Glatiramer acetate: Difference between revisions

{{Short description|Medication}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 387696338

| image = Glatiramer acetate.svg

| alt =

<!--Clinical data -->

| tradename = Copaxone,<ref name="Copaxone FDA label" /> Glatopa,<ref name="Glatopa FDA label" /> Brabio

| Drugs.com = {{drugs.com|monograph|glatiramer_acetate}}

| MedlinePlus = a603016

| DailyMedID = Glatiramer

| pregnancy_AU = B1

| routes_of_administration = [[Subcutaneous injection]]

| ATC_prefix = L03

| ATC_suffix = AX13

| legal_AU = S4

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title= Neurological therapies | website=[[Health Canada]] | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/neurological-therapies.html | access-date=13 April 2024}}</ref>

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Brabio 20 mg/mL Solution for Injection, Pre-filled Syringe - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/8536/smpc | access-date=11 November 2020}}</ref><ref>{{cite web | title=Copaxone 20 mg/ml solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC) | website=(emc) | date=29 September 2020 | url=https://www.medicines.org.uk/emc/product/183/smpc | access-date=11 November 2020}}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Copaxone FDA label">{{cite web | title=Copaxone- glatiramer acetate injection, solution | website=DailyMed | date=23 July 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa88f583-4f5f-433b-80b4-1f4c9fb28357 | access-date=11 November 2020}}</ref><ref name="Glatopa FDA label">{{cite web | title=Glatopa- glatiramer acetate injection, solution | website=DailyMed | date=31 July 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5f01e40a-b6f6-40fb-b37c-3d06f1428e86 | access-date=11 November 2020}}</ref>

<!--Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 147245-92-9

| PubChem = 3081884

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB05259

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 5M691HL4BO

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201507

<!-- Chemical data -->

| C=25 | H=45 | N=5 | O=13

'''Glatiramer acetate''' (also known as '''Copolymer 1''', '''Cop-1'''), sold under the brand name '''Copaxone''' among others, is an [[immunomodulator]] medication used to treat [[multiple sclerosis]].<ref name="Copaxone FDA label" /><ref name="Glatopa FDA label" /> Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reducing the progression of disability. [[Observational study|Observational studies]], but not randomized controlled trials, suggest that it may reduce progression of disability. While a conclusive [[diagnosis of multiple sclerosis]] requires a history of two or more episodes of symptoms and signs, glatiramer acetate is approved to treat a first episode anticipating a diagnosis. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by [[subcutaneous injection]].<ref name="Copaxone FDA label" /><ref name="Glatopa FDA label" />

It is a mixture of random-sized peptides that are composed of the four [[amino acids]] found in [[myelin basic protein]], namely [[glutamic acid]], [[lysine]], [[alanine]], and [[tyrosine]]. Myelin basic protein is the [[antigen]] in the [[myelin sheaths]] of the neurons that stimulates an [[autoimmune]] reaction in people with MS, so the peptide may work as a decoy for the attacking immune cells.

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

== History ==

Glatiramer acetate was originally discovered at the [[Weizmann Institute of Science]]. Three main clinical trials followed to demonstrate safety and efficacy: The first trial was performed in a single center, double-blind, [[placebo-controlled studies|placebo controlled trial]] and included 50 patients.<ref>{{cite journal | vauthors = Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E, Keilson M, Merriam A, Wassertheil-Smoller S, Spada V | title = A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis | journal = The New England Journal of Medicine | volume = 317 | issue = 7 | pages = 408–14 | date = August 1987 | pmid = 3302705 | doi = 10.1056/NEJM198708133170703 }}</ref>

The second trial was a two-year, multi-center, randomized, double-blind, placebo controlled trial and involved 251 patients.<ref>{{cite journal | vauthors = Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB | title = 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 | journal = Neurology | volume = 45 | issue = 7 | pages = 1268–76 | date = July 1995 | pmid = 7617181 | doi = 10.1212/WNL.45.7.1268 | s2cid = 28895177 }}</ref> The third trial was a double-blind [[MRI]] study involving participation of 239 patients.<ref>{{cite journal | vauthors = Comi G, Filippi M, Wolinsky JS | title = 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 | journal = Annals of Neurology | volume = 49 | issue = 3 | pages = 290–7 | date = March 2001 | pmid = 11261502 | doi = 10.1002/ana.64 | s2cid = 35614752 }}</ref>

== Medical uses ==

Glatiramer acetate is [[Indication (medicine)|indicated]] for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.<ref name="Copaxone FDA label" />

