Glatiramer acetate

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Glatiramer acetate
Clinical data
Trade names Copaxone,[1] Glatopa[2]
AHFS/ Monograph
License data
  • US: B (No risk in non-human studies)
Routes of
Subcutaneous injection
ATC code
Legal status
Legal status
CAS Number
PubChem CID
  • none
Chemical and physical data
Formula C25H45N5O13
Molar mass 623.65 g/mol
 NYesY (what is this?)  (verify)

Glatiramer acetate (also known as Copolymer 1, Cop-1, or Copaxone - as marketed by Teva Pharmaceuticals) is an immunomodulator drug currently used to treat multiple sclerosis. It is a random polymer of four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine, and may work as a decoy for the immune system. Glatiramer acetate is approved by the Food and Drug Administration (FDA) for reducing the frequency of relapses, but not for reducing the progression of disability. 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.

Medical uses[edit]

A 2010 Cochrane review concluded that glatiramer acetate had partial efficacy in "relapse-related clinical outcomes" but no effect on progression of the disease.[3][4]

A trial of 251 patients, after two years failed to show any advantage in halting disability progression.[5][6] As a result, it is approved by the FDA for reducing the frequency of relapses, but not for reducing the progression of disability.[7]

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.[8]

In two recent studies, both reported at the 2007 ECTRIMS meeting, the efficacy of glatiramer acetate was compared to high-dose/high-frequency interferon beta. In the REGARD study,[citation needed] Rebif was compared to glatiramer, and in the BEYOND study,[citation needed] Betaseron was compared to glatiramer. In both trials, there was no significant difference between interferon and glatiramer in the primary endpoints (time to relapse) or in any clinical endpoints, although some differences in MRI measures of disease activity have been claimed.

A double-blind 3-year study found no effect of glatiramer acetate on primary-progressive multiple sclerosis.[9]

It has FDA approval for clinically isolated syndrome, based on the PreCISe trial, which showed that glatiramer delayed the progression from the first clinical event to clinically definite multiple sclerosis with a risk reduction of 45%. 43% of patients in the placebo group converted, compared to 25% in the glatiramer group.[10]

Adverse effects[edit]

An injection site reaction on the upper left arm

According to MediGuard, 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.[11] Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness in breath, anxiety and rapid heartbeat has been reported soon after injection in up to 5% of patients (usually after injecting directly into a vein). These side effects subside within thirty minutes. Over time, a visible dent at the 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.[12]

It may also cause Jessner lymphocytic infiltrate.[13]

Mechanism of action[edit]

Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids found in myelin basic protein. The mechanism of action for glatiramer acetate is unknown. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response.[14] Given its resemblance to myelin basic protein, glatiramer acetate may also act as a decoy, diverting an autoimmune response against myelin. 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.[15]

The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS. 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 suppressor T-cells are induced and activated in the periphery.[16]


Glatiramer acetate was originally discovered by Michael Sela, Ruth Arnon and Dvora Teitelbaum at the Weizmann Institute of Science in Rehovot, Israel. Three main clinical trials followed to demonstrate safety and efficacy: The first trial, led by Murray Bornstein, was performed in a single center, double-blind, placebo controlled trial and included 50 patients.[17] The second trial was a two-year, multi-center, randomized, double-blind, placebo controlled trial and was performed in eleven United States centers involving 251 patients. This study was led by Kenneth Johnson at University of Maryland Medical Center.[18] The third trial, a double-blind, multi-center, multi-country MRI study, involved 29 MS Centers in six European countries and Canada, with the participation of 239 patients. This study was led by G. Comi at the Department of Neuroscience, San Raffaele Hospital, the University of Milan.[19]

Society and culture[edit]


Glatiramer acetate has been approved for marketing in numerous countries worldwide, including the United States, Israel, Canada and 24 European Union countries.[20][21] Approval in the U.S. was obtained in 1997.[22] Glatiramer acetate was approved for marketing in the U.K. in August 2000, and launched in December.[23] This first approval in a major European market led to approval across the European Union under the mutual recognition procedure. Iran is proceeding into domestic manufacture of Glatiramer acetate.[24][25]

Patent status[edit]

Novartis subsidiary Sandoz has marketed Glatopa since 2015, a generic version of the original Teva 20 mg formulation that requires daily injection.[26]

Teva developed a long-acting 40 mg formulation, marketed since 2015, which reduced required injections to three per week.[27] Sandoz is also developing a generic long-acting version, Momenta Pharmaceuticals M356, which is yet to be approved by the FDA and has been subject to a technical FDA warning letter.[28][29] 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.[30]

While the patent on the chemical drug expired in 2015,[31] Teva obtained new US patents covering pharmaceutical formulations for long-acting delivery.[32] Litigation from industry competitors in 2016-2017 has resulted in four of the five new patents being judged invalid, and the fifth remains under challenge.[33] The case reflects the larger controversy over evergreening of generic drugs.


