies fromthe systemic circulation into the central nervous system (CNS). In the CNS, local factorsmay upregulate the expression of endothelial adhesion molecules (intercellular adhesionmolecule-1 [ICAM-1], vascular adhesion molecule-1 [VCAM-1], and E-selectin) furtherfacilitating the entry of T cells into the CNS. Proteases, including matrix metalloproteinases(MMPs), may enhance the migration of autoreactive immune cells by degrading macro-molecules in the extracellular matrix. Proinflammatory cytokines released by activated Tcells (interferon gamma [IFNγ ] and tumor necrosis factor beta [TNFβ]), may upregulate theexpression of cell-surface molecules in lymphocytes and antigen-presenting cells (APCs).Binding of putative MS antigens (myelin basic protein [MBP], myelin associated glycopro-tein [MAG], myelin oligodendrocyte glycoprotein [MOG], proteolipid protein [PLP]) bythe trimolecular complex—the T-cell receptor (TCR) and class II major histocompatibilitycomplex (MHC) molecules on APCs—may trigger either an enhanced immune responseagainst the bound antigen or downregulate it, causing anergy, depending on the type of sig-naling that results from interactions with surface costimulatory molecules (e.g., CD28 andCTLA-4) and their ligands (e.g., B7-1 and B7-2). Downregulation of the immune responsemay lead to the release of antiinflammatory cytokines (interleukin 4 [IL-4], and IL-10)from CD4+ T cells, and consequently to the proliferation of antiinflammatory CD4+ type2 helper T (Th2) cells that may send antiinflammatory signals to the activated APCs andstimulate pathologic or repair-enhancing antibody-producing B cells. Alternatively, if anti-gen would lead to an enhanced immune response, proinflammatory cytokines (IL-12 andIFNγ ) could trigger a cascade of events, resulting in the proliferation of proinflammatoryCD4+ type 1 helper T (Th1) cells and ultimately an immune-mediated injury to myelin andoligodendrocytes. The exposed axon segments may be susceptible to further injury fromsoluble mediators of injury (including cytokines, chemokines, complement, and proteases),resulting in irreversible axonal injury (such as axonal transection and terminal axon ovoids).Several possible mechanisms of repair of the myelin membrane have been postulated, in-cluding resolution of the inflammatory response followed by spontaneous remyelination,antibody-mediated remyelination, and remyelination resulting from the proliferation, mi-gration, and differentiation of resident oligodendrocyte precursor cells.

The progress in understanding the mechanisms of T-cell activation, inactivation, andmodulation has been translated into different immunotherapeutic strategies aiming at treat-ing MS. Key attack points for selective immunointervention in MS include modulation ofantigen recognition, induction of regulatory cells, and deviation to nonpathogenic or pro-tective responses. In addition to the development of more specific immunointerventions,the recent evidence that neurodegeneration is an integral part of the disease process andthat it plays an important role in the development of disability in patients with MS suggeststherapeutic strategies to limit damage and to enhance repair in addition to antiinflammatorydrugs.

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180 M. RUGGIERI ET AL.

To date several immunomodulatory treatments have been approved for MS, including dif-ferent IFN β products, glatiramer acetate (GA, Copaxone�, cop-1, copolymer-1, YEAK)and mitoxantrone. The current clinical research focuses on the ability of these drugs tomodify the sequence of inflammation, demyelination, and axon degeneration during thecourse of the disease. This review builds on both well-established and emerging conceptsof pharmacology, pharmacokinetics, toxicology, and clinical studies with GA in MS. GAis a synthetic amino acid polymer composed of random sequences of the four amino acids(tyrosine, glutamate, alanine, and lysine in a defined molar ratio with a length of 40–100residues). GA has been shown to be effective in preventing and suppressing experimen-tal allergic encephalomyelitis (EAE) (Teitelbaum et al. 1971; Teitelbaum et al. 1996), inreducing relapse rate, slowing the progression of disability and disease activity in relapsing-remitting (RR)MS as evidenced by magnetic resonance imaging (MRI) (Comi et al. 2001).In addition, it has been recently shown that GA-reactive T cells produce neurotrophic fac-tors and are neuroprotective in vivo in animal models of neurodegeneration or CNS injury(Ziemssen et al. 2002a; Chen and Dhib-Jalbut 2003).