A 2010 [[Cochrane (organisation)|Cochrane]] review concluded that glatiramer acetate had partial efficacy in "relapse-related clinical outcomes" but no effect on progression of the disease.<ref name="2010cochrane">{{cite journal | vauthors = La Mantia L, Munari LM, Lovati R | title = Glatiramer acetate for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD004678 | date = May 2010 | pmid = 20464733 | doi = 10.1002/14651858.CD004678.pub2 }}</ref> As a result, it is approved by the FDA for reducing the frequency of relapses, but not for reducing the progression of disability.<ref name="Copaxone FDA label" /><ref name="Glatopa FDA label" />

A 15-year followup of the original trial compared patients who continued with glatiramer to patients who dropped out of the trial. Patients with glatiramer had reduced relapse rates, and decreased disability progression and transition to secondary progressive MS, compared to patients who did not continue glatiramer. However, the two groups were not necessarily comparable, as it was no longer a randomized trial. There were no long-term safety issues.<ref name="Ford2010">{{cite journal | vauthors = Ford C, Goodman AD, Johnson K, Kachuck N, Lindsey JW, Lisak R, Luzzio C, Myers L, Panitch H, Preiningerova J, Pruitt A, Rose J, Rus H, Wolinsky J | display-authors = 6 | title = Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate | journal = Multiple Sclerosis | volume = 16 | issue = 3 | pages = 342–50 | date = March 2010 | pmid = 20106943 | pmc = 2850588 | doi = 10.1177/1352458509358088 | doi-access = free }}</ref>

== Adverse effects ==

[[File:Copaxone Injection Site Reaction.JPG|thumb|An injection site reaction on the upper left arm]]

Side effects may include a lump at the injection site ([[injection site reaction]]) in approximately 30% of users, and aches, fever, chills (flu-like symptoms) in approximately 10% of users.<ref>{{cite web | url = https://www.mediguard.org/medication/view/copaxone | title = Copaxone | publisher = MediGuard }}</ref> Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness of breath, anxiety and rapid heartbeat has been reported soon after injection in up to 5% of patients (usually after inadvertently injecting directly into a vein). These side effects subside within thirty minutes. Over time, a visible dent at a repeat-injection site can occur due to the local destruction of fat tissue, known as [[lipoatrophy]], that may develop.

More serious side effects have been reported for glatiramer acetate, according to the FDA's prescribing label, these include serious side effects to the cardiovascular, digestive (including the liver), hematopoietic, lymphatic, musculoskeletal, nervous, respiratory, and urogenital systems as well as special senses (in particular the eyes). Metabolic and nutritional disorders have also been reported; however a link between glatiramer acetate and these adverse effects has not been established.<ref name="Copaxone FDA label" /><ref name="Glatopa FDA label" />

It may also cause [[Jessner lymphocytic infiltrate]].<ref>{{cite book | vauthors = Krafchik BR | veditors = Schachner LA, Hansen RC | title = Pediatric Dermatology | chapter = Reaction Patterns | date = 2011 | publisher = Elsevier Health Sciences | isbn = 978-0-7234-3665-2 | page = 1022 | chapter-url = https://books.google.com/books?id=tAlGLYplkacC&pg=PA1022 }}</ref>

== Mechanism of action ==

Glatiramer acetate is a random polymer (average molecular mass 6.4&nbsp;[[Unified atomic mass unit|kD]]) composed of four [[amino acids]] found in [[myelin basic protein]]. The mechanism of action for glatiramer acetate is not fully elucidated. It is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. Administration of glatiramer acetate shifts the population of T cells from proinflammatory [[T helper cell#Th1.2FTh2 model|Th1 T-cells]] to regulatory [[T helper cell#Th1.2FTh2 model|Th2 T-cells]] that suppress the inflammatory response.<ref>{{cite journal | vauthors = Arnon R, Sela M | url = http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdf | archive-url = https://web.archive.org/web/20030907080548/http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdf | url-status = dead | archive-date = 2003-09-07 | title = The chemistry of the Copaxone drug | pages = 12–17 | journal = Chem. Israel | year = 1999 | volume = 1 }}</ref> This is done by the inhibition of secretion of proinflammatory cytokines (IL-1, IL-12, TNF, INFγ) by Th1 T-cells, thereby inducing Th2 T-cells to cross the blood–brain barrier and produce anti-inflammatory cytokines (IL-4, IL-5, IL-13, IL-10, TGF-β).<ref>https://go.drugbank.com/drugs/DB05259; Glatiramer Mechanism of Action</ref> Given its resemblance to myelin basic protein, glatiramer acetate may act as a decoy, diverting an autoimmune response against myelin. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of [[experimental autoimmune encephalomyelitis]] (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific [[regulatory T cells]] (Tregs) are induced and activated in the periphery, inhibiting the inflammatory reaction to myelin basic protein.<ref name="Copaxone FDA label" /><ref name="Glatopa FDA label" />

