Glatiramer acetate

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.05.2021
Released 07.06.1999
Expires For CME 10.05.2024

Glatiramer acetate

Author: K K Jain MD†

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Glatiramer acetate

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Introduction

Historical note and terminology

Glatiramer acetate, formerly called copolymer-1, is one of a series of polypeptide preparations developed to stimulate myelin basic protein, a natural component of the myelin sheath. Myelin basic protein suppresses experimental allergic encephalomyelitis (the animal model of multiple sclerosis); a better suppression effect was demonstrated by the use of a synthetic basic copolymer (27). This provided the rationale for the use of copolymer in multiple sclerosis. Glatiramer acetate was developed for commercial use, and results of the first clinical trial were published in 1987. The United States Food and Drug Administration approved it in 1996 for use in multiple sclerosis patients.

Pharmacology

Glatiramer acetate consists of synthetic polypeptides containing four naturally occurring amino acids: (1) L-glutamic acid, (2) L-lysine, (3) L-alanine, and (4) L-tyrosine.

Pharmacology. The exact mode of action is not known, but glatiramer is thought to modify the immune disturbances believed to be involved in the pathogenesis of multiple sclerosis. Principal mechanisms of action are:

	(1) Glatiramer acetate binds to the major histocompatibility complex (MHC) class 2 molecules, thereby competing with the major histocompatibility complex binding of other antigens.
	(2) Glatiramer acetate-major histocompatibility competes with myelin basic protein (MBP), which is one of the major autoantigens in the pathogenesis of multiple sclerosis for binding to the antigen-specific surface receptor of T cells.
	(3) Glatiramer acetate, which is structurally like myelin basic protein, along with nanny proteins (negatively charged proteins that interact with myelin basic protein), restricts access of myelin basic protein to the 26S proteasome to protect its intracellular degradation (19).
	(4) Glatiramer acetate affects several aspects of dysregulated B-cell function in multiple sclerosis that contribute to the mechanism of action (13).
	(5) Glatiramer inhibits the activation of MBP-reactive T cells, which are believed to have access to the CNS, where they can exert anti-inflammatory and possibly neuroprotective effects.
	(6) Glatiramer acetate promotes oligodendrogenesis and remyelination by elevating levels of growth factors that promote repair.
	(7) Glatiramer enhances cytolysis of human natural killer cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells, as well as inhibits the release of cytokine interferon-gamma.
	(8) Multiple sclerosis patients treated with glatiramer show significant changes in circulating antigen-presenting cells and CD4+ T cells (24). Expression of CD40 on dendritic cells is significantly lower and is associated with relapse risk in multiple sclerosis patients treated with glatiramer.
	(9) Increase of anti-inflammatory monocytes and restoration of Treg (T regulatory cell) level are characteristic of responder patients, not only in short-term but even after as long as a decade of treatment with glatiramer acetate (26).
	(10) Findings of a 2-year longitudinal study suggested that glatiramer acetate exerts its immunomodulatory action at the level of grey matter by reducing the accumulation of cortical lesions and slowing down the progression of grey matter atrophy (09).

The remarkable reduction of the number of lesions (as demonstrated by gadolinium-enhanced MRI during treatment with glatiramer) suggests that this is due to pharmacological activity of the drug rather than spontaneous regression of the lesions. Glatiramer is considered to have a dual mechanism of action. In addition to immunoregulation, glatiramer acetate stimulates neurotrophin secretion in the central nervous system that may promote neuronal repair (03). Glatiramer acetate effectively reduces multiple sclerosis activity regardless of the severity of the MRI-detectable inflammatory process.

Pharmacokinetics. Pharmacokinetic studies have not been carried out in humans because the drug is not detectable in systemic blood circulation. Based on animal studies, it is assumed that the injected material is hydrolyzed locally, and a fraction of it enters the lymphatic circulation to reach the lymph nodes and then somehow enters the systemic circulation intact.

Pharmacogenomics/pharmacogenetics. Genotyping studies have revealed genetic biomarkers that can predict response to glatiramer acetate for relapsing multiple sclerosis. This could enable the development of pharmacogenomics-based personalized treatment for multiple sclerosis.

A study to investigate biomarkers of response to glatiramer acetate in relapsing-remitting multiple sclerosis patients found that the probability of accurately detecting response to glatiramer acetate was 85% for Response Gene to Complement 32, 90% for FasL, and 85% for interleukin-21 (18). These data suggest that these could serve as potential biomarkers for the detection of multiple sclerosis relapse and response to glatiramer therapy.

Results of a pharmacogenetic study of glatiramer acetate in late-phase clinical-trial cohorts of multiple sclerosis have shown that gene regions underlying the 4-SNP (rs80191572, rs28724893, rs1789084, and rs139890339) signature, in approximately 10% of patients who showed clinical improvements, have been linked with pathways associated with either the drug’s mechanism of action or the pathophysiology of disease (22).

