Glatiramer Acetate

Glatiramer AcetateA Review of its Use in Relapsing-Remitting Multiple Sclerosis

Dene Simpson, Stuart Noble and Caroline PerryAdis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:R. Arnon, Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; M. Filippi,Department of Neuroscience, Scientific Institute Ospendale San Raffaele, Milan, Italy; M. S. Freedman,Multiple Sclerosis Research Clinic, The Ottawa Hospital, Ottawa, Canada; G. Giovannoni, Department ofNeurochemistry, University of London, London, UK; K. P. Johnson, Department of Neurology, Universityof Maryland, Baltimore, Maryland, USA; D. Teitelbaum, Department of Immunology, Weizmann Instituteof Science, Rehovot, Israel; B. Weinstock-Guttman, Baird Center for Multiple Sclerosis, The State Universityof New York, University at Buffalo, Buffalo, New York, USA.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8261. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8292. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830

2.1 Pathogenesis of Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8302.2 Proposed Mechanisms of Action of Glatiramer Acetate . . . . . . . . . . . . . . . . . . . . . 830

2.2.1 Induction of Glatiramer Acetate-Specific Suppressor T Cells . . . . . . . . . . . . . . . . 8312.2.2 Inhibition of Myelin-Reactive T-Cell Responses . . . . . . . . . . . . . . . . . . . . . . . . 8332.2.3 Potential for Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833

2.3 Immunological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8342.3.1 Non-Neutralising Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8342.3.2 Selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834

2.4 Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8343. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835

3.1 Effects on Relapse Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8353.2 Magnetic Resonance Imaging Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8373.3 Effects on Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8393.4 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841

4. Pharmacoeconomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8415. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842

ADIS DRUG EVALUATION CNS Drugs 2002; 16 (12): 825-8501172-7047/02/0012-0825/$25.00/0

© Adis International Limited. All rights reserved.

Data Selection

Sources: Medical literature published in any language since 1980 on glatiramer acetate, identified using Medline and EMBASE,supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists ofpublished articles. Bibliographical information, including contributory unpublished data, was also requested from the company developingthe drug.

Search strategy: Medline search terms were ‘glatiramer acetate’ or ‘copolymer-1’ or ‘COP-1’. EMBASE search terms were ‘glatirameracetate’ or ‘COP-1’. AdisBase search terms were ‘glatiramer-acetate’ or ‘copolymer-1’ or ‘COP-1’. Searches were last updated 16October 2002.

Selection: Studies in patients with relapsing-remitting multiple sclerosis who received glatiramer acetate. Inclusion of studies was basedmainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology werepreferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: glatiramer acetate, relapsing-remitting multiple sclerosis, pharmacodynamics, pharmacokinetics, therapeutic use.

5.1 Injection-Site Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8435.2 Post-Injection Systemic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8435.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8447. Place of Glatiramer Acetate in the Management of Relapsing-Remitting

Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844

SummaryAbstract Glatiramer acetate is a synthetic copolymer composed of a random mixture of

four amino acids that modifies the immune response that results in the CNSinflammation, demyelination and axonal loss characteristic of relapsing-remittingmultiple sclerosis (RRMS).

In three randomised, double-blind trials in patients with RRMS, subcutaneousglatiramer acetate 20 mg/day was significantly more effective than placebo forthe primary outcome measure of each trial (mean relapse rate, proportion ofrelapse-free patients and number of gadolinium-enhancing lesions on magneticresonance imaging [MRI] scans). The mean relapse rate was significantly reducedat endpoint (approximately one-third less) in the two larger trials (the US pivotaltrial [primary endpoint] and the European/Canadian study [tertiary endpoint]) inpatients receiving glatiramer acetate compared with those receiving placebo. Therate was 78% less for glatiramer acetate than placebo patients in the pilot trialthat investigated a slightly different patient population. Glatiramer acetate sig-nificantly decreased disease activity and burden of disease, as assessed in theEuropean/Canadian study using a range of MRI measures. Patients with RRMStreated with glatiramer acetate in the US trial were significantly more likely toexperience improved disability (whereas placebo recipients were more likely toexperience worsening disability) and their overall disability status was signifi-cantly improved compared with placebo recipients. Data from the active-treatmentextension of the US trial suggest that glatiramer acetate has sustained clinicalbenefits up to 8 years.

Glatiramer acetate was generally well tolerated; the most commonly reportedtreatment-related adverse events were localised injection-site reactions and tran-sient post-injection systemic reactions. Both reactions were generally mild andself limiting but were responsible for the majority of withdrawals from treatment(up to 6.5 and 3.5%, respectively). Glatiramer acetate is not associated with theinfluenza-like syndrome or neutralising antibodies that are reported in patientstreated with interferon-β for RRMS.

The cost effectiveness of glatiramer acetate has yet to be definitively deter-mined as assessment of available data is confounded by very different models,data sources and assumptions.

Conclusion. Glatiramer acetate has shown efficacy in well controlled clinicaltrials in patients with RRMS; it reduces relapse rate and decreases MRI-assesseddisease activity and burden. It is generally well tolerated and is not associatedwith the influenza-like symptoms and formation of neutralising antibodies seenwith the interferons-β. Based on available data and current management guide-lines, glatiramer acetate is a valuable first-line treatment option for patients withRRMS.

826 Simpson et al.

© Adis International Limited. All rights reserved. CNS Drugs 2002; 16 (12)

PharmacologicalProperties

The proposed mechanism of action of glatiramer acetate in modulating the auto-immune response in relapsing-remitting multiple sclerosis (RRMS) consists oftwo components. The first is the induction of glatiramer acetate-specific suppres-sor T cells (i.e. type 2 helper T lymphocytes [Th2]) that are capable of directlyand indirectly downregulating the inflammation in the CNS associated with mul-tiple sclerosis (MS). Human studies have shown that these glatiramer acetate-reactive T cells are initially and predominantly Th1 type (pro-inflammatory), butwith exposure to glatiramer acetate there is a shift to a Th2/Th3-type response(anti-inflammatory). It is these glatiramer acetate-specific suppressor T cells, notglatiramer acetate itself, that may migrate into the CNS and downregulate theinflammation that is triggered by the antigenic products of demyelination (myelinbasic protein [MBP] and other myelin antigens). In a small study involving pa-tients with RRMS, this shift from Th1- to Th2-type T cells induced by glatirameracetate was accompanied by clinical benefits.

The second feature of glatiramer acetate’s mechanism of action is the inhibi-tion of the autoreactive MBP- and other myelin antigen-specific T cells that wouldotherwise be stimulated to proliferate and release inflammatory cytokines. Cur-rent hypotheses include glatiramer acetate acting as an altered peptide ligand andengaging various T-cell receptor (TCR)s, and glatiramer acetate engaging theTCR and downregulating the MBP-specific T-cell response possibly by deliver-ing a non-activating signal (anergy).

Recent research suggests that neuroprotection may be another mechanism ofaction accounting for the beneficial clinical effects of glatiramer acetate in RRMS.

Antibodies stimulated by glatiramer acetate treatment are non-neutralisingand do not affect the clinical efficacy of the drug.

Few pharmacokinetic data are available for glatiramer acetate; following sub-cutaneous administration, the drug is rapidly degraded in the periphery, resultingin very low or undetectable serum concentrations. Glatiramer acetate is not re-quired to be present in the serum to exert its anti-inflammatory action but absorp-tion in proportion to the dose administered was rapid.

Therapeutic Efficacy Glatiramer acetate has shown efficacy in treating patients with RRMS. In threerandomised, double-blind trials (including a 2-year pilot trial and the larger USpivotal [2-year] and European/Canadian [9-month] studies) glatiramer acetate20mg once daily, administered subcutaneously in patients with RRMS, was sig-nificantly more effective than placebo for the respective primary endpoint of eachtrial (proportion of relapse-free patients, relapse rate and number of enhancinglesions on magnetic resonance imaging [MRI] scans).

For patients receiving glatiramer acetate compared with those receiving pla-cebo in the two larger comparative studies, the mean relapse rate (covariate ad-justed) at study endpoint was 29% lower in the large US trial (where relapse ratewas the primary endpoint) and 33% lower in the European/Canadian study (whererelapse rate was the tertiary endpoint). In the pilot trial, glatiramer acetate recip-ients had a mean relapse rate 78% lower, and they were more than twice as likelyto be relapse free, than placebo recipients. Relapse-related results in this pilottrial have not been reproduced in larger trials, possibly due to the patient popu-lation’s having a shorter duration of disease and a higher baseline relapse ratethan those in subsequent studies.

Glatiramer acetate decreased disease activity and burden of disease, as assessedby analysis of MRI scans, in patients enrolled in the European/Canadian study

Glatiramer Acetate in Relapsing-Remitting MS 827


where certain MRI measures were the primary and secondary endpoints. For theprimary outcome measure, patients in the glatiramer acetate-treated group dem-onstrated 29% fewer gadolinium-enhancing CNS lesions (areas of acute inflam-mation representing disruption of the blood-brain barrier) than patients in theplacebo group. For secondary MRI outcomes, glatiramer acetate showed signif-icantly greater lesion reductions (ranging from 30 to 82.6%) than placebo. Al-though this 9-month trial period was considered too short to demonstrate asignificant reduction in the volume of hypointense T1 lesions (representing areasof demyelination and axonal loss), further analysis of these scans has shown that,after 8 months, the proportion of new T2 lesions evolving into these hypointenseT1 lesions (‘black holes’) in patients receiving glatiramer acetate was half thatshown in patients receiving placebo.

Progression to sustained disability, as measured by the Kurtzke ExpandedDisability Status Scale (EDSS), was a secondary endpoint in the two long-termtrials. Patients with RRMS treated with glatiramer acetate in the pivotal US trialwere significantly more likely to experience improved disability, and placeborecipients were more likely to experience worsening disability. The overall dis-ability status was also significantly improved in this trial, although the changewas modest. The pilot trial showed positive trends in delaying the onset or wors-ening of disability, although it did not have adequate statistical power to evaluatethis outcome.

Preliminary results data from the active-treatment extension of the US trialsuggest that glatiramer acetate has sustained clinical benefits up to 8 years.