The integrity of the [[blood–brain barrier]], however, is not appreciably affected by glatiramer acetate, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of multiple sclerosis exacerbations.<ref>{{cite web | url = http://www.mult-sclerosis.org/Copaxone.html | title = Copaxone | work = All About Multiple Sclerosis }}</ref>

==Society and culture==

=== Marketing ===

Glatiramer acetate has been approved for marketing in numerous countries worldwide, including the [[United States]], [[Israel]], [[Canada]] and 24 [[European Union]] countries.<ref>{{cite journal | vauthors = McKeage K | title = Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review | journal = CNS Drugs | volume = 29 | issue = 5 | pages = 425–32 | date = May 2015 | pmid = 25906331 | doi = 10.1007/s40263-015-0245-z | s2cid = 30186027 }}</ref><ref>{{cite journal | vauthors = Comi G, Amato MP, Bertolotto A, Centonze D, De Stefano N, Farina C, Gallo P, Ghezzi A, Grimaldi LM, Mancardi G, Marrosu MG, Montanari E, Patti F, Pozzilli C, Provinciali L, Salvetti M, Tedeschi G, Trojano M | display-authors = 6 |title=The heritage of glatiramer acetate and its use in multiple sclerosis|journal=Multiple Sclerosis and Demyelinating Disorders|date=2016|volume=1|issue=1|doi=10.1186/s40893-016-0010-2|doi-access=free}}</ref> Approval in the U.S. was obtained in 1997.<ref>{{cite web |url=http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/211/copaxone|work= CenterWatch | title = Copaxone}}</ref> Glatiramer acetate was approved for marketing in the [[U.K.]] in August 2000, and launched in December.<ref>{{cite web|url=http://www.thepharmaletter.com/article/teva-s-copaxone-approved-in-uk|title=Teva's Copaxone approved in UK | work = The Pharma Letter }}</ref> This first approval in a major European market led to approval across the [[European Union]] under the [[Heads of Medicines Agencies|mutual recognition procedure]].

Iran is proceeding with domestic manufacture of glatiramer acetate.<ref>{{cite web | url = http://tofighdaru.ir/en/products-2/glatiramer-acetate/ | publisher = Tofigh Daru Research and Engineering Company | title = Glatiramer Acetate | access-date = 2017-02-01 | archive-date = 2018-10-21 | archive-url = https://web.archive.org/web/20181021221746/http://tofighdaru.ir/en/products-2/glatiramer-acetate/ | url-status = dead }}</ref><ref>{{cite web | url = http://en.trend.az/iran/2020693.html | title = Iran to manufacture multiple sclerosis cure | work = Trend News Agency | date = 1 May 2012 | vauthors = Isayev S, Jafarov T }}</ref>

=== Patent status ===

[[Novartis]] subsidiary Sandoz has marketed Glatopa since 2015, a generic version of the original Teva 20&nbsp;mg formulation that requires daily injection.<ref>{{cite web | url = https://www.novartis.com/news/media-releases/sandoz-announces-us-launch-glatopatm-first-generic-competitor-copaxone%C2%AE-20mg | title = Sandoz announces US launch of Glatopa | year = 2015 | publisher = Novartis | access-date = 2017-02-21 | archive-date = 2018-02-03 | archive-url = https://web.archive.org/web/20180203181521/https://www.novartis.com/news/media-releases/sandoz-announces-us-launch-glatopatm-first-generic-competitor-copaxone%C2%AE-20mg | url-status = dead }}</ref>

