Aois DRUG EVALUATION
`
`.$;';,*:+.;7;,;°,?.?;;:.g;§>;g.m
`© Adis International Urnlled. All rlgfls 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. Pilippi,
`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.
`
`
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`Contents
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`Summary
`1.
`Introduction .
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`2. Pharmacological Properties
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`2.1 Pathogenesis of Multiple Sclerosis
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`2.2 Proposed Mechanisms of Action of Glatiramer Acetate .
`2.2.1 Induction of G|atiramerAcetate-Specific SuppressorTCe||s .
`2.2.2 Inhibition of Myelin-Reactive T-Cell Responses .
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`2.2.3 Potential for Neuroprotecfion .
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`2.3 Immunological Effects .
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`2.3.1 Non-Neutralisin Antibodies .
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`2.3.2 Selectivity .
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`2.4 Pharmacokinetic Properties .
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`3. Therapeutic Efficacy .
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`3.1 Effects on Relapse Rate .
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`3.2 Magnetic Resonance Imaging Assessments
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`3.3 Effects on Disability .
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`3.4 Other Effects
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`4. Pharmacoeconomics .
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`5. Tolerability .
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`. 842
`
`AMNEAL
`
`EXHIBIT NO. 1029 Page 1
`
` AMNEAL
`
`

`
`826
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`Simpson et a1.
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`Injection-Site Reactions
`5.1
`5.2 Post—|njection Systemic Reactions
`5.3 Other Effects
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`6. Dosage and Administration .
`7. Place of Glatiramer Acetate in the Management of Relapsing-Remitting
`Multiple Sclerosis
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`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 most commonly reported
`treatment-related adverse events were localised injection-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-I3 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.
`
`© Adls International Umlred. All fights reserved.
`
`CNS Drugs 2[XD; lo (12)
`
`AMNEAL
`
`EXHIBIT NO. 1029 Page 2
`
` AMNEAL
`
`

`
`Glatiramer Acetate in Relapsing-Rernitting MS
`
`827
`
`Pharmacologlcal
`Propelfles
`
`Therapeuflc Efllcacy
`
`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 T111 type (pro-inflarrnnatory), but
`with exposure to glatiramer acetate there is a shift to a T112/T1,3-type response
`(anti-inflamrnatory). 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 Th1- 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—neutra1ising
`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. Re1apse—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
`
`© Adls International Umlted. All fights reserved.
`
`CNS Drugs 2[XD; "IO (12)
`
`AMNEAL
`
`EXHIBIT NO. 1029 Page 3
`
` AMNEAL
`
`

`
`828
`
`Simpson et al.
`
`Pharmacoeconomlcs
`
`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—[3 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).
`
`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.
`
`Tolerablllty
`
`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
`
`© Adls International Umlted. All fights reserved.
`
`CNS Drugs 2[XD; 1o (12)
`
`AMNEAL
`
`EXHIBIT NO. 1029 Page 4
`
` AMNEAL
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`

`
`Glatiramer Acetate i.n 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 <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 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
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`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 52% 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-B.
`
`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).
`
`Dosage and
`Admlnlsttatlon
`
`I. Introduction
`
`Multiple sclerosis (MS) is a chronic, inflamma-
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`tory disease of the CNS usually diagnosed in young
`adults (aged 20-40 years)“] 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 agents
`in the environment,[5=7] that results in unchecked
`
`inflammation causing demyelination of areas in
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`the brain and spinal cord. Relapsing-remitting MS
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`fatigue and dizziness.[1°s”1 These relapses are in-
`terspersed with periods of complete or partial re-
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`mission. Although some patients continue on this
`course without becoming seriously disabled,[5:7"2=131
`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).[7=3-13-14] Within 10-15 years
`of a diagnosis of MS, 50% of patients are unable
`to walk unassisted,[6’151 and after 25 years 50% are
`wheelchair bound.[‘5]
`
`(RRMS) is the most common type of MS; approx-
`
`Management of RRMS includes multidiscipli-
`
`imately 85% of patients present with this type of
`MS.“'7~3] It manifests as self-limited attacks of neu-
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`rological dysfunction (relapses)[91 during which
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`the patient experiences a sudden worsening of neu-
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`rological symptoms such as numbness, tingling,
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`muscle weakness, spasticity, visual disturbances,
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`nary rehabilitation, pharmacotherapy for symp-
`toms and treatment of relapses and, more recently,
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`pharmacotherapy for modifying the underlying
`disease in an attempt to prevent relapses and delay
`the progression to disability.[5»3»12]
`Limited success (from an efficacy, tolerability
`
`© Adls International Umlted. All fights reserved.
`
`CNS Drugs 2[XD; 16 (12)
`
`AMNEAL
`
`EXHIBIT NO. 1029 Page 5
`
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`Simpson et al.
