`
`2002: 16(12): 825850
`CNS D
`ADIS DRUG EVALUATION I172770;:173/502/[131270825/325113/0
`©Adis International Limited. All rights reserved.
`
`Glatiramer Acetate
`
`A Review of its Use in Relapsing-Remitting Multiple Sclerosis
`
`Dene Simpson, Stuart Noble and Caroline Perry
`
`Adis 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 of
`Neurochemistry, University of London, London, UK; K. P. Johnson, Department of Neurology, University
`of Maryland, Baltimore, Maryland, USA; D. Teitelbaum, Department of Immunology, Weizmann Institute
`of Science, Rehovot, Israel; B. Weinstock-Guttman, Baird Center for Multiple Sclerosis, The State University
`of New York, University at Buffalo, Buffalo, New York, USA.
`
`DateSeleoti-on”
`.Sguree5'; Medical literature publishedin-any language .5i
`.
`.
`_
`supplemented by AdreEase (a proprietarydatabase of
`is International) Additinnal references were identified from thereference liet5 of
`published articles Bibliographical information including--'
`tributary: unpublisheddata, was. else requested from the.companydeveloping
`Search strategyMedlirtesearch termswere glatiramer acetate:or eepolymer—i or ‘00P.1. EMBASEsearch terms were gtatiramerI
`acetate or'fCOP 1-’.AdisBaee Search term-5 Were. glatiramer-acetate or copcttyrner t or‘COP 1’. Searches were last updated 16
`
`index termsglatiramer acetate relapstng—remitfing multiple. 555055;pharmacodynamics pharmacakinetics therapeuticuse
`
`Selection Studiesin patients-Withrelapsmgremitting multiple$555515 tnho' received giatiramer acetate. lnclusron of studie5W55.ba5ed
`mainly onthemethodssection”of the trials-When atlailable, large,WellCommitted triaI5 With appropriate sta'ti5tical-ritethpdniog tnér'5"".
`preferred. Relevant pharmacodynamic and pharmacokinetic data are also. ineiuded
`.
`..
`..
`.
`.
`
`Contents
`
`................................................... 826
`Summary
`I.
`Introduction .................................................. 829
`
`2. Pharmacological Properties ........................................ 830
`2.I Pathogenesis of Multiple Sclerosis .................................. 830
`2.2 Proposed Mechanisms of Action of Glatiramer Acetate ..................... 830
`2.2.I Induction of Glatiramer Acetate—Specific Suppressor T Cells ................ 83I
`
`2.2.2 Inhibition of My Iin—Roactiv
`T—CcII R sponscs ........................ 833
`2.2.3 Potential for Neuroprotection .................................. 833
`2.3 Immunological Effects ......................................... 834
`2.3.I Non—Neutralising Antibodies ................................... 834
`2.3.2 Selectivity ............................................. 834
`2.4 Pharmacokinetic Properties ...................................... 834
`3. Therapeutic Efficacy ............................................. 835
`3.I Effects on Relapse Rate ........................................ 835
`3.2 Magnetic Resonance Imaging Assessments ............................ 837
`3.3 Effects on Disability ........................................... 839
`3.4 Other Effects .............................................. 84i
`4. Pharmacoeconomics ............................................ 84I
`
`5. Tolerability ................................................... 842
`
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`826 Simpson et al.
`
`Injection—Site Reactions ........................................ 843
`5.l
`5.2 Post-Injection Systemic Reactions .................................. 843
`5.3 Other Effects .............................................. 844
`
`o. Dosage and Administration ......................................... 844
`7. Place of Glatiramer Acetate in the Management of Pelapsing-Remitting
`Multiple Sclerosis ............................................... 844
`
`
`Summary
`
`Abstract
`
`Glatiramer acetate is a synthetic copolymer composed of a random mixture of
`four amino acids that modifies the immune response that results in the CNS
`inflammation, demyelination and axonal loss characteristic of relapsing—remitting
`multiple sclerosis (RRMS).
