- Brain Trauma
- Neuro Imaging
- Movement Disorders
- Multiple Sclerosis
- Nervous System Disorders
- Neurodegenerative Disease
- Neurological Oncology
- Neurometabolic Disease
- Neuromuscular and Neurometabolic Disorders
- Neuropathic Pain
- Pediatric and Geriatric Neurology
- Sleep Disorders
Long-term Experience of Glatiramer Acetate (Copaxone®) in the Treatment of Clinically Isolated Syndrome and Relapsing–Remitting Multiple Sclerosis
US Neurology, 2011;7(2):126-31
AbstractMultiple sclerosis (MS) is a chronic, disabling condition with severe clinical and social consequences. glatiramer acetate (GA) has been widely used for more than 15 years as a first-line disease-modifying agent in the treatment of relapsing–remitting Ms (RRMS). it appears to have multiple modes of action, including the induction of GA-reactive T-helper 2 (Th2) immunoregulatory cells and the stimulation of neurotrophin secretion in the central nervous system, which may promote neuronal repair. clinical trial data show that GA reduces the relapse rate in RRMS, can delay or halt disability progression, and brings about improvement in magnetic resonance imaging (MRI) measures of disease activity, including reduction of brain atrophy. early treatment with GA can reduce the risk of developing clinically definite MS in patients with clinically isolated syndrome. furthermore, it has an excellent safety and tolerability profile. recent data from patients treated for 15 years have indicated that more than half of the patients on long-term GA therapy have stable or improved disability scores.
Keywords: glatiramer acetate, relapsing–remitting multiple sclerosis, long-term experience
Disclosure: Howard Zwibel, MD, is or has been a consultant to Acorda Therapeutics, Teva neuroscience, Bayer, Biogen, genentech, and eMD serono, a member of the speakers bureau for Acorda Therapeutics, Teva neuroscience, Biogen, and eMD serono, and is a member of the advisory board for WebMD, LLc (Medscape). Acknowledgments: editorial assistance was provided by James gilbart, PhD, at Touch Briefings.
Received: December 02, 2011 Accepted January 09, 2012 Citation US Neurology, 2011;7(2):126-31
Correspondence: howard Zwibel, MD, 6862 granada Boulevard, coral gables, fL 33146. e: email@example.com
As a chronic disease of the central nervous system (CNS), multiple sclerosis (MS) is characterized by a complex interplay between inflammation, demyelination, remyelination, gliosis, and neuronal injury.1 it continues to be a major cause of acquired neurologic disability in young adults worldwide, particularly in people of northern european origin.2 it affects women with twice the frequency of men and the average age of diagnosis is 37 years.3 The worldwide total estimated prevalence for the past three decades is 83 cases/100,000 population.4
The clinical course of MS is heterogeneous, with variability both between and within patients, and has been categorized as clinically isolated syndrome (CIS), relapsing–remitting MS (RRMS, which accounts for 85 % of MS patients in the initial disease course), primary progressive MS (PPMs), and secondary progressive MS (SPMS).5,6 RRMS is characterized by relapses, symptoms of which include numbness, blurred vision, difficulty walking, fatigue, and pain. symptoms are usually temporary and are followed by periods of remission.6
The immunopathogenesis of MS is thought to be heterogeneous; however, the inflammatory demyelinating plaque is characteristic of all forms of MS.7 immune-mediated injury to myelin and oligodendrocytes may occur when peptides in myelin attach to the cleft of major histocompatibility complex (MHC) class ii molecules on antigen-presenting cells (APCS) including macrophages, monocytes, and dendritic cells.8 Activation of APcs can trigger an immune response against the bound antigen and leads to secretion of pro-inflammatory cytokines and the differentiation of naive cD4+ T cells into T-helper 1 (Th1) and T-helper 17 (Th17) cells, resulting in inflammation and autoimmunity. Th1 and Th17 cells are capable of migration into the cns and have been identified in active lesions.9,10 Th1 cells undergo continued proliferation and secretion of pro-inflammatory cytokines, leading to myelin damage and neuronal loss. further activation of resident microglia can lead to cross-reactivity, which maintains inflammation and further damage to the myelin sheath.11 impaired function of regulatory T cells (Tregs), which act against autoimmunity, allows further pathologic activation of autoreactive T cells and exacerbates the feedback loop that causes continual damage to the cns.12 Additionally, activated B cells appear to be participants in the creation of myelin lesions by producing antibodies that mediate and promote demyelination.13
MS represents a considerable therapeutic challenge, because of its significant heterogeneity and unpredictable clinical course. glatiramer acetate (GA; copaxone®, co-polymer 1) was first tested in clinical trials in the mid-1980s and approved by the us food and Drug Administration (fDA) for the treatment of RRMS in 1996; previously, therapies had been limited. GA is a mixture of synthetic peptides composed of random sequences of four amino acids (tyrosine, glutamate, alanine, and lysine) in a defined molar ratio with a length of 40–100 residues, and is structurally similar to myelin basic protein (MBP), a major component of myelin.14 it is administered as a daily subcutaneous (sc) injection (20 mg).