PHARMACOLOGY

GA has two unique features. First, it is not one defined chemical substance, but rathera mixture of many synthetic peptides. Second, the peptide mixture is given to patientswith putative autoimmune disease over many years by daily injection, so it is consideredan example of therapeutic vaccination, as distinct from prophylactic vaccination againstinfectious diseases.

GA simulates MBP, but its beneficial effects in RRMS are thought to stem from themodification of immune processes implicated in the pathogenesis of the disease. Themore relevant effects to its use in the treatment of RRMS are summarized in Table 1.They are: high affinity MHC binding in the periphery (Fridkis-Hareli et al. 1997), induc-tion of suppressor T cells by a shift from Th1 type to Th2 and Th3 type (Aharoni et al.1997a; Miller et al. 1998; Duda et al. 2000b), dose-dependent inhibition of MBP-specific

TABLE 1. Relevant mechanisms of action of glatiramer acetate in multiple sclerosis.

• Inhibition of T-cell activation/proliferation• Competition with myelin antigens (MBP, PLP, MOG) for MHC binding• Downregulation of MBP-specific T-cell response as weak/partial TCR agonist• Induction of a shift from proinflammatory (Th1 type) to antiinflammatory (Th2-Th3

type) response• Increased production of IL-10, IL-4, and IL-6 and decreased IL-12 production• Induction of CD8+ regulatory cells• Migration of GA-specific Th2 type T cells into the CNS• Increased production of BDNF in GA-specific T cells

MHC = major histocompatibility complex; IL = interleukin; MBP = myelin basic protein; PLP =proteolipid protein; MOG = myelin oligodendrocyte glycoprotein; TCR = T-cell receptor; Th =T-helper cell; BDNF = brain-derived neurotrophic factor; GA = glatiramer acetate.



T-cell response (Teitelbaum et al. 1992; Gran et al. 2000), Th2-type cell migration throughthe blood–brain barrier (BBB) (Aharoni et al. 2000), cross reactivity of GA induced Tcells with MBP, MOG, and PLP (Duda et al. 2000a; Neuhaus et al. 2000; Chen et al.2001), bystander suppression (Sela and Teitelbaum 2001; Hohlfeld 1999; Dhib-Jalbut2002) and neuroprotection due to increased production of brain-derived neurotrophicfactor (BDNF) by GA-specific T cells (Ziemssen et al. 2002b; Chen and Dhib-Jalbut2003).

In 1971, Teitelbaum et al. showed that GA was able to suppress the induction of acuteEAE. Subsequently, the same authors showed that GA blocks relapsing EAE in the guineapigs and suppresses the acute and chronic hallmarks of EAE in a number of animal species,including non-human primates (Teitelbaum et al. 1971; 1974; 1997; Sela 1999). The resultsindicated that there was a remarkable degree of suppression of EAE by GA in all speciesstudied

Chronic relapsing EAE (CR-EAE), which is characterized by two or more discreteperiods with clinical or neurological signs, resembles the appearance of clinical signs inMS more closely than does the acute disease. CR-EAE can be induced in different speciesby the injection of either spinal cord homogenate, the purified PLP and MOG proteins, orsynthetic peptides based on their sequences. The effect of GA-1 on CR-EAE was testedin two species—guinea pigs and mice. GA was effective both in preventing and treatingCR-EAE induced in juvenile strain 13 guinea pigs by whole spinal cord homogenate (Keithet al. 1979). GA also blocked CR-EAE induced in (SJL/J x BALB/c) F1 mice by mousespinal cord homogenate, or by the encephalitogenic peptides PLP 139–151 and PLP 178–191 (Teitelbaum et al. 1996). Similarly, the disease induced in H-2b mice by an MOGencephalitogenic peptide, MOG 35–55, could be considerably inhibited by GA (Ben-Nunet al. 1996). Thus, the suppressive effect of GA in EAE is a general phenomenon and is notrestricted to a particular species, disease type, or the encephalitogen used for EAE induction.