`In three randomised, double—blind trials in patients with RRMS, subcutaneous
`glatiramer acetate 20 mg/day was significantly more effective than placebo for
`the primary outcome measure of each trial (mean relapse rate, proportion of
`relapse—free patients and number of gadolinium-enhancing lesions on magnetic
`resonance imaging [MRI] scans). The mean relapse rate was significantly reduced
`at endpoint (approximately one—third less) in the two larger trials (the US pivotal
`trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in
`patients receiving glatiramer acetate compared with those receiving placebo. The
`rate was 78% less for glatiramer acetate than placebo patients in the pilot trial
`that investigated a slightly different patient population. Glatiramer acetate sig—
`nificantly decreased disease activity and burden of disease, as assessed in the
`European/Canadian study using a range of MRI measures. Patients with RRMS
`treated with glatiramer acetate in the US trial were significantly more likely to
`experience improved disability (whereas placebo recipients were more likely to
`experience worsening disability) and their overall disability status was signifi—
`cantly improved compared with placebo recipients. Data from the active—treatment
`extension of the US trial suggest that glatiramer acetate has sustained clinical
`benefits up to 8 years.
`
`Glatiramer acetate was generally well tolerated; the mo st commonly reported
`treatment—related adverse events were localised inj ection—site reactions and tran—
`sient post—injection systemic reactions. Both reactions were generally mild and
`self 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 the
`influenza—like syndrome or neutralising antibodies that are reported in patients
`treated with interferon—[3 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 clinical
`trials in patients with RRMS; it reduces relapse rate and decreases MRI—assessed
`disease activity and burden. It is generally well tolerated and is not associated
`with the influenza—like symptoms and formation of neutralising antibodies seen
`with the interferons—B. Based on available data and current management guide-
`lines, glatiramer acetate is a valuable first—line treatment option for patients with
`RRMS.
`
`© Adis International Limited. All rights reserved.
`
`CNS Drugs 2002; lo (12)
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`Glatiramer Acetate in Relapsing—Remitting MS 827
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`
`
`Pharmacological
`Properties
`
`Therapeutic Efficacy
`
`The proposed mechanism of action of glatiramer acetate in modulating the auto—
`immune response in relapsing—remitting multiple sclerosis (RRMS) consists of
`two 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 directly
`and 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), but
`with 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, not
`glatiramer acetate itself, that may migrate into the CNS and downregulate the
`inflammation that is triggered by the antigenic products of demyelination (myelin
`basic protein [MBP] and other myelin antigens). In a small study involving pa-
`tients with RRMS, this shift from Thl— to Th2—type T cells induced by glatiramer
`acetate 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 would
`otherwise be stimulated to proliferate and release inflammatory cytokines. Cur—
`rent hypotheses include glatiramer acetate acting as an altered peptide ligand and
`engaging various T—cell receptor (TCR)s, and glatiramer acetate engaging the
`TCR 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 of
`action accounting for the beneficial clinical effects of glatiramer acetate in RRMS.
`
`Antibodies stimulated by glatiramer acetate treatment are non—neutralising
`and 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, resulting
`in 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.
`
`Glatiramer acetate has shown efficacy in treating patients with RRMS. In three
`randomised, double—blind trials (including a 2—year pilot trial and the larger US
`pivotal [2-year] and European/Canadian [9—month] studies) glatiramer acetate
`20mg once daily, administered subcutaneously in patients with RRMS, was sig-
`nificantly more effective than placebo for the respective primary endpoint of each
`trial (proportion of relapse—free patients, relapse rate and number of enhancing
`lesions 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 rate
`was the primary endpoint) and 33% lower in the European/Canadian study (where
`relapse 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 likely
`to be relapse free, than placebo recipients. Relapse—related results in this pilot
`trial 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 rate
`than those in subsequent studies.
`
`Glatiramer acetate decreased disease activity and burden of disease, as assessed
`by analysis of MRI scans, in patients enrolled in the European/Canadian study
`
`© Adis International Limited. All rights reserved.