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`or cost perspective) with general immunosuppres-
`sant agents (azathioprine, mitoxantrone and oth-
`ers)[1~5"51 and intravenous immunoglobu1ins[3""”]
`(not approved in the USA) and progress in under-
`standing the pathogenesis of RMS have led to the
`introduction and use of more specific immuno-
`modulatory agents, such as glatiramer acetate (pre-
`viously copolymer-1) and two forms of recombi-
`nant interferon-|3,[3"51 for altering the natural
`course of the disease (see section 7).
`
`Glatiramer acetate is a synthetic copolymer
`
`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 MSJ13] However,
`in a variety of animal species,[19’2°] it unexpectedly
`inhibited experimental autoimmune encephalitis
`(EAE), the primary animal model for MS. The sup-
`pressive and protective effects of the drug, in EAE
`induced by MBP and other myelin antigens (e.g.
`proteolipid protein [PLP] and myelin oligodendro-
`cyte glycoprotein [MOG]), are now well estab-
`lishedl“-19=2” 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).[3’22] This article reviews pharmacological
`and clinical data on the use of glatiramer acetate in
`patients with RRMS.
`
`2. Pharmacological Properlies
`
`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
`MBP, an antigen thought to be involved in MS,
`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-
`fects and exact mechanism of action of glatiramer
`
`acetate and includes studies in patients with all
`types of MS. Animal data are provided where hu-
`man data are limited.
`
`2.1 Palhogenesis of Multiple Sclerosis
`
`The pathogenesis of MS involves a cascade of
`immunological 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 inflammatory
`mediators and the upregulation of adhesion mole-
`cules[7~13] facilitate the passage of these T cells
`through an ‘altered’ blood-brain barrier into the
`CNS,[7’25v251 where they are reactivated by the anti-
`genic products of demyelination, predominantly
`MBP[3’7’27] but possibly PLP and MOG as well.
`These activated myelin-reactive T cells release
`
`cytokines 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 loss
`characteristic of MS.[3’4=7-1236331
`
`2.2 Proposed Mechanisms of Action of
`Glaiira mer 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[21’22’26’27’29] (see section 2.2.1);
`
`0 inhibition of the autoreactive MBP-specific T
`cells that would otherwise be stimulated to pro-
`liferate and release inflammatory cytokines that
`lead to CNS inflammation and damage[27’3°]
`(see section 2.2.2).
`
`Although its eventual site of action is the
`CNSJ3” glatiramer acetate itself is unlikely to
`cross the blood-brain barrierlz‘-“Z1 as it is degraded
`into smaller fragments in the periphery after sub-
`cutaneous administration (see section 2.4).[33] It is
`
`the glatiramer acetate-induced T cells that migrate
`
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`Glatiramer Acetate i.n Relapsing-Remitting MS
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`831
`
`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. l Induction of Glatiramer 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.[291 The subsequent
`binding of this glatiramer acetate/MHC complex
`to the glatiramer acetate-specific TCRW91 induces
`
`secrete predominantly T-helper (T1,) 1-type pro-
`inflammatory cytokines,[41] but with exposure to
`
`glatiramer acetate the T cells are shifted more to-
`wards the T112 type (anti-inflammatory).[34~4°=‘”=53]
`
`These suppressor T cells may migrate through the
`blood-brain barrier into the CNS [251 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 antigcns,[“°"”’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 mulfple sclerosis
`MS)"
`
`MHC binding in the periphery
`Binds to MHC with high alfinityl35l
`Promiscuous binding to multiple HLA-DR alleles,l3°l including DBFl1*1501 and DR4 haplotypes (linked to known MS susceptibility in
`cenain population groups)l37l
`Successfully corrpetes with MBP and other myelin antigens tor MHC binding [5'37‘393’
`
`Induction of suppressor T cells
`GA-reactive T cells shift from Ti-.1 type (pro-inflammatory) to Th2 and Th3 type (anti-inflamn1atory)[“”'i“*“"
`Shitt evident as early as 1 monthl“3' aftertreatment and sustained for up to 9 years,“ despite reduction in GA-reactive T-cell
`proliferation[‘‘*‘‘'‘’'‘51
`
`Inhibition of MBP-specific T-cell response
`Dose dependently inhbits proliferation of MBP-specific T cell<J27-3°]
`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 signaI)l2°-27'
`TCR antagonism demonstratedl“°] (inconsistent results in another studyl27])°
`
`T-cell migration through blood-brain barrier
`GA-induced Th2-type T cells accumulate in the CNS'‘’‘'’'
`
`Cross-reactivity
`Induces T cells cross—reactive with MBP,l“°-‘”“‘3v“71 MOGI5-4°‘ and PLPl2°~‘"1
`Cross—reactivity shown at the level of cytokine expression!”-4‘-“I
`More T-cell lines show cross-reactivity with continued GA treatment"‘°l
`
`Bystander suppression
`GA-induced suppressor T cells. reactivated by MBP. inhbit T-cell responses to other myelin antigenslz’-'2°'23-“i“-“5°] and downregulate
`turther inflammatory processes
`
`Neuroprotection
`Increased production of brain-derived neurotrophic factor detected in GA-specific T cells“ -521
`a All findings are from in vitro human studies except two studies by Aharoni et a|.l2°'3"
`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
`glyooprotein; PLP = proteolipid protein: TCFI = T-cell receptor: Tr. = T helper.