Clinical trials

Original evidence of clinical efficacy is based mainly on three controlled clinical trials. In a double-blind, randomized, placebo-controlled pilot trial involving 50 patients, 56% of the glatiramer acetate-treated patients remained relapse-free, compared to 26% in the placebo group (04). In a 2-year, multicenter, randomized, double-blind, placebo-controlled trial of 251 patients, glatiramer was shown to reduce relapses by an average of 29% when compared with placebo (16). A 2-year, longitudinal neuropsychological study of patients in a multicenter clinical trial showed no effect of glatiramer therapy on cognitive function in relapsing-remitting multiple sclerosis (28). There was, however, no decline in cognitive function, and this lack of deterioration is significant in a gradually progressive disease where some deterioration over a 2-year period is expected.

A randomized, double-blind clinical trial in patients with relapsing-remitting multiple sclerosis has shown that early treatment with glatiramer acetate is effective in delaying conversion to clinically definite multiple sclerosis and brain lesions detected by MRI. A systematic review of randomized trials concluded that glatiramer acetate is partially effective in relapsing-remitting multiple sclerosis but does not halt clinical progression of the disease (20).

Results of a randomized phase 3 dose-comparison study of glatiramer acetate showed that both the currently approved glatiramer acetate doses, 20 mg and 40 mg, were well-tolerated in patients with relapsing-remitting multiple sclerosis, with no gain in efficacy for the higher dose (08).

Results of a double-blind, randomized, controlled study of combined use of interferon beta-1a 30 μg intramuscularly weekly and glatiramer acetate 20 mg daily did not show significantly greater clinical benefit over 3 years than either agent alone in relapsing-remitting multiple sclerosis (21). The effect of combined use was associated with reduction of lesion size on MRI and a higher proportion of patients that attained disease activity-free status but whether this would translate into clinical benefit at a later stage remains to be determined by an extension study.

A multicenter, open-label, non-randomized, prospective, pilot study has shown that following discontinuation of natalizumab, 1 year of therapy with glatiramer acetate is safe and well tolerated in multiple sclerosis patients and can reduce the risk of early rebound of disease (23).

A phase 3 multicenter, randomized, placebo-controlled trial, PreCISe, assessed effects of glatiramer acetate in patients with clinically isolated syndromes that were suggestive of multiple sclerosis (02). Measurement of N-acetylaspartate (NAA) by proton magnetic resonance spectroscopy, a biomarker of neuronal integrity, and increase of NAA/creatine ratio indicated a neuroprotective effect of glatiramer acetate.

A randomized, double-blind clinical trial showed that a glatiramer acetate dose of 40 mg subcutaneously three times a week was safe and effective for patients with relapsing-remitting multiple sclerosis and provided the convenience of fewer injections (17).

Goals and duration of treatment

The duration of glatiramer acetate treatment is indefinite. The goal is to reduce relapses of multiple sclerosis. Glatiramer acetate is a first-line therapy for the treatment of relapsing-remitting multiple sclerosis with a well-characterized safety profile and establish efficacy up to 20 years of continuous use (29). Whether prolonged treatment with glatiramer acetate reduces brain atrophy development in multiple sclerosis has not yet been established. Review of data from immunological and imaging studies that quantify axonal injury in the brain indicates a neuroprotective effect of glatiramer acetate. In a pilot study of relapsing-remitting multiple sclerosis, patients treated with glatiramer acetate did not have any clinical deterioration or spinal cord atrophy at 1 year as assessed by measurement of spinal cord volume by MRI as well as comparison with healthy controls (25). Because spinal cord atrophy occurs early during the course of multiple sclerosis and is closely related to physical disability, lack of atrophy is a possible neuroprotective therapeutic outcome measure.

Results of an observational study showed that glatiramer acetate slows the progression of Expanded Disability Status Scale scores more than other multiple sclerosis therapies and achieves a greater reduction in relapses as well as improvement in patients' quality of life (14). Switching from glatiramer acetate to other multiple sclerosis therapies did not improve response to treatment.

A retrospective study of relapsing-remitting multiple sclerosis patients has shown that glatiramer acetate is safe and useful, with low rates of serious adverse events and low rates of breakthrough disease, but development of intolerance to injection proved a major limitation to glatiramer acetate use (10). Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.

Phosphorylated SIRT1 is a potential biomarker of relapse and predictor of response to glatiramer acetate treatment in patients with relapsing-remitting multiple sclerosis and its downstream activation effects are shown by measuring the trimethylation of histone 3 at lysine 9. Findings of a clinical study showed that phosphorylated SIRT1 and histone 3 at lysine 9 are potential biomarkers for relapse and histone 3 at lysine 9 is a possible biomarker for predicting response to treatment of multiple sclerosis with glatiramer acetate (07).

Data from two independent multiple sclerosis trials, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating glatiramer acetate vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates on a set of baseline predictors (05). It was possible to select criteria, based on patients' characteristics, to choose whether to treat with glatiramer acetate or IFN-β-1a, which has implications for clinical decisions in everyday clinical practice.