Teva developed a long-acting 40&nbsp;mg formulation, marketed since 2015, which reduced required injections to three per week.<ref>{{cite web|url=https://multiplesclerosisnewstoday.com/2015/10/09/new-3-times-per-week-regimen-tevas-copaxone-safe-effective-increases-patient-compliance-ectrims2015/|title=New 3-Times-Per-Week Regimen For Teva's Copaxone | work = Multiple Sclerosis News Today | date = 9 October 2015 | vauthors = Silva P }}</ref> In October 2017, the FDA approved a generic version, which is manufactured in India by [[Natco Pharma]], and imported and sold by Dutch firm [[Mylan]].<ref>{{cite news | vauthors = Erman M, Grover D | url = https://www.reuters.com/article/us-mylan-nl-stocks-teva-pharm-ind/mylan-surges-teva-slumps-after-fda-okays-copaxone-copy-idUSKCN1C91CT | title = Mylan surges, Teva slumps after FDA okays Copaxone copy | newspaper = Reuters | date = 3 October 2017 | access-date=4 October 2017 }}</ref><ref>{{cite web|url=http://www.natcopharma.co.in/about/news|title=NATCO's marketing partner Mylan receives final approval of generic glatiramer acetate, for both 20 mg/mL and 40 mg/mL versions|website=NATCO Pharma (India)|date=3 October 2017|access-date=4 October 2017|archive-date=10 January 2019|archive-url=https://web.archive.org/web/20190110005909/http://www.natcopharma.co.in/about/news/|url-status=dead}}></ref> In February 2018, Sandoz received FDA approval for their generic version.<ref>{{cite web|url=https://www.novartis.com/news/media-releases/sandoz-announces-us-fda-approval-and-launch-glatopar-40-mgml-three-times-week-generic-option-relapsing-forms-multiple-sclerosis|title=Sandoz announces US FDA approval and launch of Glatopa 40 mg/mL|website=Novartis International AG|date=February 13, 2018|access-date=May 10, 2018}}</ref> In parallel with the development and approval processes, the generic competitors have disputed Teva's newer patents, any of which if upheld, would prevent marketing of long-acting generics.<ref>{{cite web|url=http://www.biopharmadive.com/news/tevas-copaxone-still-growing-despite-patent-risks/423956/|title=Teva's Copaxone still growing despite patent risks | work = BioPharmaDive }}</ref>

While the [[Chemical patent|patent]] on the chemical drug expired in 2015,<ref>{{cite web | vauthors = Helfand C | url = http://www.fiercepharma.com/special-report/copaxone | title = Copaxone | work = FiercePharma }}</ref> Teva obtained new US patents covering pharmaceutical formulations for long-acting delivery.<ref>{{cite web | vauthors = Decker S | date = 1 September 2016 | url = https://www.bloomberg.com/news/articles/2016-09-01/teva-loses-decision-on-validity-of-302-copaxone-patent | title = Teva loses decision on validity of 302 copaxone patent | work = Bloomberg Markets }}</ref> Litigation from industry competitors in 2016-2017 resulted in the new patents being judged invalid.<ref>{{cite web | vauthors = Decker S, Flanagan C, Benmeleh Y | date = 30 January 2017 | url = https://www.bloomberg.com/news/articles/2017-01-30/teva-loses-ruling-invalidating-patents-on-copaxone-drug | title = Teva loses ruling invalidating patents on copaxone drug | work = Bloomberg Markets }}</ref><ref>{{Cite news|url=https://www.newspapers.com/clip/21233509/in_the_region/|title=Teva loses patent ruling|last=<!-- no byline -->|date=September 2, 2017|work=The Philadelphia Inquirer|access-date=June 23, 2018|agency=Bloomberg News|department=Briefcase|page=A12|via=Newspapers.com (Publisher Extra)}}</ref> In October 2018, the [[U.S. Court of Appeals]] for the [[Federal Circuit]] upheld the patent invalidation for [[Inventive step and non-obviousness|obviousness]].<ref>{{cite news|url=https://www.reuters.com/article/teva-mylan-patent/update-1-us-appeals-court-upholds-ruling-that-canceled-teva-copaxone-patents-idUSL2N1WS0PB|newspaper=Reuters|title=U.S. appeals court upholds ruling that canceled Teva Copaxone patents|date=October 12, 2018|access-date=October 12, 2018}}</ref><ref>{{cite web|url=http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/17-1575.Opinion.10-12-2018.pdf|website=United States Court of Appeals for the Federal Circuit|title=In Re: Copaxone Consolidated Cases|date=October 12, 2018|access-date=October 12, 2018}}</ref> The case reflects the larger controversy over [[evergreening]] of generic drugs.

== References ==

{{reflist}}

{{Portal bar | Medicine}}

{{DEFAULTSORT:Glatiramer Acetate}}

[[Category:Drugs with unknown mechanisms of action]]

[[Category:Israeli inventions]]

[[Category:World Health Organization essential medicines]]