Pharmacoeconomics Two studies conducted in 2000 and 2001 investigating the cost effectiveness ofglatiramer acetate in the treatment of RRMS are difficult to compare as they useddifferent models and data sources and led to different conclusions.

According to a cost-utility analysis based on the clinical outcomes of a largeplacebo-controlled trial (the US pivotal trial) and its extensions, glatiramer ace-tate is cost effective compared with best supportive care alone for RRMS, fromthe perspective of the UK National Health Service. Cost-utility ratios improvedwith a longer duration of treatment for all three cost variables. At 8 years, costper relapse avoided was £11 000, cost per disability unit avoided was £8 862 andcost per quality-adjusted life-year (QALY) gained was £22 586 (year 2000 costs).

An analysis conducted by the National Institute of Clinical Excellence usedlonger term modelling and concluded that neither glatiramer acetate nor theinterferons-β were cost effective in the treatment of RRMS. The best mean costper QALY gained (i.e. at 20 years of treatment and including MS Research Trustdata on quality of life), expressed as a range covering all the agents under inves-tigation, was between £35 000 and £104 000, which was more than the valueconsidered favourable in the UK (£30 000).

Given the complexities of cost-effectiveness assessments in RRMS, a lifelong,disabling disease (for which clinical benefits of long-term treatment have onlyrecently been published) and the limited amount of information available at pres-ent, it is impossible to draw a single definitive conclusion regarding the costeffectiveness of glatiramer acetate, and further data and evaluations in this fieldwould be useful.

Tolerability Subcutaneously administered glatiramer acetate 20mg is generally well tolerated.The most commonly reported treatment-related adverse events (data from threeplacebo-controlled clinical trials and pooled results from two of these and other

828 Simpson et al.


trials) are localised injection-site reactions and transient post-injection systemicreactions. The incidence of injection-site reactions (manifesting mainly as painand erythema) was 64 and 73% with glatiramer acetate versus 37 and 38% withplacebo (no p value reported).

Post-injection systemic reactions occurred with an incidence of 10–38% withglatiramer acetate versus <1–13% with placebo (no p value reported) and mani-fested as one or more symptoms (facial flushing, chest tightness, dyspnoea, pal-pitations, tachycardia, anxiety and/or sweating) occurring within minutes of aninjection and lasting for 30 seconds to 30 minutes.

Both reactions were generally mild and self limiting but accounted for themajority of withdrawals from treatment. Overall withdrawal rates ranged from6–8% with localised injection-site reactions accounting for up to 6.5% and post-injection systemic reactions for up to 3.5% (vs 0.8% with placebo, no p valuestated).

Serious treatment-related events occurred in ≤2% of patients enrolled in clin-ical trials and, although no anaphylaxis was reported during the trials, three non-fatal cases of allergic reaction have since been recorded.

Glatiramer acetate is not associated with the influenza-like syndrome reportedin patients treated with interferon-β.

Dosage andAdministration

Glatiramer acetate is indicated for the long-term management of RRMS and iscurrently approved in numerous countries worldwide including the USA, Canada,the UK and many other European countries. Glatiramer acetate is administeredonce daily by subcutaneous injection at a standard dose of 20mg. Data on the useof glatiramer acetate in pregnant and nursing women, the elderly, patients youn-ger than 18 years and those with impaired renal function are limited. Contraindi-cations include intravenous administration and hypersensitivity to glatirameracetate or mannitol (which is included in the injection formulation).

1. Introduction

Multiple sclerosis (MS) is a chronic, inflamma-tory disease of the CNS usually diagnosed in youngadults (aged 20–40 years)[1] and affecting an esti-mated 2.5 million people worldwide.[2] It is an auto-immune condition,[3-5] possibly triggered in genet-ically susceptible individuals by one or more agentsin the environment,[6,7] that results in uncheckedinflammation causing demyelination of areas inthe brain and spinal cord. Relapsing-remitting MS(RRMS) is the most common type of MS; approx-imately 85% of patients present with this type ofMS.[1,7,8] It manifests as self-limited attacks of neu-rological dysfunction (relapses)[9] during whichthe patient experiences a sudden worsening of neu-rological symptoms such as numbness, tingling,muscle weakness, spasticity, visual disturbances,

fatigue and dizziness.[10,11] These relapses are in-terspersed with periods of complete or partial re-mission. Although some patients continue on thiscourse without becoming seriously disabled,[6,7,12,13]

the majority (about 80%)[14] enter a phase within5–15 years in which they experience an increase inoverall disability with or without relapses (second-ary progressive MS).[7,8,13,14] Within 10–15 yearsof a diagnosis of MS, 50% of patients are unableto walk unassisted,[6,15] and after 25 years 50% arewheelchair bound.[15]

Management of RRMS includes multidiscipli-nary rehabilitation, pharmacotherapy for symp-toms and treatment of relapses and, more recently,pharmacotherapy for modifying the underlyingdisease in an attempt to prevent relapses and delaythe progression to disability.[6,8,12]

Limited success (from an efficacy, tolerability



or cost perspective) with general immunosuppres-sant agents (azathioprine, mitoxantrone and oth-ers)[1,6,16] and intravenous immunoglobulins[3,4,17]

(not approved in the USA) and progress in under-standing the pathogenesis of RRMS have led to theintroduction and use of more specific immuno-modulatory agents, such as glatiramer acetate (pre-viously copolymer-1) and two forms of recombi-nant interferon-β,[3,16] for altering the naturalcourse of the disease (see section 7).

Glatiramer acetate is a synthetic copolymercomposed of a random mixture of four amino acidsthat was initially developed to mimic myelin basicprotein (MBP), one of the antigens thought to beinvolved in the pathogenesis of MS.[18] However,in a variety of animal species,[19,20] it unexpectedlyinhibited experimental autoimmune encephalitis(EAE), the primary animal model for MS. The sup-pressive and protective effects of the drug, in EAEinduced by MBP and other myelin antigens (e.g.proteolipid protein [PLP] and myelin oligodendro-cyte glycoprotein [MOG]), are now well estab-lished.[11,19,21] In patients with RRMS, glatirameracetate downregulates the immune response to thesemyelin antigens. It is considered to be the firstagent to do this by engaging the T-cell receptor(TCR).[8,22] This article reviews pharmacologicaland clinical data on the use of glatiramer acetate inpatients with RRMS.

2. Pharmacological Properties

Glatiramer acetate consists of a mixture of fournaturally occurring amino acids ( L-glutamic acid,L-alanine, L-tyrosine and L-lysine) produced byrandom polymerisation.[23,24] This agent simulatesMBP, an antigen thought to be involved in MS,although both the pathogenesis of this disease andthe mode of action of glatiramer acetate have yetto be fully elucidated. Nevertheless, the beneficialeffects of glatiramer acetate in RRMS are thoughtto stem from its modification of immune processesimplicated in the pathogenesis of the disease. Thissection focuses on the human studies that have at-tempted to characterise the pharmacological ef-fects and exact mechanism of action of glatiramer

acetate and includes studies in patients with alltypes of MS. Animal data are provided where hu-man data are limited.

2.1 Pathogenesis of Multiple Sclerosis

The pathogenesis of MS involves a cascade ofimmunological events beginning with the activa-tion (by viral, environmental or other triggers)[6,7]

of autoreactive myelin-reactive T cells in the pe-riphery. The subsequent release of inflammatorymediators and the upregulation of adhesion mole-cules[7,13] facilitate the passage of these T cellsthrough an ‘altered’ blood-brain barrier into theCNS,[7,25,26] where they are reactivated by the anti-genic products of demyelination, predominantlyMBP[3,7,27] but possibly PLP and MOG as well.These activated myelin-reactive T cells releasecytokines and mediators, which recruit and stimu-late other inflammatory cells (microglia, astro-cytes and plasma cells) that precipitate the demy-elination, oligodendrocyte damage[9] and axonal losscharacteristic of MS.[3,4,7,12,26,28]

2.2 Proposed Mechanisms of Action ofGlatiramer Acetate

The disease-specific mechanism of action ofglatiramer acetate in modulating the immune re-sponse in MS appears to be a complex process in-volving:• induction of glatiramer acetate-specific sup-

pressor T cells that are capable of directly andindirectly downregulating the inflammation inthe CNS[21,22,26,27,29] (see section 2.2.1);

• inhibition of the autoreactive MBP-specific Tcells that would otherwise be stimulated to pro-liferate and release inflammatory cytokines thatlead to CNS inflammation and damage[27,30]

(see section 2.2.2).Although its eventual site of action is the

CNS,[31] glatiramer acetate itself is unlikely tocross the blood-brain barrier[29,32] as it is degradedinto smaller fragments in the periphery after sub-cutaneous administration (see section 2.4).[33] It isthe glatiramer acetate-induced T cells that migrate

830 Simpson et al.


into the CNS and downregulate the inflammationassociated with MS (see sections 2.2.1 and 2.2.2).

A summary of the key pharmacological effectsof glatiramer acetate of potential relevance to itsuse in the treatment of RRMS is presented in table I.