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`CNS Drugs 2002; lo (12)
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`828 Simpson et Ill.
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`where certain MRI measures were the primary and secondary endpoints. For the
`primary 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 the
`placebo 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 a
`significant reduction in the volume of hypointense T1 lesions (representing areas
`of demyelination and axonal loss), further analysis of these scans has shown that,
`after 8 months, the proportion of new T2 lesions evolving into these hypointense
`T1 lesions (‘black holes’) in patients receiving glatiramer acetate was half that
`shown in patients receiving placebo.
`Progression to sustained disability, as measured by the Kurtzke Expanded
`Disability Status Scale (EDSS), was a secondary endpoint in the two long—term
`trials. Patients with RRMS treated with glatiramer acetate in the pivotal US trial
`were significantly more likely to experience improved disability, and placebo
`recipients were more likely to experience worsening disability. The overall dis-
`ability status was also significantly improved in this trial, although the change
`was 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 evaluate
`this outcome,
`
`Preliminary results data from the active-treatment extension of the US trial
`suggest that glatiramer acetate has sustained clinical benefits up to 8 years.
`
`Two studies conducted in 2000 and 2001 investigating the cost effectiveness of
`glatiramer acetate in the treatment of RRMS are difficult to compare as they used
`different models and data sources and led to different conclusions.
`
`According to a cost—utility analysis based on the clinical outcomes of a large
`placebo—controlled trial (the US pivotal trial) and its extensions, glatiramer ace—
`tate is cost effective compared with best supportive care alone for RRMS, from
`the perspective of the UK National Health Service. Cost-utility ratios improved
`with a longer duration of treatment for all three cost variables. At 8 years, cost
`per relapse avoided was £11 000, cost per disability unit avoided was £8 862 and
`cost per quality—adjusted life—year (QALY) gained was £22 586 (year 2000 costs).
`
`An analysis conducted by the National Institute of Clinical Excellence used
`longer term modelling and concluded that neither glatiramer acetate nor the
`interferons—B were cost effective in the treatment of RRMS. The best mean cost
`per QALY gained (i,e. at 20 years of treatment and including MS Research Trust
`data 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 value
`considered favourable in the UK (£30 000).
`
`
`
`Pharmacoeconomics
`
`Given the complexities of cost—effectiveness assessments in RRMS, a lifelong,
`disabling disease (for which clinical benefits of long-term treatment have only
`recently been published) and the limited amount of information available at pres—
`ent, it is impossible to draw a single definitive conclusion regarding the cost
`effectiveness of glatiramer acetate, and further data and evaluations in this field
`would be useful.
`
`Tolera bility
`
`Subcutaneously administered glatiramer acetate 20mg is generally well tolerated.
`The most commonly reported treatment—related adverse events (data from three
`placebo—controlled clinical trials and pooled results from two of these and other
`
`© Adis International Limited. All rights reserved.
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`Glatiramer Acetate in Relapsing—Remitting MS 829
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`trials) are localised injection—site reactions and transient post—injection systemic
`
`reactions The incidence of injection—site reactions (manifesting mainly as pain
`
`and erythema) was 64 and 73% with glatiramer acetate versus 37 and 38% with
`
`placebo (no p value reported).
`Post—injection systemic reactions occurred with an incidence of 10—38% with
`
`glatiramer acetate versus <l—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 an
`
`injection and lasting for 30 seconds to 30 minutes.
`
`Both reactions were generally mild and self limiting but accounted for the
`
`majority of withdrawals from treatment. Overall withdrawal rates ranged from
`
`6—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 value
`stated).
`
`Serious treatment—related events occurred in 32% 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 reported
`in patients treated with interferon—[3.
`
`Dosage and
`Administration
`
`Glatiramer acetate is indicated for the long—term management of RRMS and is
`
`currently approved in numerous countries worldwide including the US A, Canada,
`
`the UK and many other European countries. Glatiramer acetate is administered
`
`once daily by subcutaneous injection at a standard dose of 20mg. Data on the use
`
`of 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 glatiramer
`acetate or mannitol (which is included in the injection formulation).
