Identification

Summary

Glatiramer is an immunomodulator used to reduce the frequency of relapses in Multiple Sclerosis (MS).

Brand Names
Copaxone, Glatect, Glatopa
Generic Name
Glatiramer
DrugBank Accession Number
DB05259
Background

Glatiramer acetate is a mix of synthetic polypeptides that includes L-glutamic acid, L-alanine, L-tyrosine, and L-lysine at an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively.9 Since glatiramer acetate is a heterogeneous drug, there is limited information about its physicochemical properties.5 Originally, glatiramer acetate was designed as a stimulant of myelin basic protein (MBP), a myelin antigen involved in the development of multiple sclerosis (MS), to induce experimental autoimmune encephalitis (MS animal model).5 However, the opposite was observed. Glatiramer acetate exhibits several immunomodulatory effects and reduces the relapse rate of relapsing-remitting multiple sclerosis (RRMS) by 30%.5 Along with human interferon beta, teriflunomide, and dimethyl fumarate, glatiramer acetate is a first-line drug for patients with MS.8 It was approved by the FDA in 1996, and a generic version became available in 2017.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Peptides
Protein Chemical Formula
(C5H9NO4•C3H7NO2•C6H14N2O2•C9H11NO3)x•xC2H4O2
Protein Average Weight
7000.0 Da (Range 5000-9000)
Sequences
>Example Glatiramer peptide
EAYKAAEKAYAAKEAAKEAAKAKAEKKAAYAKAKAAKYEKKAKKAAAEYKKK
References:
  1. Qi GB, Gao YJ, Wang L, Wang H: Self-Assembled Peptide-Based Nanomaterials for Biomedical Imaging and Therapy. Adv Mater. 2018 May;30(22):e1703444. doi: 10.1002/adma.201703444. Epub 2018 Feb 20. [Article]
Download FASTA Format
Synonyms
  • (T,G)-A-L
  • COP 1
  • COP-1
  • Copolymer I (synthetic peptide)
  • Copolymer-1

Pharmacology

Indication

Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.9

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Glatiramer acetate is a mix of synthetic polypeptides that includes four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. This drug is indicated for the treatment of relapsing multiple sclerosis (MS) due to its ability to modify immune processes involved in the pathogenesis of this disease. Intact and large fragments of glatiramer acetate are recognized by glatiramer acetate-reactive antibodies. In vitro and in vivo studies suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. 9 A fraction of intact or partially hydrolyzed glatiramer acetate enters lymphatic circulation and is able to reach the lymph nodes.9 Compared to placebo and IFNb-1a, patients with relapsing-remitting MS receiving 20 mg/mL of glatiramer acetate once a day had significantly lower annualized relapse rates. Similar outcomes were observed in MS patients taking 40 mg/mL of glatiramer acetate three times a week.7

Some of the patients treated with glatiramer acetate (approximately 16%) have developed immediate post-injection reactions. Most of these cases are transient and do not require treatment, but there have been reports of patients requiring emergency medical care.9 Patients taking glatiramer acetate may also experience chest pain, injection site side effects such as localized lipoatrophy and skin necrosis, and hepatic injury.9 Since glatiramer acetate modifies immune response, it may interfere with immune function.9

Mechanism of action

The mechanism of action of glatiramer acetate has not been fully elucidated; however, it is thought to act by modifying immune processes involved in the pathogenesis of multiple sclerosis (MS).9 MS is characterized by damage to the myelin layer that covers nerve cells (demyelination) and axonal degeneration.2,6 Also, it has been suggested that the myelin basic protein (MBP), a myelin autoantigen, plays a role in the development of MS.2

Several mechanisms of action have been proposed. For instance, glatiramer acetate binds strongly to several major histocompatibility complex (MHC) class II molecules on MBP-specific antigen-presenting cells, preventing MBP from stimulating these cells.2,7 Glatiramer acetate also has the ability to shift the immune system from a pro-inflammatory to an anti-inflammatory pattern. It inhibits the secretion of pro-inflammatory cytokines (IL-2, IL-12, IFNγ, TNF) released by T helper 1 (Th1) cells, and induces T helper 2 (Th2) suppressor cells that are able to cross the blood-brain barrier and produce anti-inflammatory cytokines (IL-4, IL-5, IL-13, IL-10, TGF-β).6,7 It has also been suggested that glatiramer acetate induces the production of T-regulatory cells associated with the suppression of MS, such as CD4+, CD8+ and CD4+CD25+ cells.1,7

TargetActionsOrganism
UHLA class II histocompatibility antigen, DRB1-1 beta chain
binder
Humans
UHLA class II histocompatibility antigen, DRB1-15 beta chain
binder
Humans
UHLA class II histocompatibility antigen, DRB1-4 beta chain
binder
Humans
Absorption

After subcutaneous administration, most glatiramer acetate is rapidly absorbed and hydrolyzed locally.9 In 7 out of 9 healthy volunteers that received 60 mg of glatiramer acetate subcutaneously, the Cmax ranged from 69 to 126 ng/mL, while the other two subjects showed significantly higher values (605 and 301 ng/mL).10 AUC values showed great variability, ranging from 1,644 to 67,532 min⋅ng/mL.10 The Tmax of glatiramer acetate went from 15 to 30 min, and in all subjects, glatiramer acetate levels returned to baseline after 30-60 min.5,10 In healthy volunteers given 60 mg of glatiramer acetate subcutaneously, immunorecognizable fragments were no longer detected after 24 hours.6,10 The systemic bioavailability of glatiramer acetate is considered to be minimal.5 The pharmacokinetic parameters of glatiramer acetate in multiple sclerosis (MS) patients have not been determined.5

Volume of distribution

Not available.