2.2.1 Induction of Glatiramer Acetate-SpecificSuppressor T CellsGlatiramer acetate binds to the major histo-

compatibility complex (MHC) class II moleculeon the antigen-presenting cells[35,36] in the periph-ery at the injection sites or in the lymph nodesdraining the injection sites.[29] The subsequentbinding of this glatiramer acetate/MHC complexto the glatiramer acetate-specific TCR[29] induces

the proliferation of glatiramer acetate-specific T-cell lines. The glatiramer acetate-reactive T cellssecrete predominantly T-helper (Th) 1-type pro-inflammatory cytokines,[41] but with exposure toglatiramer acetate the T cells are shifted more to-wards the Th2 type (anti-inflammatory).[34,40,41,53]

These suppressor T cells may migrate through theblood-brain barrier into the CNS[25] where they en-counter MBP and other pathogenic myelin antigens(products of CNS inflammation and demyelin-ation) presented by the MHC. Because glatirameracetate is cross-reactive with these antigens,[40,41,43,47]

the glatiramer acetate-activated T cells are reacti-vated to produce Th2 anti-inflammatory cytokines,

Table I. Pharmacological effects of glatiramer acetate (GA) of relevance to its use in the treatment of relapsing-remitting multiple sclerosis(MS)a

MHC binding in the peripheryBinds to MHC with high affinity[35]

Promiscuous binding to multiple HLA-DR alleles,[36] including DBR1*1501 and DR4 haplotypes (linked to known MS susceptibility incertain population groups)[37]

Successfully competes with MBP and other myelin antigens for MHC binding [5,37-39]b

Induction of suppressor T cellsGA-reactive T cells shift from Th1 type (pro-inflammatory) to Th2 and Th3 type (anti-inflammatory)[34,40-44]

Shift evident as early as 1 month[43] after treatment and sustained for up to 9 years,[28] despite reduction in GA-reactive T-cellproliferation[40-42,45]

Inhibition of MBP-specific T-cell responseDose dependently inhibits proliferation of MBP-specific T cells[27,30]

Downregulates the MBP-specific T-cell response by engaging the TCR and inducing anergy (acts as an altered peptide ligand anddelivers a non-activating signal)[26,27]

TCR antagonism demonstrated[46] (inconsistent results in another study[27])c

T-cell migration through blood-brain barrierGA-induced Th2-type T cells accumulate in the CNS[25]

Cross-reactivityInduces T cells cross-reactive with MBP,[40,41,43,47] MOG[5,48] and PLP[20,41]

Cross-reactivity shown at the level of cytokine expression[27,41,49]

More T-cell lines show cross-reactivity with continued GA treatment[40]

Bystander suppressionGA-induced suppressor T cells, reactivated by MBP, inhibit T-cell responses to other myelin antigens[22,26,28,41,44,48,50] and downregulatefurther inflammatory processes

NeuroprotectionIncreased production of brain-derived neurotrophic factor detected in GA-specific T cells[51,52]

a All findings are from in vitro human studies except two studies by Aharoni et al.[25,34]

b Unlikely to be relevant in vivo as GA and MBP remain in separate sites.

c Unlikely to be relevant in vivo as MBP-specific T cells and GA remain in separate sites.

HLA = human leucocyte antigen; MBP = myelin basic protein; MHC = major histocompatibility complex; MOG = myelin oligodendrocyteglycoprotein; PLP = proteolipid protein; TCR = T-cell receptor; Th = T helper.



which directly and indirectly downregulate theCNS-based inflammation associated with MS[22,29]

(figure 1). The ability of glatiramer acetate in theperiphery to induce this remote suppression of in-flammation in the CNS is due to the cross-reactivityof glatiramer acetate-specific T cells with not onlyMBP,[26,27,29,41,48] but also other myelin antigensimplicated in the pathogenesis of MS (possiblyMOG[5,48] and PLP[20,41]). This phenomenon, where-by the anti-inflammatory cytokines secreted are in-dependent of the primary autoantigen or antigenspecificity of the T cells, is known as ‘bystandersuppression’.[22,26,28,41,44,50,54]

Evidence of a shift of T-cell generation frompredominantly Th1-type (pro-inflammatory) to Th2-and Th3-type T cells (both anti-inflammatory) wasaccompanied by clinical benefits in a nonblindstudy that enrolled ten patients with RRMS treatedwith subcutaneous glatiramer acetate 20mg oncedaily for 12 months.[44] There was a 2- to 6-foldincrease in serum and peripheral blood lymphocyte(PBL) levels of indicators for the anti-inflamma-tory Th2- and Th3-type T cell at 3 or 6 months oftreatment compared with pretreatment levels. At12 months the levels were higher than baseline val-ues.[44] Patients with active MS have been shownto have defective production and low levels ofinterleukin (IL)-10, IL-4 and transforming growthfactor β (TGFβ) [anti-inflammatory cytokines].[44]

The mean serum level of IL-10 in patients treatedwith glatiramer acetate increased nearly 2-fold at3 months compared with baseline (from approxi-mately 1.4 to 2.6 ng/L, p = 0.04 [estimated from agraph]), although the increase was not significantat 6 and 12 months. Messenger RNA (mRNA) ex-pression of IL-4 and TGFβ in the PBLs (estimatedfrom graph) showed a 4- and 6-fold enhancementat 6 months (p = 0.03 vs baseline), and transform-ing growth factor-β remained significantly higherthan baseline at 12 months (p = 0.02).[44]

mRNA expression of the pro-inflammatoryTh1-type cytokine tumour necrosis factor-α inPBLs had decreased 78% from the pretreatmentlevel at 12 months (estimated from a graph) [p <0.004].[44] A decrease from baseline was also ob-

APC MHC

APC

MHC

APC

MHC

MBPT cell

GAT cell

Th1

Th2/Th3

Th2/Th3

Proliferation ofGA-reactive T cells

Binding of GA to the MHC

Inhibition of MBP T-cellresponse (anergy orTCR antagonism?)

Th2/Th3 cytokines downregulateinflammation in the CNS

Shift from Th1 toTh2/Th3cytokine secretion

Migration of GAT cells through blood-brain barrier

GA T cells secreteTh2/Th3 cytokines inresponse to stimulationby MBP (cross-reactivity)

GA

MBP

CNS

Periphery

Fig. 1. Proposed mechanisms of action of glatiramer acetate (GA)in the treatment of relapsing-remitting multiple sclerosis. APC =antigen-presenting cell; MBP = myelin basic protein; MHC = majorhistocompatibility complex; TCR = T-cell receptor; Th = T helper.

832 Simpson et al.


served at 12 months in the mean level of solubleIL-2 receptor; there was substantial interpatientvariability in this reduction at all timepoints. The12-month decrease, which was not significant, waspreceded by an increase at 3 months (p = 0.04 vsbaseline).[44]

The shift from Th1- to Th2- and Th3-type T cellswas accompanied by improvements in clinicalmarkers of disease activity. There was a significantreduction in mean annual relapse rate (1.4 to 0.6,p = 0.001), and nine of ten patients had improvedor stable disability, according to absolute changesin the Kurtzke Expanded Disability Status Scale(EDSS) score.[44]

There is recent evidence of a sustained shift incytokine profile of the glatiramer acetate-inducedT cells[28] in ten patients treated with glatirameracetate for 6–9 years.[55] This shift, coupled withthe cross-reactivity between glatiramer acetate andMBP and other myelin antigens, is consistent withthe anti-inflammatory effects of glatiramer acetateand the phenomenon of ‘bystander suppression’(see above).

The induction of glatiramer acetate-specific,protective T cells is detected early and the timerequired for the development of an adequate andeffective T-cell population is reflected in the tim-ing of the onset of significant therapeutic action ofglatiramer acetate (see section 3).[28,31,32,54]

2.2.2 Inhibition of Myelin-Reactive T-Cell ResponsesThe beneficial effects of glatiramer acetate are

further explained by the inhibition of the autoreac-tive MBP- and other myelin antigen-specific T-cellresponses implicated in the pathogenesis of MS(figure 1). Studies have shown that after initiallyinducing proliferation of the T cells, glatiramer ac-etate inhibits both their proliferation[27,30] and theirsecretion of IL-2 (a Th1 cytokine).[30] It has beensuggested that glatiramer acetate can alter the Tcells in some way. Indeed, possibly acting as analtered peptide ligand, it engages various TCRs,altering the T-cell cytokine secretion to a Th2 pro-file. It may also downregulate the MBP-specificT-cell response by delivering a non-activating sig-

nal (anergy)[26,27] [figure 1]. TCR antagonism(competition for the TCR by the glatiramer acetate/MHC and MBP/MHC complexes), which is anothermechanism proposed for this T-cell inhibition, islikely to remain an in vitro observation as glatira-mer acetate remains in the periphery and MBP inthe CNS.[29,46]

Glatiramer acetate might also interfere with theinteraction between activated T cells and micro-glia in the CNS (which leads to the production ofinflammatory cytokines), thereby accounting forthe reduced inflammation in the CNS observedwith glatiramer acetate treatment of RRMS.[56]

2.2.3 Potential for NeuroprotectionNeuroprotection, induced by treatment with

glatiramer acetate, has been demonstrated in ani-mal[57] and in vitro human[51] studies. In experi-mental crush lesions of the optic nerve in a ratmodel, adoptive transfer of the nonpathogenicglatiramer acetate-reactive T cells or vaccinationwith glatiramer acetate on the day of CNS injuryhas been shown to confer a measure of neuro-protection, preventing secondary degeneration ofnerve fibres.[57]

Recent research[51,52] suggests that neuropro-tection, besides that effected by bystander suppres-sion, possibly in the form of increased levels ofbrain-derived neurotrophic factor (BDNF), may beanother mechanism of action for glatiramer acetatein the treatment of RRMS. BDNF is an importantfactor for neuronal survival, neurotransmitter re-lease and dendritic growth. Increased production ofBDNF was detected in glatiramer acetate-specificT cells from MS patients and healthy donors fol-lowing in vitro restimulation with the drug.[51]

BDNF was also more likely to be produced byglatiramer acetate-reactive T cells than those reac-tive to MBP, and there was a positive correlationbetween BDNF levels and IL-5 (Th2 indicator), butnot with interferon-γ, in glatiramer acetate-reactiveT-cell lines derived from patients with MS treatedwith glatiramer acetate.[52] BDNF and its major re-ceptor, gp145trkB, are expressed in active MS le-sions;[58] BDNF is found primarily in immune cellsand reactive astrocytes, and the receptors have



been located in reactive astrocytes (but not immunecells) and in neurones in the immediate vicinity ofMS plaques. The number of BDNF immune-positivecells correlates with the extent of demyelinatingactivity.[58]

2.3 Immunological Effects

2.3.1 Non-Neutralising AntibodiesAn ancillary study[45] of 217 patients selected

from three different clinical trials (selection pro-cess not described) demonstrated the developmentof non-neutralising antibodies to glatiramer ace-tate. Immunoglobulin (Ig) G1 levels were 2- to 3-fold higher than IgG2 in all 130 glatiramer acetate-treated patients, and neither Ig was detected inplacebo-treated patients. The antibody levels peakedat 3 months, decreased at 6 months and settled at alevel slightly higher than baseline.[45] All patientstested developed these antibodies, which did notaffect the therapeutic efficacy of glatiramer acetateor correlate with reported adverse events.[45,59]

Recent research, in a murine model of demye-linating disease (induced by Theiler’s virus), indi-cates that these predominantly IgG1 and IgG2 anti-bodies to glatiramer acetate may even enhanceoligodendrocyte-mediated remyelination in chroniclesions by several possible mechanisms,[60] includ-ing stimulation of glia or immune cells to producemyelogenic factors, deactivation of pathogeniccytokines, opsonisation and clearance of cellulardebris and direct binding to early oligodendro-cytes.