The precise mechanism or mechanisms by which GA prevents the development of EAEand ameliorates MS are not yet fully understood. Nevertheless, some important antiinflam-matory and neuroprotective properties of this copolymer have been discovered over the last10 years (Table 1; Fig. 1).

Antiinflammatory Properties

GA can serve as an antagonist of the T-cell receptor for the immunodominant MBP epi-tope (Aharoni et al. 1998). It can also bind to various MHC class II molecules (Fridkis-Hareliet al. 1997) and prevent them from binding to T cells with several antigen-recognition prop-erties. In a recently published commentary (Hafler 2002), GA is considered as a “universalaltered peptide ligand (APL)” or an “universal antigen.” Passive transfer of GA-specific Tcells was found to prevent the development of EAE induced in rats or mice by MBP (Aha-roni et al. 2003), PLP (Teitelbaum et al. 1996), or whole spinal cord homogenate (Aharoniet al. 1997a).

In humans, daily administration of GA resulted in the development of a Th2/Th3-typeresponse overtime (Farina et al. 2001) and the Th2 cells secrete antiinflammatory cytokinesin response to activating stimuli. Coculture experiments in vitro have demonstrated thatGA sensitive T cells suppress production of proinflammatory cytokines (i.e., IFNγ ) byMBP-reactive T cells (Duda et al. 2000a).



FIG. 1. Glatiramer acetate–mediated changes of adaptive immune system. Treatment with glatiramer ac-etate leads to the induction of a specific Th2 population in the periphery, which may enter the CNS. Here,some of these cells are reactivated by means of their cross-reactivity with myelin antigens. In response theysecrete antiinflammatory cytokines, which dampen the local inflammatory process (bystander suppression).Furthermore, they produce neurotrophic factors, such as BDNF, which might favor remyelination and axonalprotection.

Following activation, by regular administration of GA, Th2 cells can leave the circulationacross the vascular wall at sites of inflammatory activity. Data from animal experiments haveshown that GA-sensitive Th2 cells from chronically treated animals acquire the capacity topenetrate the CNS (Aharoni et al. 2000). Moreover in MS, inflammatory lesions creatinglocal BBB breakdown may facilitate the infiltration of immunocompetent cells into theCNS. It is unlikely that GA itself enters the CNS in vivo. Once in the CNS, these GA-activated Th2 cells can be reactivated by local antigens. The nature of these antigens isunclear. Animal experiments using the EAE model suggested that these antigens may befragments of MBP (Aharoni et al. 1997a; Aharoni et al. 1999). Whatever the nature of thelocal reactivating antigen, the Th2 cells begin to secrete antiinflammatory cytokines thatattenuate the ongoing inflammatory process by a bystander suppression effect (Aharoniet al. 1998; Hohlfeld 1999). While GA is known to induce a Th2 bias in CD4+ T cells, adistinct pattern of “deviation” in GA-reactive CD8+ T cells has been recently demonstrated(Dressel et al. 2006). Among GA-specific CD8+ T cells, secretion of a variety of Th1-and Th2-associated cytokines is diminished in GA-treated RRMS patients. These resultsemphasize the need to investigate both CD4+ and CD8+ T cell responses in MS duringdevelopment of new treatments.



Apoptotic Properties

Autoreactive T lymphocytes are believed to mediate the disease process in MS. Thesecells are eliminated by apoptosis either in the periphery or in the CNS (Zipp 2000). Animpaired regulation of apoptotic pathways may lead to an insufficient immunological controlof these autoreactive T cells (Pender et al. 1998; Zipp et al. 1999). Our recent study (Ruggieriet al. 2006) found lower Bax and cytosolic Cyt-c protein expressions and lower Bax/Bcl-2,cytosolic Cyt-c/Bcl-2, and APAF-1/Bcl-2 ratios in untreated MS patients than in healthycontrols (HCs). This was consistent with previous reports showing lower Bax/Bcl-2 ratioin MS compared to HCs (Sharief et al. 2002) and in active MS compared to stable MS andHCs (Sharief et al. 2003).