`
`1. Introduction
`
`Multiple sclerosis (MS) is a Chronic, inflamma-
`
`tory disease ofthe CNS usually diagnosed in young
`adults (aged 20—40 years)[11 and affecting an esti-
`mated 2.5 million people worldwidepl It is an auto-
`immune condition,[3'5] possibly triggered in genet-
`
`ically susceptible individuals by one or more agents
`in the environment,[6s7l that results in unchecked
`
`inflammation causing demyelination of areas in
`
`the brain and spinal cord. Relapsing-remitting MS
`
`fatigue and dizzinesslmvl” These relapses are in-
`
`terspersed with periods of complete or partial re-
`
`mission. Although some patients continue on this
`course without becoming seriously disabled,[6’7512513]
`the majority (about 80%)[14] enter a phase within
`
`5—15 years in which they experience an increase in
`
`overall disability with or without relapses (second-
`ary progressive MS).[758513214] Within 10—15 years
`
`of a diagnosis of MS, 50% of patients are unable
`to walk unassistedlésm and after 25 years 50% are
`wheelchair bound.[15]
`
`(RRMS) is the most common type of MS; approx-
`
`Management of RRMS includes multidiscipli—
`
`imately 85% of patients present with this type of
`MS.[1=758] It manifests as self-limited attacks of neu-
`
`nary rehabilitation, pharmacotherapy for symp-
`
`toms and treatment of relapses and, more recently,
`
`rological dysfunction (relapses)[9] during which
`
`pharmacotherapy for modifying the underlying
`
`the patient experiences a sudden worsening of neu-
`
`rological symptoms such as numbness, tingling,
`
`disease in an attempt to prevent relapses and delay
`the progression to disability.[628212]
`
`muscle weakness, spasticity, visual disturbances,
`
`Limited success (from an efficacy, tolerability
`
`© Adis International Limited. All rights reserved.
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`830
`Simpson et Ill.
`
`or cost perspective) with general immunosuppres-
`
`acetate and includes studies in patients with all
`
`sant agents (azathioprine, mitoxantrone and oth-
`ers)[1s6516] and intravenous immunoglobulinsB’4’17]
`(not approved in the USA) and progress in under-
`
`types of MS. Animal data are provided where hu-
`man data are limited.
`
`standing the pathogenesis of RRMS have led to the
`
`2.l Pathogenesis of Multiple Sclerosis
`
`introduction and use of more specific immuno-
`
`modulatory agents, such as glatiramer acetate (pre-
`
`The pathogenesis of MS involves a cascade of
`
`viously copolymer-l) and two forms of recombi-
`nant interferon—[313516] for altering the natural
`course of the disease (see section 7).
`
`immunological events beginning with the activa-
`tion (by viral, environmental or other triggers)[6’7l
`of autoreactive myelin-reactive T cells in the pe-
`
`Glatiramer acetate is a synthetic copolymer
`
`riphery. The subsequent release of inflammatory
`
`composed of a random mixture of four amino acids
`
`that was initially developed to mimic myelin basic
`
`protein (MBP), one of the antigens thought to be
`involved in the pathogenesis of MS.“81 However,
`in a variety of animal species,[19:20] it unexpectedly
`inhibited experimental autoimmune encephalitis
`
`(EAE), the primary animal model for MS. The sup-
`
`mediators and the upregulation of adhesion mole-
`cules[7’13l facilitate the passage of these T cells
`through an ‘altered’ blood-brain barrier into the
`CNS,[7325=26] where they are reactivated by the anti-
`genic products of demyelination, predominantly
`MBP[3=7’27] but possibly PLP and M06 as well.
`These activated myelin-reactive T cells release
`
`pressive and protective effects of the drug, in EAE
`
`cytokines and mediators, which recruit and stimu-
`
`induced by MBP and other myelin antigens (e.g.