The analysis of the humoral immune responseof 40 patients with RRMS (20 treated with glatira-mer acetate and 20 untreated) and 20 healthy do-nors for all isotypes of glatiramer acetate-reactiveIg revealed low but detectable titres of IgG4 anti-bodies in patients treated with glatiramer acetate (n =18) but no IgG4 antibodies in untreated patients orhealthy donors.[61] This is consistent with the evi-dence of induction of Th2 suppressor T cells in pa-tients treated with glatiramer acetate, as IL-4 is aknown switch factor for IgG4.[61]

2.3.2 SelectivityBecause glatiramer acetate modifies the im-

mune response and is antigenic, the likelihood thatit could potentially interfere with other useful im-mune functions or induce untoward immune re-sponses has been considered. The antigen-specificnature of the immune response generated by glatira-mer acetate has been confirmed in animal[62,63] andhuman[42,45] studies. These studies demonstratethat the humoral and cellular immune responses tononrelevant antigens (including ovalbumin, a re-combinant influenza virus vaccine, a shigella vac-cine, purified protein derivative and tetanus tox-oid) are unchanged following daily subcutaneousadministration of glatiramer acetate. Moreover,glatiramer acetate did not prevent the induction ofsystemic lupus erythematosus in an experimentalmurine model of the disease or have any effect onthe already established condition.[64]

2.4 Pharmacokinetic Properties

Few pharmacokinetic data are available for gla-tiramer acetate; following subcutaneous adminis-tration, the drug is rapidly degraded in the periph-ery, resulting in very low or undetectable serumconcentrations.[33] In vitro studies have shown thatit is degraded to small oligopeptides and freeamino acids in skin and muscle homogenates.[33]

Glatiramer acetate is not required to be presentin the serum to exert its anti-inflammatory actionin the CNS as it acts indirectly through T cells,following a sequence of events that begins in theperiphery (see section 2.2). Clear evidence of clin-ical benefits[31,65] and formation of antibodies[45,59]

after long-term treatment with glatiramer acetatesupport the hypothesis that glatiramer acetate isbioavailable and active.[33]

The optimal dose and frequency of administra-tion in humans have not yet been established, butthe pharmacokinetic properties of radiolabelledglatiramer acetate following long-term subcutane-ous administration were similar to those observedafter a single subcutaneous dose in animal stud-ies.[33] Glatiramer acetate was rapidly absorbedleaving only a small fraction at the injection site,

834 Simpson et al.


and the amount absorbed was proportional to thedose administered. The maximum plasma concen-tration was achieved after 1–2 hours in rats and 2–4hours in monkeys.[33]

3. Therapeutic Efficacy

The therapeutic efficacy of subcutaneous gla-tiramer acetate 20mg once daily in patients withRRMS has been evaluated in two large, random-ised, double-blind, placebo-controlled, multicentre,phase III trials. One (a US pivotal trial) was con-ducted over 2 years[65] and the other (referred to asthe ‘European/Canadian study’) was of 9 months’duration.[31] These trials were conducted aftercompletion of an earlier dose-finding study in 16patients with MS[66] and a 2-year pilot study (double-blind and placebo-controlled) in 50 patients withRRMS.[24]

Key design details for the three comparativestudies[24,31,65] are summarised in table II. Ambu-latory patients with RRMS who had experiencedat least one[31] or two[24,65] documented relapses inthe 2-year pretreatment period were included. Ex-clusion criteria (not reported for the pilot study[24])were based mainly on previous or concurrent ther-apy with standard or experimental treatments forMS.[31,65]

More recent trial reports[31,65] use the term ‘re-lapse’ for an attack of neurological dysfunction,whereas the earlier trial[24] refers to an ‘exacerba-tion’. The term ‘relapse’ is used throughout thisreview and is clearly defined for each trial in table II.

The primary endpoints for the three main trialswere proportion of relapse-free patients,[24] meannumber of relapses[65] and the total number of en-hancing lesions on magnetic resonance imaging(MRI) scans[31] (see table II). Secondary endpointsincluded relapse rate,[24] proportion of relapse-freepatients,[65] status of and progression to disability(as assessed on the EDSS)[24,65] and a range of MRI-assessed parameters (see sections 3.1, 3.2 and3.3).[31]

Some trial-extension data[67-70] have been in-cluded in this section, where appropriate (see sec-tions 3.1, 3.2 and 3.3). The nonblind extensions[68-70]

should be interpreted cautiously because of the po-tential for multiple biases.

3.1 Effects on Relapse Rate

Relapse rate was the primary endpoint in the USstudy,[65] a secondary endpoint in the pilot study[24]

and a tertiary endpoint in the European/Canadianstudy.[31] In the two larger studies,[31,65] patientstreated with glatiramer acetate had significantlyfewer relapses compared with those receiving pla-cebo (p = 0.007 and p = 0.012, respectively). Atendpoint, the mean relapse-rate reductions weresimilar (29% [covariate adjusted] in the US trial[65]

[p = 0.007] and 33% in the European/Canadianstudy[31] [p = 0.012]) despite the study periods’being different for the two trials (24 vs 9 months,respectively) [see table III]. In the smaller trial,[24]

in which patients had a shorter duration of disease(table II) and a higher baseline relapse rate (seetable III), results such as the mean relapse-rate re-duction at endpoint (78% lower for glatiramer ac-etate patients than for those receiving placebo) andthe proportion of relapse-free patients (56 vs 26%with placebo, p < 0.045) have not been reproducedin subsequent larger trials.[31,65] Nonetheless, theproportion of relapse-free glatiramer acetate pa-tients compared with those receiving placebo be-came significant during the controlled extensionphase of the US trial.[67]

The beneficial effect of glatiramer acetate com-pared with placebo on relapse rate appeared to bemore pronounced in patients with less severe RRMSat study entry (as determined by the EDSS score)in both long-term trials,[24,65] although results of ameta-analysis of the 540 patients[71] participatingin the three main comparative clinical trials[24,31,65]

do not support this observation.The relapse-rate data for the extension periods

of the US trial (see table II) suggest a sustained bene-fit for patients receiving glatiramer acetate versusthose receiving placebo (in the placebo-controlledextension[67]) and for those receiving glatirameracetate throughout the study (in the active-treatmentextensions[68,69]). In the placebo-controlled exten-sion phase (up to 35 months),[67] the mean relapse



Table II. Key design details of studies of glatiramer acetate (GA) 20mg (administered subcutaneously once daily) in patients withrelapsing-remitting multiple sclerosis (MS)

Johnson et al.[65]a Comi et al.[31]b Bornstein et al.[24]

No. of patients enrolled 251 (GA 125, PL 126)c 239 (GA 119, PL 120)c 50 (GA 25, PL 25)d

Study design r, dbf, pc, mc r, dbe, pc, mc r, dbf, pc

Mean duration of diseaseGA/PL (y)

7.3/6.6 7.9/8.3 4.9/6.4

Duration of treatment 2y 9mo 2y

Inclusion criteria Clinically definite MS withrelapsing-remitting course

Clinically definite MS withrelapsing-remitting courseg

Clinically definite MS withrelapsing-remitting course

Age 18–45y Age 18–45y Age 20–35y

≥2 documented relapses in 2ypretreatment periodh

≥1 documented relapse in 2ypretreatment period

≥2 documented relapses in 2ypretreatment period

EDSS 0–5i EDSS 0–5 EDSS ≤6j

Neurologically stable and steroidfree for 30d prior to randomisation

Neurologically stable andcorticosteroid free for 30d prior torandomisation

One enhancing lesion on screeningMRI

Primary endpoint Mean no. of relapses Total no. of enhancing lesions (MRIevidence)

Proportion of relapse-freepatients

Definition of relapse Appearance of new orreappearance of existingneurological symptoms, persistingfor ≥48h, following a stable orimproving neurological state for≥30d and accompanied by a0.5-point deterioration on EDSSor 1 point in two or more FS

Appearance of one or more newneurological symptoms orreappearance of one or morepre-existing symptoms, persisting for≥48h, after a stable or improvingneurological state for ≥30d andaccompanied by a 0.5-pointdeterioration on EDSS or 1 point intwo or more FS or 2 points in one FS

Rapid onset of new or worseningof pre-existing symptoms thatpersisted for ≥48h accompaniedby a 1-point deterioration on theEDSS or 1 on the FS scorek

Trial extensions (1) A pc extension of 11mo(mean 5–6mo) to a total of 35mo,n = 203[67]l

Active-treatment extension of 9mo,all patients received glatirameracetate, n = 224[70]m

(2) Active-treatment extension toa total of 8y, all patients receivedglatiramer acetate, n = 208[68,69]n

a US pivotal trial.

b European/Canadian study.

c Intention-to-treat analysis.

d Per protocol analysis, 48 patients evaluated.

e Blinding not assessed but treating neurologist and patient warned of discussing adverse effects with examining neurologist.

f Physicians assessing disability were blinded to treatment and adverse effects.

g For at least 1y.

h Last relapse <1y prior to randomisation.

i A score on the Kurtzke EDSS corresponding to ‘ambulatory without assistance’. The Kurtzke EDSS is an ordinal scale ranging from 0(a normal neurological examination) to 10 (death due to MS) in 0.5-point increments.

j Ambulatory with assistance.

k Part of the EDSS score that rates pyramidal, cerebellar, brainstem, visual, sensory, bowel, bladder and cerebral function.

l 194 patients completed this controlled phase.

m 215 patients completed the extension phase (study available as an abstract).

n All patients were required to have been randomised in db phase but not to have completed it. 90% of patients entered this phase within28d of exiting the db phase; the remainder had breaks of 58–829d. There were 142 patients still participating after 8y. Data to 6y arefully published, but data to 8y are available as an abstract. Study is ongoing and planned to run for a total of 12y.

db = double-blind; EDSS = Expanded Disability Status Scale; FS = functional systems; mc = multicentre; MRI = magnetic resonance imaging;pc = placebo-controlled; PL = placebo; r = randomised.