- goodin Ds, frohman eM, garmany gP Jr, et al., Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment subcommittee of the American Academy of neurology and the MS council for clinical Practice guidelines, Neurology, 2002;58:169–78.
- compston A, coles A, Multiple sclerosis, Lancet, 2002;359:1221–31.
- hogancamp We, rodriguez M, Weinshenker Bg, The epidemiology of multiple sclerosis, Mayo Clin Proc, 1997;72:871–8.
- Pugliatti M, sotgiu s, rosati g, The worldwide prevalence of multiple sclerosis, Clin Neurol Neurosurg, 2002;104:182–91.
- Bates D, Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials, Neurology, 2011;76:s14–25.
- Lublin fD, reingold sc, Defining the clinical course of multiple sclerosis: results of an international survey. national Multiple sclerosis society (usA) Advisory committee on clinical Trials of new Agents in Multiple sclerosis, Neurology, 1996;46:907–11.
- inglese M, grossman ri, filippi M, Magnetic resonance imaging monitoring of multiple sclerosis lesion evolution, J Neuroimaging, 2005;15:22s–29s.
- stoeckle c, Tolosa e, Antigen processing and presentation in multiple sclerosis, Results Probl Cell Differ, 2009;51:149–72.
- hedegaard cJ, Krakauer M, Bendtzen K, et al., T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis, Immunology, 2008;125:161–9.
- Jadidi-niaragh f, Mirshafiey A, Th17 cell, the new player of neuroinflammatory process in multiple sclerosis, Scand J Immunol, 2011;74:1–13.
- Mao ys, Lu cZ, Wang X, Xiao Bg, induction of experimental autoimmune encephalomyelitis in Lewis rats by a viral peptide with limited homology to myelin basic protein, Zozulga AL, Wiendl h, The role of regulatory T cells in multiple sclerosis, Nat Clin Pract Neurol, 2008;4;384–98.
- Hemmer B, cepok s, nessler s, sommer n, Pathogenesis of multiple sclerosis: an update on immunology, Curr Opin Neurol, 2002;15:227–31.
- Bornstein MB, Miller A, slagle s, et al., A pilot trial of cop 1 in exacerbating-remitting multiple sclerosis, N Engl J Med, 1987;317:408–14.
- Weber MS, hohlfeld r, Zamvil ss, Mechanism of action of glatiramer acetate in treatment of multiple sclerosis, Neurotherapeutics, 2007;4:647–53.
- Lalive Ph, neuhaus o, Benkhoucha M, et al., glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action, CNS Drugs, 2011;25:401–14.
- Johnson KP, glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update, Expert Opin Drug Metab Toxicol, 2010;6:643–60.
- Begum-haque s, sharma A, Kasper ir, et al., Downregulation of iL-17 and iL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis, J Neuroimmunol, 2008;204:58–65.
- Ruggieri M, Pica c, Lia A, et al., combination treatment of glatiramer acetate and minocycline affects phenotype expression of blood monocyte-derived dendritic cells in multiple sclerosis patients, J Neuroimmunol, 2008;197:140–6.