Protein binding

Glatiramer acetate is highly bound to plasma proteins.6

Metabolism

Glatiramer acetate ​​is a mixture of synthetic polypeptides hydrolyzed by proteases.6,9

Route of elimination

In vivo studies have shown that glatiramer acetate is mainly excreted through urine.6

Half-life

Not available.

Clearance

Not available.

Adverse Effects
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Toxicity

In mice given 60 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis), glatiramer acetate did not increase systemic neoplasms. Similar results were obtained in rats given 30 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis).9 In vitro studies suggest that glatiramer acetate is non-mutagenic. No adverse effects were observed on reproductive or developmental parameters during in vivo studies.9 Overdose information regarding glatiramer acetate is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatic injury, lipoatrophy and skin necrosis at the injection site.9 Symptomatic and supportive measures are recommended.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Glatiramer.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Glatiramer.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Glatiramer.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Glatiramer.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Glatiramer.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Glatiramer.
Allogeneic processed thymus tissueThe therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Glatiramer.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Glatiramer.
AmsacrineThe risk or severity of adverse effects can be increased when Amsacrine is combined with Glatiramer.
AnakinraThe risk or severity of adverse effects can be increased when Anakinra is combined with Glatiramer.
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Glatiramer acetate5M691HL4BO147245-92-9Not applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CopaxoneInjection, solution40 mg/1mLSubcutaneousTeva Neuroscience, Inc.2014-01-29Not applicableUS flag
CopaxoneSolution40 mg / mLSubcutaneousTEVA Canada Limited2016-08-26Not applicableCanada flag
CopaxoneSolution40 mg / mLSubcutaneousTEVA Canada LimitedNot applicableNot applicableCanada flag
CopaxoneInjection, solution20 mg/1mLSubcutaneousTeva Neuroscience, Inc.2008-04-28Not applicableUS flag
CopaxoneSolution20 mg / mLSubcutaneousTEVA Canada Limited2002-05-01Not applicableCanada flag
CopaxonePowder, for solution20 mg / vialSubcutaneousTeva Pharmaceutical Industries1997-10-142011-04-28Canada flag
CopaxoneInjection20 mg/1mLSubcutaneousSanofi Aventis2002-04-222010-01-31US flag
GlatectSolution20 mg / mLSubcutaneousPharmascience Inc2017-08-21Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Glatiramer AcetateInjection, solution40 mg/1mLSubcutaneousMylan Pharmaceuticals Inc.2017-10-04Not applicableUS flag
Glatiramer AcetateInjection, solution20 mg/1mLSubcutaneousMylan Pharmaceuticals Inc.2017-10-04Not applicableUS flag
GlatopaInjection, solution20 mg/1mLSubcutaneousbryant ranch prepack2015-06-18Not applicableUS flag
GlatopaInjection, solution40 mg/1mLSubcutaneousSandoz Inc2018-02-12Not applicableUS flag
GlatopaInjection, solution40 mg/1mLSubcutaneousbryant ranch prepack2018-02-12Not applicableUS flag
GlatopaInjection, solution20 mg/1mLSubcutaneousSandoz Inc2015-06-18Not applicableUS flag
Teva-glatiramer AcetateSolution40 mg / mLSubcutaneousTEVA Canada LimitedNot applicableNot applicableCanada flag
Teva-glatiramer AcetateSolution20 mg / mLSubcutaneousTEVA Canada LimitedNot applicableNot applicableCanada flag

Categories

ATC Codes
L03AX13 — Glatiramer acetate
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
U782C039QP
CAS number
28704-27-0

References

Synthesis Reference

Dolitzky, BZ. (2006). Process for producing polypeptide mixtures using hydrogenolysis (U.S. Patent No. US 2006/0172942 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/b6/b3/7d/a80568fe5c6998/US20060172942A1.pdf