836 Simpson et al.


rate (covariate adjusted) was 32% lower for gla-tiramer acetate recipients than for placebo recipi-ents (1.34 vs 1.98, p = 0.002).

The annualised relapse rate for patients who hadreceived glatiramer acetate throughout the 6-yearactive-treatment extension phase[68] was 72% lessthan the annualised relapse rate at study entry (p =0.0001). Patients receiving glatiramer acetate for8 years had an annualised relapse rate for theeighth year of 0.16 (equivalent to one relapse in 6years) compared with a baseline annualised rate of1.49 (based on the rate for the 2-year pretreatmentperiod).[69]

Further results for the placebo-controlled ex-tension of the US study[67] show that 33.6% of theglatiramer acetate group were relapse free at 35months, compared with 24.6% of the placebo group(p = 0.035). In the 6-year active-treatment exten-sion, more patients who had received glatirameracetate throughout the study[68] were relapse freecompared with patients who received placebo be-fore being switched to active treatment (25.7 vs19.6%).[65]

No controlled trials have compared glatirameracetate directly with other immunomodulatorytherapies for RRMS, but two nonrandomised, non-blind studies have been conducted.[72,73] An 18-month study enrolled treatment-naïve patients withRRMS[72] with similar baseline characteristics, in-cluding an EDSS score ≤4, who then received oneof three treatments (glatiramer acetate, interferon-β-1a or interferon-β-1b) or remained untreated.Results of this study suggest that glatiramer acetateand interferon-β-1b may be more optimal choicesfor therapy for RRMS than interferon-β-1a. Therelapse-rate reduction in patients receiving one ofthese two agents was significantly different fromthat of untreated patients, whereas the relapse-ratereduction with interferon-β-1a was not. Of 156 pa-tients enrolled, 122 did not switch treatments dur-ing the study period and were included in the analy-sis. The annualised mean number of relapses forglatiramer acetate, interferon-β-1b, interferon-β-1aand untreated patients was 0.49 (p = 0.001 vs un-

treated patients), 0.55 (p = 0.001 vs untreated pa-tients), 0.81 and 1.02, respectively.[72]

Glatiramer acetate showed the greatest reductionin annual relapse rate in a 12-month study[73] (n =304) comparing this agent to the interferons (intra-muscular interferon-β-1a, subcutaneous interferon-β-1a and interferon-β-1b) and intravenous immuno-globulins (specific ones not stated) for the treatmentof RRMS (63 vs 42, 40, 27 and 16.5%, respectively,p values not reported).

3.2 Magnetic Resonance Imaging Assessments

Although only formally validated as a surrogatemarker for relapse rate (and only in trials investi-gating glatiramer acetate or agents with a similarmechanism of action),[74] MRI has proved to be auseful and widely accepted measure for assessingprogression of RRMS. Subclinical disease activityin RRMS, as assessed by the number and volumeof CNS lesions on MRI scans, is detected five toten times more frequently than a change in disabil-ity level.[75] MRI results are also more reproduci-ble, can be measured on a continuous scale (ratherthan an ordinal scale of measurement such as theEDSS) and more closely reflect the pathologicalaspects of the disease than clinical endpoints (e.g.relapse rate).[74,76]

Various MRI assessments were the primary andsecondary endpoints in the most recent clinicaltrial (the European/Canadian study) of glatirameracetate[31] in which 239 patients, in 29 centres,were randomised to receive daily subcutaneous in-jections of glatiramer acetate 20mg or placebo (ta-ble II). As previous trial results had shown the pos-itive effect of glatiramer acetate on the course ofRRMS,[24,65] the placebo-controlled phase of thisclinical trial was limited to 9 months[77] and followedby a 9-month noncomparative, active-treatmentextension (see table II).

Patients underwent pretreatment and monthlyMRI scans, which were analysed for:[31]

• gadolinium-enhancing T1 lesions (areas ofacute inflammation representing disruption ofthe blood-brain barrier)



• T2 lesions (lesion load or burden of disease)• hypointense T1 ‘black holes’ (areas of demye-

lination and axonal loss representing irre-versible damage).Glatiramer acetate showed beneficial effects on

all of the MRI outcomes, with significantly greaterimprovements than placebo on all but one outcomemeasure (table IV). Reductions in number and vol-ume of lesions favoured glatiramer acetate, andtreatment effects on the number of new gadolinium-enhancing lesions and new T2 lesions paralleledthat of the total number of enhancing lesions at theend of the trial (33, 30 and 29% greater reductionswith glatiramer acetate, all p < 0.003 comparedwith placebo). The declining rate of accumulationof enhancing lesions and new T2 lesions ran sim-ilar time courses. The effect was observed after 2months and became statistically significant (p <

0.01) at approximately 6 months.[31] The onset ofthe effect of glatiramer acetate on enhancing andnew lesions is consistent with the drug’s proposedmechanism of action of inducing a suppressorT-cell population, a process that is detected earlybut is thought to take some months for full ef-fect.[28,31,32,54,78]

Glatiramer acetate significantly reduced the ac-cumulated and total burden of disease; the totalnumber of new T2 lesions was 30% less in glatira-mer acetate recipients than in placebo recipients (p =0.01), and the mean change from baseline in totalT2 lesion volume was 34.5% less in patients re-ceiving glatiramer acetate than in those receivingplacebo (p < 0.006).[31]

Glatiramer acetate tended to limit the extent ofirreversible neurodegenerative damage, as assessedby the change in hypointense T1 lesion (‘black

Table III. Efficacy of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). Effect of treatment with subcutaneous GA 20mgdaily on relapsea-related endpoints and disease progression

Study Treatment(duration)

Mean relapse rate Proportion ofrelapse-freepatients (%)

EDSSb Patients withsustained diseaseprogression (%)c

baselined mean relapserate at endpoint

baseline mean change atendpointe

Bornstein et al.[24] GA (24mo) 3.8 0.6 56*f 2.9 –0.5 (EDSS 0–2)g 20**

+0.3 (EDSS 3–6)g

PL (24mo) 3.9 2.7 26f 3.1 +1.2 (EDSS 0–2)g 50h

+0.4 (EDSS 3–6)g

Comi et al.[31] GA (9mo) 2.8 0.51* 55.5 2.3 +0.02 NR

PL (9mo) 2.5 0.76 49.2 2.4 +0.05 NR

Johnson et al.[65,67]i GA (24mo) 2.9 1.19**f,j,k 33.6l 2.8 –0.05* 21.6m

PL (24mo) 2.9 1.68f 27 2.4 +0.21 24.6

a See table II for definition.

b Kurtzke EDSS, an ordinal scale reflecting disability status, ranging from 0 (a normal neurological examination) to 10 (death due to MS)in 0.5-point increments.

c Increase of ≥1 point on the EDSS that persisted for at least 3mo.

d For 2y pretreatment period.

e Negative value indicates improvement; positive value indicates deterioration.

f Primary endpoint.

g Patients were stratified according to baseline EDSS score.

h Placebo patients assessed at 18mo.

i 24mo US trial with extension to 35mo.

j Covariate adjusted mean.

k At 35mo, mean relapse rate was 1.34 with GA vs 1.98 with PL (p = 0.002).

l At 35mo, proportion of relapse-free patients was 33.6% with GA vs 24.6% with PL (p = 0.035).

m At 35mo, 41.6% of GA patients had worsened by ≥1.5 points on the EDSS compared with 21.6% of PL patients (p = 0.001) [Kaplan-Me-ier analysis].

EDSS = Kurtzke Expanded Disability Status Scale; NR = not reported; PL = placebo; * p ≤ 0.05, ** p ≤ 0.01 vs PL.

838 Simpson et al.


hole’) volume (see table IV), but this 9-month active-treatment study period[31] was possibly too short todemonstrate a significant reduction compared withplacebo. Further analysis[79] of the MRI scans per-formed in this European/Canadian study[31] hasshown that after 8 months, the proportion of newT2 lesions evolving into permanent ‘black holes’in patients receiving glatiramer acetate was 50%less than that shown in patients receiving placebo(15.6 vs 31.4%, p = 0.002). The effect became sig-nificant at 7 months (18.9 vs 26.3%, p = 0.04).[79]

During the 9-month extension to this trial,[70]

patients who had initially received placebo andthen switched to active treatment showed reduc-tions in the total number (12.9 to 5.8 [55%]) andvolume (1.79 to 0.84ml [53%]) of enhancing le-sions. For patients who received only glatirameracetate throughout the main study and its exten-sion, the reductions in number and volume of en-hancing lesions continued in a downward trend(6.9 to 5.3 [23%] and 0.98 to 0.65ml [33.6%]). Thelesion load (total T2 lesions) remained stable inboth groups of patients.[31,70]

The reduction in relapse rate (a tertiary end-point) observed in glatiramer acetate-treated pa-tients in this trial[31] (see section 3.1 and table III)parallels the positive effects seen on MRI meas-ures of disease activity and severity.

MS patients show a reduction in brain paren-chymal tissue with progression of the disease, al-though the rate of brain atrophy in patients with

RRMS has yet to be fully elucidated. The annualreduction in brain volume, measured in a cohort of27 patients from one centre involved in the 2-yearUS trial,[80] was significantly less in glatiramer ac-etate recipients than in placebo recipients (0.6 vs1.8%, p = 0.0078), although there was no differ-ence in T2 lesion number and volume between thetwo groups. MRI scans of 227 of the original 239patients in the 18-month European/Canadian trial[81]

(including extension) demonstrated no differencesin brain volume changes between glatiramer acetate-and placebo-treated patients in the first 9 monthsof the study and no significant change over thewhole study period. However, in patients who hadreceived only glatiramer acetate, there was a 50%greater reduction in the rate of brain volume lossduring the second 9 months compared with the firstphase, whereas patients randomised to placebo be-fore active treatment was initiated had similar de-creases in brain volume in each phase.