- Karandikar nJ, crawford MP, yan X, et al., glatiramer acetate (copaxone) therapy induces cD8(+) T cell responses in patients with multiple sclerosis, J Clin Invest, 2002;109:641–9.
- Aharoni r, eilam r, Domev h, et al., The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice, Proc Natl Acad Sci USA, 2005;102:19045–50.
- Aharoni r, Kayhan B, eilam r, et al., glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ, Proc Natl Acad Sci USA, 2003;100:14157–62.
- Ziemssen T, schrempf W, glatiramer acetate: mechanisms of action in multiple sclerosis, Int Rev Neurobiol, 2007;79:537–70.
- Blanchette f, neuhaus o, glatiramer acetate: evidence for a dual mechanism of action, J Neurol, 2008;255(suppl. 1):26–36.
- Johnson KP, Brooks Br, cohen JA, et al., copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase iii multicenter, double-blind placebo-controlled trial. The copolymer 1 Multiple sclerosis study group, Neurology, 1995;45:1268–76.
- Johnson KP, Brooks Br, cohen JA, et al., extended use of glatiramer acetate (copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. copolymer 1 Multiple sclerosis study group, Neurology, 1998;50:701–8.
- Ford c, goodman AD, Johnson K, et al., continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the us prospective openlabel study of glatiramer acetate, Mult Scler, 2010;16:342–50. 28. filippi M, rovaris M, rocca MA, et al., glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”, Neurology, 2001;57:731–3.
- Comi g, filippi M, Wolinsky Js, european/canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—measured disease activity and burden in patients with relapsing multiple sclerosis. european/canadian glatiramer Acetate study group, Ann Neurol, 2001;49:290–7.
- Sormani MP, Bruzzi P, comi g, filippi M, The distribution of the magnetic resonance imaging response to glatiramer acetate in multiple sclerosis, Mult Scler, 2005;11:447–9.
- Sormani MP, rovaris M, Valsasina P, et al., Measurement error of two different techniques for brain atrophy assessment in multiple sclerosis, Neurology, 2004;62:1432–4.
- Khan o, Bao f, shah M, et al., effect of disease-modifying therapies on brain volume in relapsing-remitting multiple sclerosis: results of a five-year brain Mri study, J Neurol Sci, 2012;312(1–2):7–12.
- Mikol DD, Barkhof f, chang P, et al., comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the rebif vs glatiramer Acetate in relapsing MS Disease [regArD] study): a multicentre, randomised, parallel, open-label trial, Lancet Neurol, 2008;7:903–14.
- Filippi M, rocca MA, Perego e, et al., Benefit of early treatment with glatiramer acetate: Mri results from the 5-year prospectively planned follow up in patients with clinically isolated syndrome enrolled in the Precise study, Presented at: 26th congress of the european committee for Treatment and research in Multiple sclerosis (ecTriMs), gothenburg, sweden, october 13–16, 2010.
- Comi g, Martinelli V, rodegher M, et al., effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (Precise study): a randomised, double-blind, placebo-controlled trial, Lancet, 2009;374:1503–11.
- O’connor P, filippi M, Arnason B, et al., 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study, Lancet Neurol, 2009;8:889–97.
- Cadavid D, Wolansky LJ, skurnick J, et al., efficacy of treatment of MS with ifnbeta-1b or glatiramer acetate by monthly brain Mri in the BecoMe study, Neurology, 2009;72:1976–83. 38. Zwibel hL, glatiramer acetate in treatment-naive and prior interferon-beta-1b-treated multiple sclerosis patients, Acta Neurol Scand, 2006;113:378–86.
- Caon c, Din M, ching W, et al., clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis, Eur J Neurol, 2006;13:471–4.
- Carra A, onaha P, Luetic g, et al., Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina, Eur J Neurol, 2008;15:386–93.
- Ziemssen T, carra A, Del Klippel n, et al., insights from thecoptimize study: characteristics of relapsing remitting multiple sclerosis (RRMS) patients switching to glatiramer acetate, Presented at: 63rd Annual Meeting of the American Academy of neurology, honolulu, hi, April 9–16, 2011.