US20100036092
General References
  1. Weber MS, Hohlfeld R, Zamvil SS: Mechanism of action of glatiramer acetate in treatment of multiple sclerosis. Neurotherapeutics. 2007 Oct;4(4):647-53. [Article]
  2. Arnon R, Aharoni R: Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A. 2004 Oct 5;101 Suppl 2:14593-8. Epub 2004 Sep 15. [Article]
  3. Francis DA: Glatiramer acetate (Copaxone). Int J Clin Pract. 2001 Jul-Aug;55(6):394-8. [Article]
  4. Li Q, Milo R, Panitch H, Swoveland P, Bever CT Jr: Glatiramer acetate blocks the activation of THP-1 cells by interferon-gamma. Eur J Pharmacol. 1998 Jan 26;342(2-3):303-10. [Article]
  5. Song JY, Larson NR, Thati S, Torres-Vazquez I, Martinez-Rivera N, Subelzu NJ, Leon MA, Rosa-Molinar E, Schoneich C, Forrest ML, Middaugh CR, Berkland CJ: Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation. J Control Release. 2019 Jan 10;293:36-47. doi: 10.1016/j.jconrel.2018.11.007. Epub 2018 Nov 7. [Article]
  6. Messina S, Patti F: The pharmacokinetics of glatiramer acetate for multiple sclerosis treatment. Expert Opin Drug Metab Toxicol. 2013 Oct;9(10):1349-59. doi: 10.1517/17425255.2013.811489. Epub 2013 Jun 25. [Article]
  7. McKeage K: Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review. CNS Drugs. 2015 May;29(5):425-32. doi: 10.1007/s40263-015-0245-z. [Article]
  8. Gajofatto A, Benedetti MD: Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clin Cases. 2015 Jul 16;3(7):545-55. doi: 10.12998/wjcc.v3.i7.545. [Article]
  9. FDA Approved Drug Products: COPAXONE (glatiramer acetate), injection for subcutaneous use [Link]
  10. FDA Approval Package: COPAXONE (glatiramer acetate), injection for subcutaneous use [Link]
  11. Teva Pharmaceuticals: Glatiramer acetate SDS [Link]
PubChem Substance
46505299
RxNav
214582
ChEMBL
CHEMBL1201507
Therapeutic Targets Database
DAP001315
PharmGKB
PA449760
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Glatiramer_acetate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionMultiple Sclerosis1
4CompletedTreatmentMultiple Sclerosis4
4CompletedTreatmentMultiple Sclerosis, Relapsing Forms of Multiple Sclerosis1
4CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)4
4RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Relapsing Multiple Sclerosis (RMS)1
4RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4TerminatedPreventionRelapsing Remitting Multiple Sclerosis (RRMS)1
4TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4Unknown StatusTreatmentDiabetic Retinopathy (DR)1
4Unknown StatusTreatmentMultiple Sclerosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Baxter International Inc.
  • Ben Venue Laboratories Inc.
  • Sanofi-Aventis Inc.
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
Injection, solutionParenteral
InjectionSubcutaneous20 mg/1mL
Injection, powder, for solutionSubcutaneous20 mg/ml
Injection, solutionSubcutaneous20 mg/1mL
Injection, solutionSubcutaneous40 mg/1mL
Injection, solutionSubcutaneous40 MG/ML
Powder, for solutionSubcutaneous20 mg / vial
SolutionSubcutaneous20 mg / mL
SolutionSubcutaneous40 mg / mL
Injection, solutionSubcutaneous
SolutionSubcutaneous36 mg
Injection, solutionSubcutaneous20 MG/ML
SolutionSubcutaneous40 mg
Injection, solution
SolutionSubcutaneous20 mg
Injection, solution20 mg/ml
Injection, solution40 mg/ml
Prices
Unit descriptionCostUnit
Copaxone 20 mg/ml Kit 20 mg Solution, 1 Box = 30 Pre-Filled Syringes3775.25USD box
Copaxone 20 mg injection kit2264.26USD kit
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5981589No1999-11-092014-05-24US flag
CA2191088No2004-09-282015-05-23Canada flag
US8232250No2012-07-312030-08-19US flag
US8399413No2013-03-192030-08-19US flag
US8969302No2015-03-032030-08-19US flag
US9155776No2015-10-132030-08-19US flag
US9402874No2016-08-022030-08-19US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>236°C SDS

Targets

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1. HLA class II histocompatibility antigen, DRB1-1 beta chain
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Glatiramer binds MHC class II molecule HLA-DR1.
References
  1. Arnon R, Aharoni R: Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A. 2004 Oct 5;101 Suppl 2:14593-8. Epub 2004 Sep 15. [Article]
  2. Fridkis-Hareli M, Strominger JL: Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol. 1998 May 1;160(9):4386-97. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Glatiramer binds MHC class II molecule HLA-DR2 (HLA-DR15).
General Function
Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
Specific Function
Mhc class ii protein complex binding
Gene Name
HLA-DRB1
Uniprot ID
P01911
Uniprot Name
HLA class II histocompatibility antigen, DRB1-15 beta chain
Molecular Weight
29965.985 Da
References
  1. Fridkis-Hareli M, Strominger JL: Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol. 1998 May 1;160(9):4386-97. [Article]
3. HLA class II histocompatibility antigen, DRB1-4 beta chain
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Glatiramer binds MHC class II molecule HLA-DR4.
References
  1. Fridkis-Hareli M, Strominger JL: Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol. 1998 May 1;160(9):4386-97. [Article]

Drug created at November 18, 2007 18:22 / Updated at August 08, 2022 14:39