3.3 Effects on Disability

The extent of disability experienced by patientswith RRMS can be measured using the EDSS, anordinal scale of MS severity ranging from 0–10 (in0.5-point increments) describing the extent of neu-rological and functional disability (0 represents anormal neurological examination, 1 a neurologicalabnormality with no functional consequence and10 death due to MS).[75] The scale uses functional

Table IV. Effects of glatiramer acetate (GA) on disease activity (as assessed by magnetic resonance imaging scan analysis) inrelapsing-remitting multiple sclerosis.[31] Effects of subcutaneous GA 20mg daily for 9 months

GA(n = 119)

PL(n = 120)

Relative difference(%) in favour of GA

Total Gd-enhancing lesionsa 25.96 36.80 29*

Total new Gd-enhancing lesionsb 17.4 26 33*

Change from baseline in Gd-enhancing lesion volume (%) –33.6 –18.4 82.6*

Total new T2 lesionsb 9.4 13.5 30*

Mean change from baseline in T2 lesion volume (%) 15 22.9 34.5*

Median change from baseline in T2 lesion volume (%) 12.3 20.6 40*

Mean change from baseline in hypointense T1 lesion volume (%) 23.5 32.5 27.7

a Primary endpoint.

b Number at baseline determined by comparing pre-enrolment scan for study-entry assessment with baseline scan that was not morethan 28d later.

Gd = gadolinium; PL = placebo; * p ≤ 0.01.



systems (FS) scores (for pyramidal, cerebellar,brainstem, visual, sensory, bowel, bladder and ce-rebral functions) to differentiate the extent of im-pairment in ambulatory patients (lower EDSSscores), walk distance and assistance requirementsfor walking in patients who are not fully ambula-tory (scores of 5–7) and residual functions (armmovement, eating and communication) in patientsrestricted to a wheelchair or bed.[75,82] Limitationsof this scale include its ordinal nature and its lackof sensitivity to disability status changes. Beingspecific for FS in the lower grades and controlledmainly by the extent of ambulation in the highergrades, a 1-point change at the lower end of thescale may represent a smaller change than at theupper end of the scale.

The issue of whether any improvement orslowed deterioration in disability during a clinicaltrial, as measured on the EDSS, represents a drug-related effect or is merely part of the natural cycleof symptom fluctuations or the progressive disabil-ity, characteristic of RRMS, is partly overcome bymonitoring sustained progression[83] (a deteriora-tion of 1 point on the EDSS that persists for 3months, i.e. present at two clinic visits). It has,however, been reported that a substantial propor-tion of patients can recover even after long periodsof worsening disability[84] and, moreover, that recov-ery from a relapse can take more than 6 months.[85]

Other outcome measures (e.g. area under theEDSS-time curve and categorical classification ofdisease trends) have been considered for compar-ative trials of RRMS,[84] in an attempt to explaindiscrepancies in results of traditional clinical out-come measures (significant reduction of relapserate but inconsistent effects on disability out-comes) observed in recent trials investigating dif-ferent immunomodulatory therapies.[84]

Disability status and progression to disabilitywere secondary endpoints in the two long-termtrials[24,65] and a tertiary endpoint in the European/Canadian study.[31] Modest changes in neurologi-cal and functional disability (as assessed by themean change from baseline in the EDSS score) wereobserved with both glatiramer acetate and placebo

(table III). In the longer-term trials (the pilotstudy[24] and the pivotal US trial[65]) the disabilitystatus of glatiramer acetate recipients was onlyslightly improved compared with the status of pla-cebo recipients, but was nevertheless statisticallysignificant (p = 0.023) in the larger study[65] (tableIII). No significant improvements in disability sta-tus were expected in the European/Canadian studybecause of its short duration.[31]

In the US trial, patients treated with glatirameracetate were more likely to experience improveddisability (by ≥1 point on the EDSS) than thosereceiving placebo (24.8 vs 15.2%), and placebo re-cipients were more likely than glatiramer acetate-treated patients to worsen by ≥1 point on the scale(28.8 vs 20.8%) [p = 0.037 for categorical-repeatedmeasures analysis and p = 0.024 for baseline to24-month analysis].[65]

Fewer patients receiving glatiramer acetate ex-perienced sustained disease progression than thosereceiving placebo in the two long-term trials,[24,65]

although the result was significant (p < 0.005) inthe smaller trial only[24] (see table III). However,during the double-blind extension phase of the UStrial (to 35 months),[67] using the Kaplan-Meiersurvival analysis to determine time to disease pro-gression of at least 1.5 points on the EDSS, morepatients receiving placebo worsened (41.6%) anddid so more rapidly (p = 0.004) than patients re-ceiving glatiramer acetate (21.6%, p = 0.001).[67]

Although the 142 patients remaining in the active-treatment extension phase of the US study (whichhas now been running for 8 years) constitute a dif-ferent population from the original trial partici-pants as a result of patient withdrawals,[69] theyshow a slower progression to disability when com-pared with untreated patients with RRMS of thesame duration (natural history data). The mean ofthe EDSS scores of study participants, who havean average of 15 years’ disease duration (7 yearsprior to study and 8 years study participation), isnow 3.1, whereas a mean score of >4 would beexpected for an untreated population with the sameduration of disease, with >50% reaching an EDSSscore of 6.[69] The annual change in EDSS scores,

840 Simpson et al.


in years 2, 3 and 4, for patients who receivedglatiramer acetate throughout the study was statis-tically different from that of patients who had orig-inally been randomised to placebo for the first 3years of the study. Evidence of the treatment effectof glatiramer acetate on the glatiramer acetate/placebo group might explain the observation that,by year 5, the difference was no longer apparent.[69]

3.4 Other Effects

The effect of glatiramer acetate and the interferons-β on fatigue, a common symptom of RRMS, wasassessed in a nonblind cohort study of patients withMS who had completed 6 months of therapy (136patients received glatiramer acetate and 86 re-ceived one of the interferons-β).[86,87] At 6 months,fatigue improvement, as measured on the fatigueimpact scale (which has three subscales: physical,cognitive and social) was more than twice as likelyto be experienced by patients in the glatiramer ac-etate group than those in the interferon-β group (25vs 12%, p = 0.02). Although baseline characteristicsdiffered between treatment groups (glatiramer ace-tate patients were younger, had lower EDSS scoresand were more likely to have the relapsing-remittingtype of MS than patients receiving interferon-β),stratified analysis did not suggest any confoundingfactors.[86,87] The proportion of patients in eachtreatment group who received symptomatic ther-apy during the study to reduce fatigue was not de-termined.[87] Fatigue is a common adverse event oftreatment with interferons-β; hence fatigue wasevaluated only after 6 months to avoid the con-founding effect caused by the influenza-like symp-toms associated with early interferon-β therapy.[87]

4. Pharmacoeconomics

RRMS affects young adults during their mostproductive years, impacting their functional statusrather than mortality. Although indirect costs (lossof earnings and costly lifelong supportive care),rather than direct costs, represent the greater pro-portion of overall healthcare costs associated withthe management of RRMS, the introduction ofexpensive disease-modifying treatments does, how-

ever, contribute to the economic burden of the dis-ease.

Two studies conducted in 2000[88] and 2001[89]

investigating the cost effectiveness of glatirameracetate in the treatment of RRMS were modelledon quite different scenarios involving different as-sumptions and data sources, which makes themdifficult to compare.

According to the one fully published cost-utilityanalysis,[88] glatiramer acetate is cost effectivecompared with best supportive care for RRMSwhen assessed over several years (for which actualtrial data were available). The perspective of thismodel was that of the UK National Health Service(NHS), and all costs were in pounds sterling (year2000 costs).

The major clinical outcomes used in the modelwere patient-assessed EDSS scores and relapserates from the main study and extension periods ofthe large US placebo-controlled trial by Johnson etal. (see section 3).[65,67-69] Outcomes for glatirameracetate were available for up to 6 (published) and 8(unpublished at the time but now available as anabstract) years. Actual trial data for placebo wereonly available for up to 35 months (at which pointthe trial entered a nonblind phase and placebo re-cipients could switch to active treatment); clinicaloutcomes beyond this point were therefore basedon published natural history data for RRMS.

The main cost inputs for the model were as fol-lows:[88]

• acquisition cost of glatiramer acetate in the UK(£6 650 per patient, per annum)

• direct medical and caregiver costs (at variousEDSS levels) for patients in remission (basedon data from the literature)

• direct medical costs per relapse (caregiver costsfor relapse were not available as a separateitem).The assignment of utility values for each EDSS

level and a utility loss during relapse (duration as-sumed to be 2 months for base-case analysis) wasbased on the published literature.



Base-case incremental cost-utility values forglatiramer acetate compared with placebo aresummarised in table V.

Cost-utility ratios improved with a longer dura-tion of treatment for all three cost variables: costper relapse or disability unit avoided and cost perquality-adjusted life-year (QALY) gained (tableV). Costs per QALY gained were well within thosecited by the authors as being considered favourablein the UK (i.e. below £30 000). Key results fromsensitivity analyses were that cost per QALY gainedat 8 years improved by 7% to £20 929 if differentialdiscounting (as currently recommended in UKguidelines) was applied, but that cost per QALYgained was nearly 3-fold higher (at £64 636) if theduration of relapse was reduced from 2 months to1 month.[88]

The second study was conducted by the Na-tional Institute of Clinical Excellence (NICE) toassess the cost effectiveness of both glatiramer ac-etate and the interferons-β.[89] Their model assumedthat there would be continuous benefit on treat-ment and that, after cessation of treatment, benefitsaccrued would be maintained but that disease pro-gression would return to the natural history ratefrom that point.