Two reports (Aktas et al. 2001; Rieks et al. 2003) provided evidence of a modulationin peripheral T-cell apoptosis, during treatment with GA. Rieks et al. (2003) showed aGA-induced apoptosis of CD4+ T cells together with an increase in activated and IL-4-producing T cells. Considering apoptosis as a tightly regulated biochemical process thatdepends on the ability of cells to self-destruct by activation of an intrinsic suicide program(Lenardo et al. 1999; Van Parijs and Abbas 1998), it is possible that GA therapy willfoster the elimination of detrimental T cells restoring a correct balance in the process ofapoptosis. We provided (Ruggieri et al. 2006) in vivo evidence of a GA-linked improvementin the pro-apoptotic Bax/Bcl-2 ratio in MS peripheral blood mononuclear cells (PBMNCs),and, in vitro evidence, a decrease of oxygen consumption by PBMNCs in presence ofGA or in GA-treated patients. It could be of interest to investigate whether GA therapydifferentially modulates anti- and pro-apoptotic protein expression in different T-cell subsetsand B cells separately. These results provide new insights into the therapeutic effects of GAand suggest that apoptotic pathways could become possible targets of intervention to modifyMS pathology and the corresponding clinical course.

Neuroprotective Properties

Several ongoing studies are investigating neuroprotective effects of GA therapy in MS.An initial assumption was that GA, by cross-reacting with MBP or other components ofmyelin, might enable GA-specific T cells to recognize the damaged tissue, accumulatethere, and undergo activation resulting in neuroprotection (Kipnis et al. 2000).

In vitro data indicate that GA has the potential to increase the synthesis of BDNF byhuman T cells, of both Th1 and Th2 types (Ziemssen et al. 2002a). Initial evidence forthe intrathecal production of BDNF by GA-treated T cells comes from animal studiesshowing GA-specific T cells in the brain express 2/3 cytokines and BDNF in situ (Aharoniet al. 2003). Moreover, histological analysis of immunostained brain sections in GA-treatedEAE showed augmentation in the expression of BDNF, NT-3, and NT-4 in various brainregions (Aharoni et al. 2005). BDNF is important for neuronal and axonal survival and itis involved in synaptic plasticity and many other neuronal and glial functions; it has alsoimmunomodulatory potential (Ziemssen et al. 2002b). In chronic EAE, GA therapy hasbeen demonstrated to reduce axonal damage and degeneration (Gilgun-Sherki et al. 2003).BDNF secreted by GA-reactive Th2 and Th1 cells may have a trophic and protective effectin CNS tissue of patients with MS, and this may represent an additional mechanism of GAaction. In an optic nerve crush injury model, GA treatment showed preservation of axonalfunction (Kipnis et al. 2000).



In vivo examination of axonal integrity by quantifying N-acetylaspartate (NAA) in brainproton magnetic resonance spectroscopy (MRS) supports axonal metabolic recovery andprotection from sublethal axonal injury with GA treatment. NAA is a neuronal marker thatis used in combination with creatine (Cr) as a metabolic signal. A decrease in the NAA:Crratio has been demonstrated in MS, and further decrease in the ratio over time indicatesdisease progression and worsening of axonal degeneration (De Stefano et al. 1998).

In a pilot study, brain MRS follow-up studies were performed in order to investigate theeffects of GA on axonal injury. The results (after 2 years and confirmed after 3 years ofobservation) showed that NAA:Cr in the GA MS-treated group increased significantly, by10.7% compared with an expected decline of 8.9% in the untreated MS group (Khan et al.2005).