`
`late other inflammatory cells (microglia, astro-
`
`proteolipid protein [PLP] and myelin oligodendro-
`
`cyte glycoprotein [MOG]), are now well estab-
`lished.[11519’21] In patients with RRMS, glatiramer
`acetate downregulates the immune response to these
`
`myelin antigens. It is considered to be the first
`
`agent to do this by engaging the T-cell receptor
`(TCR).[8722] This article reviews pharmacological
`and clinical data on the use of glatiramer acetate in
`
`patients with RRMS.
`
`2. Pharmacological Properties
`
`Glatiramer acetate consists of a mixture of four
`
`naturally occurring amino acids ( L—glutamic acid,
`
`L-alanine, L-tyrosine and L—lysine) produced by
`random polymerisation.[23’24] This agent simulates
`
`cytes and plasma cells) that precipitate the demy-
`elination, oligodendrocyte damagem and axonal loss
`characteristic of MS.[37477712126’28]
`
`2.2 Proposed Mechanisms of Action of
`Glatiramer Acetate
`
`The disease-specific mechanism of action of
`
`glatiramer acetate in modulating the immune re—
`
`sponse in MS appears to be a complex process in-
`
`Volving:
`
`0
`
`induction of glatiramer acetate-specific sup-
`
`pressor T cells that are capable of directly and
`
`indirectly downregulating the inflammation in
`the CNS[21522’26=27’29] (see section 2.2.1);
`
`0
`
`inhibition of the autoreactive MBP-specific T
`
`MBP, an antigen thought to be involved in MS,
`
`cells that would otherwise be stimulated to pro-
`
`although both the pathogenesis of this disease and
`
`the mode of action of glatiramer acetate have yet
`
`to be fully elucidated. Nevertheless, the beneficial
`
`effects of glatiramer acetate in RRMS are thought
`
`to stem from its modification of immune processes
`
`implicated in the pathogenesis of the disease. This
`section focuses on the human studies that have at-
`
`tempted to characterise the pharmacological ef-
`
`liferate and release inflammatory cytokines that
`lead to CNS inflammation and damagemfio]
`(see section 2.2.2).
`
`Although its eventual site of action is the
`CNSPI] glatiramer acetate itself is unlikely to
`cross the blood-brain barriermfiz] as it is degraded
`into smaller fragments in the periphery after sub-
`cutaneous administration (see section 2.4).[33] It is
`
`fects and exact mechanism of action of glatiramer
`
`the glatiramer acetate-induced T cells that migrate
`
`© Adls International Limited. All rights reserved.
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`831
`Glatiramer Acetate in Relapsing—Remitting MS
`
`
`into the CNS and downregulate the inflammation
`associated with MS (see sections 2.2.1 and 2.2.2).
`
`the proliferation of glatiramer acetate—specific T-
`
`cell lines. The glatiramer acetate—reactive T cells
`
`A summary of the key pharmacological effects
`
`of glatiramer acetate of potential relevance to its
`
`use in the treatment of RRMS is presented in table I.