Using longer term modelling to 20 years, theanalysis concluded that neither glatiramer acetatenor the interferons-β were cost effective in thetreatment of RRMS. As with the previous study,[88]

the cost per QALY gained, according to the NICEevaluation,[89] decreased as the time horizonslengthened. The mean cost per QALY gained (ex-pressed as a range covering all the agents under

discusssion) for 5, 10 and 20 years was estimatedto be £380 000–780 000, £190 000–425 000 and£40 000–90 000, respectively. Further data onquality of life (from the MS Research Trust) bringsthe cost per QALY gained (at 20 years) to between£35 000 and £104 000, although this is still morethan the value considered favourable in the UK.[88]

Two of the assumptions in the model used in theNICE study (continued benefits on treatment andthe return of the natural history rate of progressionafter treatment cessation) are highlighted as beingincreasingly unreliable with extrapolation. More-over, there is no evidence that progression of thedisease is halted in the long term, which suggeststhat the benefits of treatment might not be main-tained, which in turn increases the cost per QALYgained after 20 years (to between £120 000 and£339 000).[89]

Each analysis has inherent advantages and dis-advantages. A shorter term analysis[88] avoids therisks of extrapolation errors, as it can rely on hardclinical data, but it may lose the potential for longerterm gains. A longer term analysis[89] increasesthe risk of extrapolation errors but may capturelong-term benefits. Given the complexities of cost-effectiveness assessments in this area and the lim-ited amount of information available at present, itis impossible to draw a single definitive conclu-sion, and further data and evaluations in this fieldwould be useful in clarifying the overall cost effec-tiveness of glatiramer acetate.

5. Tolerability

Data on the tolerability profile of glatiramer ac-etate are available from three placebo-controlledclinical trials in a total of 540 patients withRRMS[24,31,65] (see section 3) and a review ofpooled data from studies (approximately 25% ofwhich were controlled) in 857 patients with MS.[23,90]

Most of the patients (91%) referred to in the pooleddata had RRMS, approximately 8.5% were classi-fied as having chronic-progressive MS, and thetype of disease was not stated in 0.5% of patients.No statistical information for adverse events was

Table V. Cost utility of glatiramer acetate in the treatment ofrelapsing-remitting multiple sclerosis.[88] Incremental cost-utilityvalues for glatiramer acetate compared with placebo are based ona model using clinical outcomes data from patients in the clinicaltrial by Johnson et al.[65] and cost data from the literature. Costs arein pounds sterling and are year 2000 values

6 years 8 yearsa

Cost per relapse avoided 13 626 11 000

Cost per disability unit avoided 11 935 8 862

Cost per quality-adjusted life-year gained 28 515 22 586

a Data unpublished at the time but have since become availableas an abstract.

842 Simpson et al.


reported in these trials or reviews, except wherestated.

Subcutaneously administered glatiramer ace-tate 20mg was generally well tolerated in clinicaltrials. The most commonly reported treatment-related adverse events were localised injection-sitereactions and transient post-injection systemic re-actions, both of which were generally mild and selflimited.[23,24,31,65] The incidence of injection-sitereaction (manifesting mainly as pain and erythema)was 64 and 73% with glatiramer acetate versus 37and 38% with placebo (see section 5.1), and post-injection systemic reaction occurred with an inci-dence of 10–38% with glatiramer acetate versus<1–13% with placebo (see section 5.2). Seriousadverse events considered to be treatment-relatedoccurred in <2% of patients.[31,65] No cases of ana-phylaxis following the use of glatiramer acetateinjection were documented in clinical trials, al-though three nonfatal cases of allergic reactionhave since been recorded.[32,91]

An influenza-like syndrome, commonly associ-ated with interferon-β treatment,[92-95] occurredwith no greater incidence in patients treated withglatiramer acetate than in placebo recipients (9 and10%, respectively, during the first 6 months, andthe incidence decreased in both groups over the24-month study period).[90]

Withdrawals from treatment because of adverseevents (6% in the US pivotal trial[65] as reviewedby Korczyn and Nisipeanu[90] and 8%[23] in anotherreview) were primarily attributed to post-injectionsystemic reactions[65,90] and injection-site reac-tions.[90]

5.1 Injection-Site Reactions

Injection-site reactions were localised, showedno signs of necrosis and required no medical inter-vention. Although the fully published reports of thetwo large controlled trials[31,65] did not mention thatthis reaction contributed to patient withdrawals,prescribing information[23] reports a 6.5% discon-tinuation rate associated with this adverse effect.The most common manifestations of injection-sitereactions were pain and erythema. According to

pooled data[23] and results of the US pivotal trial,[65]

the incidence of pain was 73[23] and 64%[65] withglatiramer acetate versus 38[23] and 37%[65] withplacebo, and the incidence of erythema was 66[23]

and 57%[65] with glatiramer acetate versus 19[23]

and 13%[65] with placebo. Mild erythema and in-duration[65] or unstated symptoms[31] occurred atleast once in 90[65] and 70.6%[31] of patients receiv-ing glatiramer acetate versus 59[65] and 28.3%[31]

of those receiving placebo. The inclusion of man-nitol in the formulation used in the US pivotaltrial[65] was cited as a possible reason for the higherincidence of localised sensitivity in placebo recip-ients in this trial compared with that in similarstudies. Injection-site reactions were significantlymore common in glatiramer acetate than in pla-cebo recipients in the smaller controlled study.[24]

The incidence of each symptom (soreness, redness,itching and swelling) was 64–92% in glatirameracetate recipients and 17–48% in the placebogroup (statistically significant differences betweengroups for soreness and swelling [p < 0.001] anditching [p < 0.01]).

There have been seven isolated reports oflipoatrophy at the injection site after prolongedsubcutaneous administration of glatiramer acetate(2–18 years).[96,97]

5.2 Post-Injection Systemic Reactions

Post-injection systemic reactions were unpre-dictable, transient, generally self limiting and in-volved one[31] or more[24,65] of the following symp-toms: facial flushing, chest tightness, dyspnoea,palpitations, tachycardia, anxiety and sweating.[23,90]

Symptoms generally became evident some monthsafter treatment initiation,[23] occurred within min-utes of an injection and lasted for 30 seconds to 30minutes.[23,24,31,65,90] The sporadic nature of thesereactions suggests that they are not immune re-lated.[90]

This transient systemic reaction (when definedas a combination of symptoms) was experienced by10[90] and 15.2%[65] of patients receiving glatira-mer acetate compared with <1[90] and 3.2%[65] ofthose receiving placebo. When the reaction was



defined as the occurrence of just one of the symp-toms described above, the incidence was 37.8%[31]

in patients receiving the drug and 13.3%[31] inthose receiving placebo.

Withdrawal rates attributable to this post-injectionsystemic reaction were <3[90] and 3.5%[65] forglatiramer acetate recipients (compared with 0.8%for the placebo group in the comparative trial[65]).

5.3 Other Effects

Transient chest pain of unknown origin, whichwas sometimes associated with systemic post-injection reactions, was experienced by 26% of pa-tients receiving glatiramer acetate compared with10% of those receiving placebo.[23] These episodesappeared to be of no important clinical conse-quence as, although ECG monitoring was not per-formed at the time of the event, there was no evi-dence of abnormal cardiac function on subsequentroutine ECGs.[23]

The true incidence of lymphadenopathy (indi-cating immune activation) in glatiramer acetate re-cipients is not clear. Postmarketing surveillance re-ports suggest that 55 of the 30 000 (<0.2%) adverseevents reported with glatiramer acetate were lym-phadenopathy[98] (patient incidence not reported).A review of pooled data from trials[23] states thatthe proportions of glatiramer acetate and placeborecipients with lymphadenopathy were 12 and 6%and, in another study, 9 of 27 patients treated withglatiramer acetate for RRMS[98] had generalisedtender swelling of lymph nodes that lasted through-out the treatment period but did not affect the effi-cacy of glatiramer acetate and did not warrant dis-continuation of treatment.

No changes in routine laboratory parameters orvital signs were observed during the controlled tri-als,[24,31,65] and there were no reports of withdraw-als due to laboratory abnormalities.[23,90]

Previous treatment with interferon-β-1b (dosenot stated), compared with no prior treatment, didnot adversely affect the tolerability of subcutane-ous glatiramer acetate 20mg daily, administered for3.5 years, in 777 patients with RRMS.[99]

6. Dosage and Administration

Glatiramer acetate is indicated for the long-termmanagement of RRMS and is currently approvedin numerous countries worldwide including theUSA, Canada, the UK and many other Europeancountries.

The international prescribing information forglatiramer acetate[23] recommends a dosage of 20mgonce daily, administered by subcutaneous injec-tion, with no recommendations for any dosage ad-justments in special patient groups. It is availableas single-use vials for reconstitution,[23] althougha more convenient prefilled syringe has recentlybeen introduced in North America.[100,101] Patientsare advised to avoid using the same injection areamore than once a week.[23] Localised injection-sitereactions and isolated cases of lipoatrophy havebeen reported (see section 5).

Data on the use of glatiramer acetate in pregnantand nursing women, the elderly, patients youngerthan 18 years and those with impaired renal func-tion are limited.[23] Treatment during pregnancyshould be initiated only if absolutely necessary,and treatment of nursing mothers should be under-taken with caution. Contraindications include in-travenous administration and hypersensitivity toglatiramer acetate or mannitol (included in the in-jection formulation). Although there were no re-ports of anaphylaxis from premarketing clinicaltrials, three nonfatal cases of allergic reaction havesince been documented (see section 5).[32,91]

There appeared to be no significant interactionsbetween glatiramer acetate and other drugs com-monly prescribed for RRMS, including corticoste-roids administered for up to 28 days.[23]

7. Place of Glatiramer Acetate in theManagement of Relapsing-RemittingMultiple Sclerosis

The chronic and debilitating nature of RRMSand its appearance during a young adult’s mostproductive years impacts heavily on patients, theirfamilies and caregivers, and medical resources, re-

844 Simpson et al.


sulting in a significant physical, emotional andeconomic burden to all involved.[89]

Only a minority of patients follow the benigncourse of the disease.[14,89] The majority face a poorprognosis of progressively deteriorating disability[14]

involving physical and often cognitive impair-ment.[1] There is no cure for RRMS and long-termmanagement of the disease requires a comprehen-sive program of rehabilitation, physical therapyand drug treatment.