Other Preclinical Studies

Only few data on GA pharmacokinetics are available. It is known that after subcutaneousadministration, GA is rapidly degraded in the periphery to small oligopeptides and freeamino acids, so that it is not possible to measure any systemic plasma levels or excretionrates (Ziemssen et al. 2001).

All patients on GA develop IgG1 binding antibodies (Brenner et al. 2001) that peaked at 3months; however, unlike IFN β, neutralizing antibodies are not known to exist with GA ther-apy. Recent research, in a murine model of demyelinating disease, indicates that these IgG1antibodies to GA may even enhance oligodendrocyte-mediated remyelination in chroniclesions by several possible mechanisms (Ure and Rodriguez 2002), including stimulationof glia or immune cells to produce myelogenic factors, deactivation of pathogenic cytokines,opsonization and clearance of cellular debris, and direct binding to early oligodendrocytes.

Clinical benefits (Johnson et al. 1995; Comi et al. 2001) and antibody formation (Brenneret al. 2001; Qin et al. 2000) after long-term treatment with GA demonstrate that this drugis bioavailable and active (Ziemssen et al. 2001).

Actually, the frequency of administration and the optimal dose in humans have not beenestablished, but animal studies exist and they demonstrated similar effects between long-term and single-dose effects following subcutaneous administration.

It is widely assumed that GA acts primarily as an antigen for T lymphocytes. To date,there are few lines of evidence for any immunosuppressive effects of GA. Recent studiesindicated that in vitro GA directly inhibits dendritic cells and monocyte reactivity (Weberet al. 2004). GA showed a broad inhibitory effect on all measures of monocyte reactivity(induction of signaling lymphocyte activation molecule [SLAM], CD25, and CD69, andproduction of TNFα) regardless of which stimulator was used (ligands for TLR-2, TLR-4,and TLR-5, as well as IFNγ and GM-CSF). It is unlikely that this reflects a simple toxiceffect, because monocyte viability and CD14 expression were unaffected. In a second seriesof experiments, the properties of monocytes cultured ex vivo from eight GA-treated MSpatients, eight untreated MS patients, and eight healthy subjects were investigated (Weberet al. 2004). The investigators found that lipopolysaccharide (LPS)investigators– inducedexpression of SLAM and TNFα production was significantly reduced in monocytes fromGA-treated patients compared to controls. These results demonstrate for the first time thatGA inhibits monocyte reactivity in vitro, significantly extending the current concept of themechanism of action of GA.



CLINICAL STUDIES

The pharmacological effects of GA were translated into clinical benefits. In the initialphase II trial in RRMS patients, GA reduced relapse rates by 76% (Bornstein et al. 1987).Further clinical development confirmed this finding: The relapse rates were reduced by athird and a high proportion of patients became relapse-free (Johnson et al. 1995).

Similar effects were obtained in follow-up studies over more than 5 years of treatment.These studies demonstrated sustained efficacy for GA in slowing the progression of disabil-ity in patients with MS. In one trial after double-blind treatment for a mean of 30 months,all patients were offered active treatment as part of an ongoing, prospective, open-labelstudy. Clinical efficacy results were reported at 6 and 8 years after randomization of GAtherapy. The differences in clinical outcomes were compared in patients who received GAfrom study inception versus those who began treatment approximately 2.5 years later (i.e.,patients originally randomized to placebo). The comparison demonstrated the benefits ofearly GA therapy compared with delayed therapy (Johnson et al. 1998; Johnson et al. 2000;Johnson et al. 2003; Johnson et al. 2005). Despite the fact that these studies were open,these results deserve consideration.