JNK and phospho-Bcl-2 are possible biomarkers of multiple sclerosis relapse and therapeutic response to glatiramer acetate in relapsing-remitting multiple sclerosis patients. One study found significantly higher levels of JNK1 p54 as well as JNK2 p54 and significantly lower levels of p-Bcl-2 in relapse patients and in non-responders to glatiramer acetate (01). These biomarkers may be useful for the personalized therapy of multiple sclerosis with glatiramer acetate.

References

01: Anselmo F, Tatomir A, Boodhoo D, et al. JNK and phosphorylated Bcl-2 predict multiple sclerosis clinical activity and glatiramer acetate therapeutic response. Clin Immunol 2020;210:108297.** PMID 31698073
02: Arnold DL, Narayanan S, Antel S. Neuroprotection with glatiramer acetate: evidence from the PreCISe trial. J Neurol 2013;260(7):1901-6. PMID 23589190
03: Blanchette F, Neuhaus O. Glatiramer acetate: evidence for a dual mechanism of action. J Neurol 2008;255 Suppl 1:26-36. PMID 18317674
04: 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(7):408-14. PMID 3302705
05: Bovis F, Kalincik T, Lublin F, et al. Treatment response score to glatiramer acetate or interferon beta-1a. Neurology 2021;96(2):e214-27.** PMID 33024022
06: Braenne I, Zeng L, Willenborg C, et al. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. PLoS One 2017;12(8):e0182999. PMID 28829817
07: Ciriello J, Tatomir A, Hewes D, et al. Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp Mol Pathol 2018;105(2):175-80.** PMID 30028960
08: Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M; FORTE Study Group. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol 2011;69(1):75-82. PMID 21280077
09: Crescenzo F, Marastoni D, Zuco C, et al. Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2019;27:305-11.** PMID 30453199
10: Fernández-Fournier M, Tallón-Barranco A, Chamorro B, Martínez-Sánchez P, Puertas I. Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon. BMC Neurol 2015;15:141. PMID 26286576
11: Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR, et al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series. CNS Drugs 2010;24(11):969-76. PMID 20806993
12: Giannini M, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol 2012;12:124. PMID 23088447
13: Ireland SJ, Guzman AA, O'Brien D, et al. The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol 2014;71(11):1421-8. PMID 25264704
14: Izquierdo G, García-Agua Soler N, Rus M, García-Ruiz AJ. Effectiveness of glatiramer acetate compared to other multiple sclerosis therapies. Brain Behav 2015;5(6):e00337. PMID 26085963
15: Johnson KP. Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother 2012;12(4):371-84. PMID 22449210
16: 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. Neurology 1998;50(3):701-8. PMID 9521260
17: Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013;73(6):705-13. PMID 23686821
18: Kruszewski AM, Rao G, Tatomir A, et al. RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp Mol Pathol 2015;99(3):498-505.** PMID 26407760
19: Kuzina E, Kudriaeva A, Smirnov I, Dubina MV, Gabibov A, Belogurov A Jr. Glatiramer acetate and nanny proteins restrict access of the multiple sclerosis autoantigen myelin basic protein to the 26S proteasome. Biomed Res Int 2014;2014:926394.** PMID 25276831
20: La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 2010;5:CD004678. PMID 20464733
21: Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013;73(3):327-40. PMID 23424159
22: Ross CJ, Towfic F, Shankar J, et al. A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis. Genome Med 2017;9(1):50.** PMID 28569182
23: Rossi S, Motta C, Studer V, et al. Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab. Eur J Neurol 2013;20(1):87-94. PMID 22741530
24: Sellebjerg F, Hesse D, Limborg S, et al. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis. Mult Scler 2013;19(2):179-87. PMID 22653658
25: Singhal T, Tauhid S, Hurwitz S, Neema M, Bakshi R. The effect of glatiramer acetate on spinal cord volume in relapsing-remitting multiple sclerosis. J Neuroimaging 2017;27(1):33-6.** PMID 27466943
26: Spadaro M, Montarolo F, Perga S, et al. Biological activity of glatiramer acetate on Treg and anti-inflammatory monocytes persists for more than 10years in responder multiple sclerosis patients. Clin Immunol 2017;181:83-8. PMID 28642148
27: Teitelbaum D, Webb C, Bree M, Meshorer A, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer. Clin Immunol Immunopathol 1974;3(2):256-62. PMID 4141659
28: Weinstein A, Schwid SI, Schiffer RB, McDermott MP, Giang DW, Goodman AD. Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol 1999;56(3):319-24. PMID 10190822
29: Ziemssen T, Ashtamker N, Rubinchick S, Knappertz V, Comi G. Long-term safety and tolerability of glatiramer acetate 20 mg/ml in the treatment of relapsing forms of multiple sclerosis. Expert Opin Drug Saf 2017;16(2):247-55.** PMID 27989217

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Glatiramer acetate

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Glatiramer acetate

Glatiramer acetate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label and investigational uses:

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Serotonin syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Glatiramer acetate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label and investigational uses:

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Serotonin syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

This is an article preview.
Start a Free Account
to access the full version.