`
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`832
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`Simpson et al.
`
`
`
`.GA Binding of GA to the MHC
`
`
`
`,,,h5bm°,, ofMBPT_ce"
`response lane-_r9v 0'
`TOR a"'a9°"'sm?)
`
`_
`_
`22:33:: f.-fceus
`
`S""”'°""Th‘ ‘°
`secretion
`
`CNS
`
`Migration of GA
`T °°"‘ ""°“9"
`blood-brain barrier
`
`GA T cells secrete
`
`Th2fT,.,3 cytokines in
`response to stimulation
`
`W MBP (°'°55"°3°“V“Y)
`
`
`
`
`
`inflammation in the CNS
`
`
`
`_Fi9-1-P'°P°5ed '"e°"a"lf5'“5°‘a_°f‘°"°‘9'?“'a"'°'a°‘%'3t°(GA)
`IN the treatmentofrelapslng-remitting multiple sclerosus.APc=
`antigen-presenting oell; MBP = myelin basic protein; MHC = major
`histocompatibility complex; TcFl =T-cell receptor; Tr. = T helper.
`
`which directly and indirectly downregulate the
`CNS-based inflammation associated with MS [2239]
`
`(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=27=29’4"431 but also other myclin antigens
`implicated in the pathogenesis of MS (possibly
`MOG[5~43] and PLP[2°"”1). 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» .[22,26,28,4l ,44,so,s4]
`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.[‘'‘‘1 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.l44] 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-inflarrnnatory cytokines].[“"']
`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-B remained significantly higher
`than baseline at 12 months (p = 0.02).[44]
`mRNA expression of the pro-inflammatory
`
`Thl-type cytokine tumour necrosis factor-oi 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 0b-
`
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`Glatiramer Acetate i.n Relapsing-Remitting MS
`
`served at 12 months in the mean level of soluble
`
`IL-2 receptor; there was substantial interpatient
`variability in this reduction at all timepoints. The
`12-month decrease, which was not significant, was
`preceded by an increase at 3 months (p = 0.04 vs
`baseline).[‘‘‘‘]
`
`The shift from Th1- to Th2- and Th3-type T cells
`
`was accompanied by improvements in clinical
`markers of disease activity. There was a significant
`reduction in mean annual relapse rate (1.4 to 0.6,
`
`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.[441
`There is recent evidence of a sustained shift in
`
`cytokine profile of the glatiramer acetate-induced
`T cellsm] 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).[23v31'32’54]
`
`2.2.2 Inhibition of Myelin -Reactive
`T-Cell Responses
`
`The beneficial effects of glatiramer acetate are
`further explained by the inhibition of the autoreac-
`tive MBP- and other myelin antigen-specific T-cell
`
`responses implicated in the pathogenesis of MS
`(figure 1). Studies have shown that after initially
`inducing proliferation of the T cells, glatiramer ac-
`etate inhibits both their proliferation 97-301 and their
`secretion of IL-2 (a Th1 cytokine).[3°] It has been
`suggested that glatiramer acetate can alter the T
`cells in some way. Indeed, possibly acting as an
`altered peptide ligand, it engages various TCRs,
`altering the T-cell cytokine secretion to a Th2 pro-
`file. It may also downregulate the MBP-specific
`T-cell response by delivering a non-activating sig-
`
`nal (anergy)[2‘5=27] [figure 1]. TCR antagonism
`(competition for the TCR by the glatiramer acetate!
`MHC and MBP/MHC complexes), which is another
`mechanism proposed for this T-cell inhibition, is
`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-
`
`glia in the CNS (which leads to the production of
`inflammatory cytokines), thereby accounting for
`the reduced inflammation in the CNS observed
`
`with glatiramer acetate treatment of RRMSJ56]
`
`2.2.3 Potential for Neuroprotecfion
`
`induced by treatment with
`Neuroprotection,
`glatiramer acetate, has been demonstrated in ani-
`malls" and in vitro human[51] studies. In experi-
`mental crush lesions of the optic nerve in a rat
`model, adoptive transfer of the no