Glatiramer acetate has been found to be protective in a mouse model of cerebral malaria.[34]

In 2015 researchers presented results of a small, uncontrolled study of glatiramer acetate given to girls with Rett syndrome, showing association with improvement in symptoms.[35]

Copaxone was the subject of a phase 1 clinical trial (2008-2013) of its potential therapy for dry age-related macular degeneration (AMD).[36]

See also[edit]


  1. ^ "Copaxone® (official Web site)". 
  2. ^ "Glatopa® (official Web site)". 
  3. ^ La Mantia, L; Munari, LM; Lovati, R (12 May 2010). "Glatiramer acetate for multiple sclerosis.". The Cochrane database of systematic reviews (5): CD004678. PMID 20464733. 
  4. ^ La Mantia L, Munari LM, Lovati R (2010). "Glatiramer acetate for multiple sclerosis". Cochrane Database of Systematic Reviews. 5: CD004678. PMID 20464733. doi:10.1002/14651858.CD004678.pub2. 
  5. ^ Johnson KP, Brooks BR, Cohen JA, et al. (July 1995). "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. 45 (7): 1268–76. PMID 7617181. doi:10.1212/WNL.45.7.1268. 
  6. ^ Johnson KP, Brooks BR, Cohen JA, et al. (March 1998). "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. 50 (3): 701–8. PMID 9521260. doi:10.1212/WNL.50.3.701. 
  7. ^ Prescribing Information (Package insert) Label approved on 02/27/2009 (PDF) for COPAXONE, NDA no. 020622 at Drugs@FDA
  8. ^ Ford C, Goodman AD, Johnson K, et al. (March 2010). "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" (PDF). Multiple Sclerosis. 16 (3): 342–50. PMC 2850588Freely accessible. PMID 20106943. doi:10.1177/1352458509358088. 
  9. ^ Wolinsky J, Narayana P, O'Connor P, et al. (January 2007). "Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial" (PDF). Ann Neurol. 61 (1): 14–24. PMID 17262850. doi:10.1002/ana.21079. 
  10. ^ Early Treatment With COPAXONE Demonstrated Robust Protection Against Progression To Clinically Definite Multiple Sclerosis In The PreCISe Study
  11. ^ Copaxone satisfaction and usage data | Monitoring more than 2,100 patients | Drug safety information | MediGuard
  12. ^ FDA Copaxone Label
  13. ^ Schachner, Lawrence A.; Hansen, Ronald C. (2011). Pediatric Dermatology. Elsevier Health Sciences. p. 1022. ISBN 0723436657. 
  14. ^ The chemistry of the Copaxone drug{}
  15. ^ Copaxone. All About Multiple Sclerosis.
  16. ^ "Copaxone (glatiramer acetate) injection, solution". Daily Med.
  17. ^ Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E, Keilson M, Merriam A, Wassertheil-Smoller S, Spada V, et al. (1987). "A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis". New Engl J Med. 317 (7): 408–14. 
  18. ^ Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW,Panitch HS, Rose JW, Schiffer RB (July 1995). Neurology 45 (7): 1268-76.
  19. ^ Comi G, Filippi M, Wolinsky JS (March 2001). Ann Neurol 49 (3): 290-7.
  20. ^ McKeage K. "Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review". CNS Drugs. 29: 425–32. PMID 25906331. doi:10.1007/s40263-015-0245-z. 
  21. ^ "The heritage of glatiramer acetate and its use in multiple sclerosis". 
  22. ^ "CenterWatch: Copaxone". 
  23. ^ "Teva's Copaxone approved in UK". 
  24. ^ "Tofigh Daru Research and Engineering Company: Glatiramer Acetate". 
  25. ^ "Iran to manufacture multiple sclerosis cure". 
  26. ^ "Sandoz announces US launch of Glatopa (2015)". 
  27. ^ "New 3-Times-Per-Week Regimen For Teva’s Copaxone". 
  28. ^ "M356 (Generic three times weekly COPAXONE® 40mg)". 
  29. ^ "Momenta Pharmaceuticals Announces FDA Warning Letter to Contracted Glatopa". 
  30. ^ "Teva's Copaxone still growing despite patent risks". 
  31. ^ "Copaxone". 
  32. ^ "Teva loses decision on validity of 302 copaxone patent". 
  33. ^ "Teva loses ruling invalidating patents on copaxone drug". 
  34. ^ Lackner P, Part A, Burger C, et al. (February 2009). "Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study" (PDF). Malar. J. 8 (1): 36. PMC 2651188Freely accessible. PMID 19250545. doi:10.1186/1475-2875-8-36. 
  35. ^ Djukic A; et al. "OP23 – 2759: Pharmacological treatment of Rett syndrome with glatiramer acetate (Copaxone)". European Journal of Paediatric Neurology. 19: S8. doi:10.1016/S1090-3798(15)30024-6. 
  36. ^ U.S. National Institutes of Health (May 2, 2013). "Weekly Vaccination With Copaxone as a Potential Therapy for Dry Age-related Macular Degeneration". 

External links[edit]