Recently, a 10-year follow-up report provided further information on the long-termefficacy of GA therapy in RRMS (Ford et al. 2006). This is the longest study of patientswith RRMS on any immunomodulatory therapy. The primary aim was to evaluate theeffects of 10 years of GA therapy. The secondary aim was to collect data on patients whowithdrew from the study. A total of 232 patients comprised the modified intention-to-treatgroup, which was defined as anyone who received at least one dose of GA. Of these, 108remained in the study after 10 years and formed the “ongoing” cohort and 124 formed the“withdrawn” cohort. The mean annual relapse rate decreased by almost 50%. It was 1.18in the modified intention-to-treat cohort at 2 years prior to GA therapy and 0.61 in the firstyear of treatment. At the last observation, after almost 10 years of therapy, the relapse ratereduction was >80%. For the “ongoing” cohort patients, expanded disability status scale(EDSS) increased by 0.50 ± 1.65. Sixty-two percent of patients either remained stable orimproved; and 24.8% and 1% reached EDSS of 4, 6, and 8, respectively. For “withdrawn”cohort patients at 10 years (last follow-up), EDSS increased 2.24 ± 1.86; twenty-eightpercent of patients were stable or improved; and 68%, 50%, and 10% reached EDSS 4,6, and 8, respectively. While on GA, nearly all patients (mean disease duration 15 years)remained ambulatory. Given the open-label design, several limitations of open-label trialsnecessitate careful interpretation of the results.

A recent meta-analysis from three randomized, double-blind, placebo-controlled trials(n = 540) provided additional evidence of the ability of GA to reduce relapse rate andslow the development of disability (Boneschi et al. 2003). Unlike with IFN-β, this studybenefited from uniform dosage (20 mg/day), route of administration, and preparation type.In addition, individual patient data were available to the investigators, allowing explorationof the potential role of baseline clinical variables as predictors of treatment response. Theadjusted annualized relapse rate was reduced 28% by GA compared to placebo (adjustedmean rate difference = 0.31with 95% confidence interval (CI) 0.10–0.52, p = 0.004).Beneficial effects of similar magnitude were found for on-trial relapse totals and timeto first relapse. Sustained 3-month increase in EDSS scores (accumulated disability) wasobtained in an exploratory analysis by a Cox proportional hazard model, but was limitedby the short duration of the trials (24, 35, and 9 months). The results favored GA (risk ratio



0.6; CI 0.4–0.9, p = 0.02). This study determined that drug assignment, baseline EDSSscore, and 2-year pre-relapse rate were significant predictors of on-trial relapse rates, butother clinical factors were not.

More recently, Cochrane meta-analysis of GA therapy concluded that the drug did notaffect disease progression, ostensibly at least in part because the authors used group datafrom published studies only (Munari et al. 2004). This conclusion was further supportedby the progressive MS trial that failed to demonstrate a treatment effect of GA on primaryprogressive (PP) patients (Wolinsky et al. 2007).

Lesion burden assessed by MRI has shown a beneficial profile for GA in RR patients. Inthese trials GA reduced the frequency of new enhancing lesions and lesion load comparedto baseline pretreatment measures (Mancardi et al. 1998; Comi et al. 2001).

A large study in Europe and Canada (Comi et al. 2001) randomized 239 patients withRRMS to either GA or placebo, and obtained monthly brain MRI scans for 9 months. Afterthe 9-month double-blind, placebo-controlled phase, patients were followed on GA for anadditional 9 months in an open-label extension. The primary outcome measure, the meannumber of gadolinium-enhancing lesions at the end of the double-blinded phase, showeda 29% reduction in the GA-treated group compared with placebo. Secondary outcomes,including the number of new enhancing lesions, the volume of enhancing lesions, and thechanges in the volume and number of T2-weighted images, were also significantly reducedby treatment with GA. No significant difference in percentage brain volume change, ameasure of neurodegeneration in MS, was found during the double-blind phase. However,during the open-label extension, the mean percentage brain volume change was significantlyless for the GA patients.

No significant clinical improvement in the course of the disease with GA has beendemonstrated for secondary progressive (SP)MS patients (Teitelbaum et al. 1997) and thelargest ever randomized, placebo-controlled study in PPMS with GA failed to show anoverall significant effect on disease progression (Wolinsky et al. 2007). An oral form ofGA failed to show efficacy as monotherapy for RRMS in a large multi-center study (Filippiet al. 2006).