`
`2.2. 1 Induction of Glatircrmer Acetate-Specific
`Suppressor T Cells
`
`Glatiramer acetate binds to the major histo-
`
`compatibility complex (MHC) class II molecule
`on the antigen—presenting cells[35’36] in the periph—
`
`ery at the injection sites or in the lymph nodes
`draining the injection sites.[29] The subsequent
`
`binding of this glatiramer acetate/MHC complex
`to the glatiramer acetate—specific TCRDg] induces
`
`secrete predominantly T-helper (Th) l-type pro-
`inflammatory cytokines,[41] but with exposure to
`
`glatiramer 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 the
`blood-brain barrier into the CNSiZS] Where they en-
`
`counter MBP and other pathogenic myelin antigens
`
`(products of CNS inflammation and demyelin-
`
`ation) presented by the MHC. Because glatiramer
`acetate is cross—reactive with these antigens,[40541=43s47]
`
`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
`(MSF
`
`MHC binding in the periphery
`Binds to MHC with high affinity[351
`Promiscuous binding to multiple HLA—DR alleles,[36] including DBR1*1501 and DR4 haplotypes (linked to known MS susceptibility in
`certain population groups)[371
`Successfully competes with MBP and other myelin antigens for MHC binding [5'37'391b
`
`Induction of suppressor T cells
`GA—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 monthm’] after treatment and sustained for up to 9 yearsizsl despite reduction in GA—reactive T-cell
`proliferationl4o'42’45]
`
`Inhibition of MBP-specific T-cell response
`Dose dependently inhibits proliferation of MBP—specific T cellsl27-301
`Downregulates the MBP-specific T-cell response by engaging the TCR and inducing anergy (acts as an altered peptide ligand and
`delivers a non—activating signal)[26-27]
`TCR antagonism demonstrated[46] (inconsistent results in another studyl27l)C
`
`T-cell migration through blood-brain barrier
`GA-induced Th2-type T cells accumulate in the CNSIZS]
`
`Cross-reactivity
`Induces T cells cross-reactive with Mpr[40.41.43,47] MOG[5’48] and PLP[2°'411
`Cross—reactivity shown at the level of cytokine expressioni27'41'4g]
`More T-cell lines show cross-reactivity with continued GA treatmentl‘ml
`
`Bystander suppression
`GA-induced suppressorT cells, reactivated by MBP, inhibit T-cell responses to other myelin antigenlezvzerzsv“144148150] and downregulate
`further inflammatory processes
`
`Neuroprotection
`Increased production of brain—derived neurotrophic factor detected in GA—specific T cellsl51v52]
`a All findings are from in vitro human studies except two studies by Aharoni et al.[25v34]
`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 oligodendrocyte
`glycoprotein; PLP = proteolipid protein; TCFI = T—cell receptor; Th 2 T helper.
`
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`
`which directly and indirectly downregulate the
`CNS-based inflammation associated with MS [22,29]
`
`(figure 1). The ability of glatiramer acetate in the
`
`periphery to induce this remote suppression of in-
`
`flammation in the CNS is due to the cross-reactivity
`
`of glatiramer acetate-specific T cells with not only
`MBP,[26=27529=41548] but also other myelin antigens
`
`implicated in the pathogenesis of MS (possibly
`MOG[5’48] and PLP[20’41]). This phenomenon, where-
`
`by the anti—inflammatory cytokines secreted are in-
`
`dependent of the primary autoantigen or antigen
`
`specificity of the T cells, is known as ‘bystander
`suppression’ _[22,26,28,41,44,50,54]
`Evidence of a shift of T-cell generation from
`
`predominantly Thl—type (pro-inflammatory) to Th2-
`
`and Th3 —type T cells (both anti—inflammatory) was
`
`accompanied by clinical benefits in a nonblind
`
`study that enrolled ten patients with RRMS treated
`
`with subcutaneous glatiramer acetate 20mg once
`daily for 12 months.[44] There was a 2- to 6-fold
`
`increase 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 of
`
`treatment compared with pretreatment levels. At
`
`12 months the levels were higher than baseline val-
`ues.[44] Patients with active MS have been shown
`
`to have defective production and low levels of
`
`interleukin (IL)—10, IL-4 and transforming growth
`factor [3 (TGFB) [anti-inflammatory cytokines] .[44]
`
`The mean serum level of IL—10 in patients treated
`
`with glatiramer acetate increased nearly 2-fold at
`
`3 months compared with baseline (from approxi-
`
`mately 1.4 to 2.6 ng/L, p = 0.04 [estimated from a
`
`graph]), although the increase was not significant
`
`at 6 and 12 months. Messenger RNA (mRNA) ex-
`pression of IL—4 and TGFB in the PBLs (estimated
`
`from graph) showed a 4- and 6-fold enhancement
`
`at 6 months (p = 0.03 vs baseline), and transform-
`ing growth factor—[3 remained significantly higher
`than baseline at 12 months (p = 0.02).[44]
`
`mRNA expression of the pro-inflammatory
`
`Thl—type cytokine tumour necrosis factor—0i
`
`in
`
`PBLS had decreased 78% from the pretreatment
`
`level at 12 months (estimated from a graph) [p <
`0.004].[44] A decrease from baseline was also ob-
`
`
`
`.GA Binding of GAto the MHC
`
`
`
`Inhibition of MBP T—cell
`response (anergy or
`
`TCR antagonism?)