- Chinea A, rodriguez L, Bryan J, clinical experience in hispanic MS patients switching from natalizumab to copaxone®, Presented at: 5th Joint Triennial congress of the european and Americas committees for Treatment and research in Multiple sclerosis, Amsterdam, The netherlands, october 19–22, 2011.
- Rossi s, ristori g, studer V, et al., An open-label, nonrandomized, prospective, multicenter study to evaluate the safety and tolerability of glatiramer acetate 20 mg sc once daily in patients with severe relapsing-remitting multiple sclerosis that have discontinued natalizumab after 12 to 18 months therapy. Preliminary results, Presented at: 63rd Annual Meeting of the American Academy of neurology, honolulu, hi, April 9–16, 2011, PD6.005.
- Salminen hJ, Leggett h, Boggild M, glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes, J Neurol, 2010;257:2020–3.
- Brochet B, [Long-term effects of glatiramer acetate in multiple sclerosis], Rev Neurol (Paris), 2008;164:917–26.
- Edgar cM, Brunet Dg, fenton P, et al., Lipoatrophy in patients with multiple sclerosis on glatiramer acetate, Can J Neurol Sci, 2004;31:58–63.
- Zwibel h, Pardo g, smith s, et al., A multicenter study of the predictors of adherence to self-injected glatiramer acetate for treatment of relapsing-remitting multiple sclerosis, J Neurol, 2010;258:402–11.
- Jongen PJ, hengstman g, hupperts r, et al., Drug adherence and multidisciplinary care in patients with multiple sclerosis: protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (cAir study), BMC Neurol, 2011;11:40.
- Halpern r, Agarwal s, Dembek c, et al., comparison of adherence and persistence among multiple sclerosis patients treated with disease-modifying therapies: a retrospective administrative claims analysis, Patient Prefer Adherence, 2011;5:73–84.
- Oleen-Burkey MA, Dor A, castelli-haley J, Lage MJ, The relationship between alternative medication possession ratio thresholds and outcomes: evidence from the use of glatiramer acetate, J Med Econ, 2011;14:739–47.
- Castelli-haley J, oleen-Burkey M, Lage MJ, Johnson KP, glatiramer acetate versus interferon beta-1a for subcutaneous administration: comparison of outcomes among multiple sclerosis patients, Adv Ther, 2008;25:658–73.
- Castelli-haley J, oleen-Burkey MA, Lage MJ, Johnson K, glatiramer acetate and interferon beta-1a for intramuscular administration: a study of outcomes among multiple sclerosis intent-to-treat and persistent-use cohorts, J Med Econ, 2010;13:464–71.
- Castelli-haley J, oleen-Burkey MA, Lage MJ, Johnson KP, glatiramer acetate and interferon beta-1b: a study of outcomes among patients with multiple sclerosis, Adv Ther, 2009;26:552–62.
- Lage MJ, castelli-haley J, oleen-Burkey MA, effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis, Work, 2006;27:143–51.
- Teva Pharmaceuticals, A study in subjects with relapsingremitting multiple sclerosis (RRMS) to sssess the efficacy, safety and tolerability of glatiramer acetate (GA) injection 40 mg administered three times a week compared to placebo (gALA), ncT01067521, 2011. Available at: http://clinicaltrials.gov/ct2/results?term=ncT01067521 (accessed november 24, 2011).
- Carra A, onaha P, halfon J, The impact of glatiramer acetate on progression of disability over a decade of continuous therapy, Mult Scler, 2007;13(suppl. 2):s68.
- Debouverie M, Moreau T, Lebrun c, et al., A longitudinal observational study of a cohort of patients with relapsing-remitting multiple sclerosis treated with glatiramer acetate, Eur J Neurol, 2007;14:1266–74.
- Miller A, spada V, Beerkircher D, Kreitman rr, Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis, Mult Scler, 2008;14:494–9.
- Trojano M, Paolicelli D, Tortorella c, et al., natural history of multiple sclerosis: have available therapies impacted long-term prognosis?, Neurol Clin, 2011;29:309–21.
Keywords: glatiramer acetate, relapsing–remitting multiple sclerosis, long-term experience