Generally, it is viewed that GA has the most favorable adverse effect profile comparedwith the other therapeutic options available for MS. Unlike IFNβ, GA does not cause liverfunction abnormalities, leukopenia, or thyroid disease and is not associated with depression.The typical flu-like reaction characteristic of IFNβ does not occur with GA. However,approximately 15% of patients experience a self-limited, postinjection systemic reactioncharacterized by chest tightness, flushing, anxiety, dyspnea, and palpitations. This reactionis unpredictable, can occur at any time during treatment, and may be mistaken for cardiacischemia. Skin site reactions may occur. Laboratory values do not need to be monitored inpatients treated with GA.

There are several ongoing clinical trials evaluating GA, including investigations on higherdoses than those currently used, new oral compounds (TV-3606, which consists of smallorganic molecules, derivatives of propargyl trifluoromethoxy-amino-benzothiazole, whichhad an impressive effect in acute and chronic EAE models), GA in patients with clinicallyisolated syndrome (PreCISe), GA in combination with other therapies. To investigate thepotential superiority of high-dose GA 40 mg/day, s.c., a randomized, double-blind, parallel-group study comparing 20 versus 40 mg of daily GA s.c. therapy was conducted (Cohenet al. 2006). Results showed that the 40 mg/day dose may be more effective in reducingevidence of MRI activity.



There is in vitro evidence suggesting superior efficacy of combining GA and IFNβ (Miloand Panitch 1995). Two studies have suggested that combining GA with mitoxantrone inRRMS patients with clinically and brain MRI active disease may be more effective thanGA alone in this population (Ramtahal et al. 2006; Vollmer et al. 2006). A pilot study isunderway combining GA with oral minocycline in RRMS. A study is underway examiningthe effect of estriol in combination with GA. Studies of other combinations of GA, such asGA with booster doses of oral corticosteroids and GA plus statins (Stuve et al. 2006) arealso underway.

CONCLUSIONS

Over the last decade, great progress has been made in elucidating the mechanism ofaction of GA in providing long-term clinical benefit in MS. The well-characterized im-munomodulatory effects of GA have recently been complemented by data suggesting thatthis copolymer has also a neuroprotective effect (Kipnis et al. 2000). The immunomodu-latory effects are detectable in the periphery where GA provokes a phenotypic shift in aspecific population of helper T lymphocytes. The hypothetical mechanism of action includesthe migration of antiinflammatory Th2 cells into the CNS at the site of active lesions wherethey exert a bystander suppression effect. The neuroprotective effect is mediated within theCNS where the GA-specific Th2 cells release BDNF upon stimulation, which will act uponneurons and astrocytes to promote axonal repair. The clinical correlates of these two mech-anisms of action may be different, with the immunomodulatory effect being responsible forreducing inflammation in active lesions and thus reducing the risk of relapses. The neu-roprotective effects, on the other hand, may be more relevant to long-term outcome, sinceprotection against axonal loss may well slow the rate of accrual of irreversible disability.

GA is a unique noninterferon nonsteroidal therapy for MS. Not only has it been shownin randomized controlled clinical trials to be at least as effective as the beta interferons, butits efficacy appears to increase with time. Furthermore, it has the most favorable side effectprofile of all agents available for the treatment of MS. Therefore, it should be considered asthe first-line therapy for ambulatory patients with clinically definite or laboratory-supporteddefinite RRMS. There is some evidence that GA therapy should be started as soon as possibleafter the diagnosis is established (Johnson et al. 2003). In addition, GA therapy is suitable asan alternative therapy for patients treated with IFNβ who are unable to tolerate the drug orwho are able to take it only at reduced dosage because of persistent side effects or laboratoryabnormalities, and for patients treated successfully with IFNβ who, after a period of time,resume an unacceptable rate of relapses or progression associated with the development ofneutralizing antibodies.

Finally, it will be of interest to investigate the effects of the GA treatment in otherhuman primarily degenerative disorders of CNS to better elucidate its neuroprotective andneuroreparative mechanisms of action.

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Glatiramer Acetate in Multiple Sclerosis: A Review - NCBI

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