`
`Proliferation of
`GA-reactive T cells
`
`Periphery
`
`Shift from Th1 to
`Th2frh3
`cytokine secretion
`
`Migration of GA
`T cells through
`blood—brain barrier
`
` GA T cells secrete
`
`Th2fl'h3 cytokines in
`response to stimulation
`by MBP (cross—reactivity)
`
`Th2fl'h3 cytokines downregulate
`
`inflammation in the CNS
`
`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 2 major
`histocompatibility complex; TCFl = T—cell receptor; Th 2 T helper.
`
`© Adis International Limited. All rights reserved.
`
`CNS Drugs 2002; 10(12)
`
`MYLAN INC. EXHIBIT NO. 1029 Page 8
`
`MYLAN INC. EXHIBIT NO. 1029 Page 8
`
`
`
`833
`Glatiramer Acetate in Relapsing—Remitting MS
`
`
`served at 12 months in the mean level of soluble
`
`nal (anergy)[26’27] [figure 1]. TCR antagonism
`
`IL-2 receptor; there was substantial interpatient
`
`(competition for the TCR by the glatiramer acetate/
`
`variability in this reduction at all timepoints. The
`
`MHC and MBP/MHC complexes), which is another
`
`12-month decrease, which was not significant, was
`
`mechanism proposed for this T-cell inhibition, is
`
`preceded by an increase at 3 months (p = 0.04 vs
`baseline).[44]
`
`The shift from Thl- to Th2- and Th3-type T cells
`
`was accompanied by improvements in clinical
`
`markers of disease activity. There was a significant
`
`likely to remain an in vitro observation as glatira—
`
`mer acetate remains in the periphery and MBP in
`the CNS.[29=46]
`
`Glatiramer acetate might also interfere with the
`interaction between activated T cells and micro-
`
`reduction in mean annual relapse rate (1.4 to 0.6,
`
`glia in the CNS (which leads to the production of
`
`p = 0.001), and nine of ten patients had improved
`
`or stable disability, according to absolute changes
`
`in the Kurtzke Expanded Disability Status Scale
`(EDSS) score.[44]
`There is recent evidence of a sustained shift in
`
`cytokine profile of the glatiramer acetate-induced
`T cellsps] in ten patients treated with glatiramer
`acetate for 6—9 years.[55] This shift, coupled with
`
`the cross-reactivity between glatiramer acetate and
`
`MBP and other myelin antigens, is consistent with
`
`the anti-inflammatory effects of glatiramer acetate
`
`and the phenomenon of ‘bystander suppression’
`(see above).
`
`The induction of glatiramer acetate-specific,
`
`protective T cells is detected early and the time
`
`required for the development of an adequate and
`
`effective T—cell population is reflected in the tim—
`
`ing of the onset of significant therapeutic action of
`glatiramer acetate (see section 3).”8’3152’54]
`
`2.2.2 inhibition of Myeiin -Reactive
`T-Ceii Responses
`
`inflammatory cytokines), thereby accounting for
`the reduced inflammation in the CNS observed
`
`with glatiramer acetate treatment of RRMS.[56]
`
`2.2.3 Potential for Neuroprotection
`
`Neuroprotection,
`
`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 rat
`
`model, adoptive transfer of the nonpathogenic
`
`glatiramer acetate-reactive T cells or vaccination
`
`with glatiramer acetate on the day of CNS injury
`has been shown to confer a measure of neuro-
`
`protection, preventing secondary degeneration of
`nerve fibres.[57]
`
`Recent researchmfiz] suggests that neuropro-
`tection, besides that effected by bystander suppres—