The pharmacotherapy of RRMS includes treat-ment of relapses, symptom control and, more re-cently, disease-modifying treatment focusing onthe autoimmune reaction. A short course of intra-venous or oral corticosteroids reduces the severityof, and accelerates the recovery from, a relapse,[102]

and a variety of other agents control symptomscommon in RRMS, such as spasticity, impairedbladder function, fatigue, tremor and pain.

Immunomodulatory therapies alter the courseof the disease on the immunological level, whichtranslates on a clinical level to a reduced incidenceof relapses and slower progression to disability.[92]

A range of immunosuppressive agents have proveddisappointing from an efficacy (e.g. azathioprine)or toxicity (e.g. mitoxantrone) perspective[1,102]

and are considered second-line therapy in selectedpatients experiencing efficacy or tolerability prob-lems with other treatments.[14,103] The cost and riskassociated with intravenous immunoglobulin (notapproved in the USA)[8] and inadequate evidenceof its therapeutic efficacy[1,14] have limited thewidespread use of this agent in RRMS. Newer im-munomodulatory agents, primarily glatiramer ac-etate and two forms of interferon-β (interferon-β-1aand interferon-β-1b), have subsequently been in-vestigated and have been approved for clinical usewithin the last decade.[1]

The introduction of various subtypes of interferon-β in the early 1990s proved a major advance in thetreatment of patients with RRMS and, although themechanism of action of these agents in treating MSis not yet fully understood, their immunomodula-tory actions are thought to include the antagonismof the pro-inflammatory cytokine interferon-γ,

reduction in T-cell activation and inhibition ofblood-brain barrier leakage.[28,92] Large randomised,controlled trials have shown the clinical benefitsof the individual interferons (intramuscular andsubcutaneous interferon-β-1a and subcutaneousinterferon-β-1b)[93-95] over a 2-year period and havebeen extensively reviewed.[1,9,102,104,105] In sepa-rate trials of the individual interferons-β, relapserates for recipients of interferon-β-1b and subcuta-neous interferon-β-1a were reduced by approxi-mately one-third, and for intramuscular interferon-β-1a the reduction was 18%.[102] Progression todisability was variably affected by the different in-terferons; there was some significant slowing ofprogression to disability with intramuscular[93]

and subcutaneous interferon-β-1a[94] (as a primaryand secondary endpoint, respectively) but not withinterferon-β-1b.[95] All the interferons-β showedreduction of disease activity and severity as assessedby various MRI outcome measures.[9,102] However,influenza-like symptoms (headache, fever, chillsand myalgia) lasting up to 48 hours after injectionswere troublesome and reported in more than halfof all patients treated with interferon-β.[17,102] Inaddition, neutralising antibodies developed in 38,22 and ≤5% of patients receiving interferon-β-1b,intramuscular interferon-β-1a and subcutaneousinterferon-β-1a, respectively;[102] these neutralis-ing antibodies are cross-reactive between the treat-ments and can reduce the clinical efficacy of theseagents.[15,92] Laboratory testing of complete bloodcell counts and liver function are essential whenmonitoring treatment with interferon-β. Depend-ing on the type of interferon-β, administration issubcutaneous or intramuscular, once weekly, threetimes weekly or on alternate days.[102,105] Localinjection-site reactions, although minimal with theintramuscular form of interferon-β-1a, can be se-vere with subcutaneously administered interferon-β; cutaneous necrosis occurred in approximately5% of patients.[106]

The clinical development and approval of glatira-mer acetate has provided another immunomodula-tory agent (with a different mechanism of action tothat of interferon-β) for the treatment of RRMS



(see section 2). Glatiramer acetate has an antigen-specific mode of action that includes the inductionof anti-inflammatory T cells and inhibition of pro-inflammatory, myelin-reactive T cells implicatedin the autoimmune inflammatory reaction associ-ated with RRMS (section 2.2). Neuroprotection,recently demonstrated in animal and human stud-ies, may be another mechanism of action for thebeneficial effect of glatiramer acetate in the treat-ment of RRMS (see section 2.2.3).

In placebo-controlled trials, glatiramer acetatehas shown efficacy in RRMS. The reduction in re-lapse rate appears to be broadly similar (on anintertrial basis) to the interferons-β, and glatirameracetate appears to have a more favourable toler-ability profile, although direct comparisons in con-trolled trials have not been conducted. For patientsreceiving glatiramer acetate, the mean relapse rate(as primary and tertiary endpoints) in the twolarger trials was approximately one-third less thanfor placebo recipients (see section 3.1). There wasevidence of decreased disease activity and burdenof disease in patients with RRMS enrolled in theEuropean/Canadian study, in which various MRImeasures were the primary and secondary end-points (see section 3.2). There is also evidence thatglatiramer acetate may reduce the accumulation ofpermanent CNS damage; significantly fewer newlesions in patients receiving the drug evolved intopermanent ‘black holes’ than in placebo recipients(see section 3.2). Patients treated with glatirameracetate were also more likely to experience im-proved disability, whereas placebo recipients weremore likely to experience worsening disability (seesection 3.3).

Glatiramer acetate is generally well tolerated[32,92]

(see section 5). It is not associated with the adverseevents (e.g. influenza-like syndrome) reported inpatients using interferon-β and, unlike interferon-β antibodies, the antibodies that form in responseto glatiramer acetate treatment are non-neutralisingand do not appear to affect its clinical efficacy (seesection 2). Glatiramer acetate treatment is not as-sociated with the depression[90] that emerged in thepivotal trial of interferon-β-1b; depression is not

considered a risk factor or exclusion criterion whenconsidering a patient for treatment with glatirameracetate. Although subsequent trials of the interferons-β have not demonstrated a significantly higher rateof depression with the drug compared with pla-cebo, official prescribing information advises cau-tion in this respect when initiating treatment withany of the interferons-β.[26,106] Glatiramer acetatetreatment does not require any laboratory testsother than those normally required for monitoringpatients with MS. Localised injection-site reactionsin glatiramer acetate-treated patients, although acommon adverse event (see section 5.1), appear tobe milder than those in patients receiving interferon-β and are not associated with necrosis. Direct com-parisons of glatiramer acetate and interferon-βhave, however, not been conducted. Glatiramer ac-etate is associated with systemic post-injection re-actions, although they are generally short lived andself limiting (see section 5.2). Glatiramer acetatetreatment for RRMS requires a daily subcutaneousinjection.

The high acquisition costs for both glatirameracetate and the interferons-β contribute less to theeconomic burden of RRMS than indirect costs (dis-ability payments, homecare costs and loss of pro-ductivity and income), which account for a greaterproportion of the overall cost of disease.[107] Thedifficulty in designing a valid economic model ofcost effectiveness for treatment of a long-term, dis-abling condition such as MS presents a significantchallenge. Studies based on different models aredifficult to compare (see section 4). In one study,[88]

glatiramer acetate was cost effective in the treat-ment of RRMS, from the UK NHS perspective,compared with best supportive care alone, usingactual clinical trial data (albeit from trial extensionperiods of up to 6 and 8 years). However, a sub-sequent analysis conducted by NICE[89] investigat-ing the cost effectiveness of glatiramer acetate andthe interferons-β (which relied upon considerableextrapolation and numerous assumptions for their20-year assessment) found neither to be cost effec-tive (see section 4). Further pharmacoeconomic re-

846 Simpson et al.


search would be useful, especially with respect tolong-term treatment of RRMS.

Glatiramer acetate and the interferons-β havenot been compared for the treatment of RRMS inwell controlled clinical trials.[8,17] A nonblindstudy,[72] comparing glatiramer acetate, the differ-ent interferons-β and no treatment, has suggestedthat glatiramer acetate and interferon-β-1b mightbe more optimal choices for RRMS treatment com-pared with interferon-β-1a based on their respec-tive relapse-rate reductions (see section 3.1).[72] Inthe absence of well designed and more conclusivestudies, the initial choice of treatment should bebased on individual patient considerations[92,103]

including expected adverse events associated withthe therapeutic agent and practical issues regard-ing drug administration. Head-to-head controlledtrials comparing glatiramer acetate and the differ-ent forms of interferon-β would prove useful inevaluating the relative efficacies of these first-linetreatments.

Two recent disease management consensusstatements[103,108] recommend glatiramer acetateor an interferon-β as first-line treatment for pa-tients with RRMS who have evidence of active dis-ease (by history, repeated clinical relapses or dem-onstration of active CNS lesions on MRI scans).[103]

Treatment should be initiated as soon as possiblein newly diagnosed patients[15,85,103,104,108,109] asearly disease benefits may improve long-termprognosis.[7,85,92,104] Treatment should also be con-tinued indefinitely unless efficacy or tolerabilityconcerns emerge,[103,108] in which case treatmentcan be switched according to the individual pa-tient’s response.[104,108] Although results of trialextensions should be interpreted cautiously be-cause of the potential for multiple biases, the fullypublished results of the nonblind extension phase(to 6 years) of the US trial[68] and the preliminaryresults for an 8-year period (available as an ab-stract)[69] suggest improved clinical benefits ofglatiramer acetate in patients who had receivedglatiramer acetate for the entire study period com-pared with those who had been randomised to pla-cebo for the first 3 years of the study (see section 3.1).

The heterogeneous nature, unpredictablecourse and long-term duration of RRMS make theefficacy of agents with therapeutic potential diffi-cult to assess without prohibitively large and long-term, controlled clinical trials.[110] The extent towhich short-term improvements in clinical fea-tures of RRMS (see section 3) affect the severityof this disease in the long term remains un-clear.[7,15,109] The US study of glatiramer acetatefor treatment of RRMS, including the main trialand extension phases, is the longest running studyof a treatment for RRMS, and there are data for 142participants (of the original 251 enrolled) for an8-year period.[69] This study is planned to run fora total of 12 years.

In conclusion, glatiramer acetate has shown effi-cacy in well controlled trials in patients with RRMS;it reduces relapse rate and decreases MRI-assesseddisease activity and burden. It is generally welltolerated and is not associated with the influenza-like symptoms and formation of neutralising anti-bodies seen with the interferons-β. Based onavailable data and current management guidelines,glatiramer acetate is a valuable first-line treatmentoption for patients with RRMS.

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Correspondence: Dene Simpson, Adis International Limited,41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auck-land 10, New Zealand.E-mail: [email protected]

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