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Glatiramer acetate

File:Glatiramer acetate.png
Clinical data
ATC code	L03AX13 (WHO)
Identifiers
IUPAC name acetic acid; (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid; (2S)-2-aminopentanedioic acid; (2S)-2-aminopropanoic acid; (2S)-2,6-diaminohexanoic acid
CAS Number	147245-92-9
PubChem CID	3081884
DrugBank	APRD00999
UNII	5M691HL4BO
CompTox Dashboard (EPA)	DTXSID30163637
ECHA InfoCard	100.248.824
Chemical and physical data
Formula	C25H45N5O13
Molar mass	623.65 g/mol g·mol

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. Although the clinical definition of multiple sclerosis requires two or more episodes of symptoms and signs, glatiramer acetate is approved for treatment after single episodes. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by subcutaneous injection.

Mechanism of action

Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids that are found in myelin basic protein. The mechanism of action for glatiramer is unknown, although several have been proposed. Administration of glatiramer shifts the population of T cells from pro-inflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response. Given its resemblance to myelin basic protein, glatiramer may also act as a sort of decoy, diverting an autoimmune response against myelin. The integrity of the blood-brain barrier, however, is not appreciably affected by glatiramer, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of exacerbations.

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.

Development

Glatiramer acetate was originally discovered by Professor Ruth Arnon, Professor Michael Sela, and Dr. Dvora Teitelbaum at the Weizmann Institute of Science in Rehovot, Israel. The efficacy and safety of glatiramer acetate were demonstrated in three main clinical trials. The first trial, led by Professor Murray Bornstein, was performed in a single center, double-blind, placebo controlled trial and included 50 patients. The second trial was a 2-year, multi-center, randomized, double-blind, placebo controlled trial and was performed in eleven US centers involving 251 patients. This study was led by Professor Kenneth Johnson, Chairman of the Department of Neurology, University of Maryland Medical Center, Baltimore. 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 Professor G. Comi, Department of Neuroscience, San Raffaele Hospital, the University of Milan.

Marketing and distribution

Glatiramer acetate has been approved for marketing in 47 countries worldwide, including the United States, Israel, Canada, 22 European Union Countries including the new accessors, Switzerland, Australia, Russia, Brazil, Argentina and Czech republic.

Approval in the US was obtained in 1996. Glatiramer acetate was approved for marketing in the U.K. in August 2000, and launched in December. This first approval in a major European market enabled Teva to file for approval all over the European Union under the mutual recognition procedure.

Side effects

Side effects can include a lump at the injection site (injection site reaction) in approximately 30% of users, and aches, fever, chills (flu-like symptoms) in 10% of users. (?) Copaxone is the only disease modifying drug that does not cause flu like symptoms in patients. Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness in breath, anxiety & 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 body's Cardiovascular System, Digestive System (including Liver), Hemic and Lymphatic System, Musculoskeletal System, Nervous System, Respiratory System, Special Senses (in particular the eyes), Urogenital System; also reported have been Metabolic and Nutritional Disorders; however a link between glatiramer acetate and these adverse effects has not been definitively established.

Effectiveness

Evidence supporting the effectiveness of glatiramer acetate in decreasing the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RR MS) derives from two placebo-controlled trials, both of which used a glatiramer acetate dose of 20 mg/day. (No other dose or dosing regimen has been studied in placebo-controlled trials of RR MS). A comparative trial of the approved 20 mg dose and the 40 mg dose showed no significant difference in efficacy between these doses.

In its pivotal trial of 251 patients, after 2 years Copaxone failed to show any advantage in halting disability progression (78% of treated patients were Progression-free versus 75% Progression-free on placebo).

A 2004 Cochrane Medical review pointed out that "Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses."

As a result, the FDA marketing label for Copaxone does not as yet have an indication for reducing the progression of disability.

On February 25, 2010, a long-term study on Copaxone was published in the February issue of the journal Multiple Sclerosis. It was the longest prospective and continuous evaluation ever conducted in relapsing-remitting multiple sclerosis. The fifteen-year clinical study showed that more than 80 percent of patients were still walking without assistance, despite a mean MS disease duration of 22 years, and two-thirds of the patients have not as yet transitioned to secondary progressive MS. Patients who remained in the study over 15 years showed a reduction in relapse rate from baseline, as well as minimal increase on the Expanded Disability Status Scale (EDSS.) It also established the long-term safety profile associated with Copaxone.

In 2 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, Rebif was compared to glatiramer, and in the BEYOND study, 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 recent study by the Department of Neurology at The University of Texas Health Science Center argues that a double-blind three year study failed to demonstrate a treatment effect of Glatiramer acetate on Primary-Progressive Multiple Sclerosis.

In February, 2009, the FDA approved an expanded indication for Copaxone "for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis."

The expansion of Copaxone's indication to include patients with a Clinically Isolated Syndrome (CIS) is based on a clinical trial (PreCISe) which showed that Copaxone delayed the progression from the first clinical event to Clinically Definite Multiple Sclerosis (CDMS) in a statistically significant and clinically meaningful manner, corresponding to a risk reduction of 45%. The proportion of patients who converted to CDMS was 43% for the placebo group and 25% in the Copaxone group.

Research

Glatiramer has been found to be protective in a mouse model of cerebral malaria.

Glatiramer is currently in Phase I clinical trials for Dry Age-Related Macular Degeneration (AMD).

References

1. The chemistry of the Copaxone drug
2. www.mult-sclerosis.org
4. iGuard.org TSQM survey results (n=1700+): http://www.iguard.org/medication/copaxone
5. FDA Copaxone Label: http://www.fda.gov/cder/foi/label/2001/20622s15lbl.pdf
6. http://www.copaxone.com/pdf/PrescribingInformation.pdf
7. the 9006 trial; Cohen JA et al. Neurology. 2007;68:939-944)
8. FDA marketing label - http://www.copaxone.com/pdf/PrescribingInformation.pdf
9. Cochrane Medical review of Copaxone - http://www.cochrane.org/reviews/en/ab004678.html
10. Copaxone marketing materials - http://www.copaxone.com/NewlyDiagnosed/pivotTrial.aspx
11. The study “Continuous Long-Term Immunomodulatory Therapy in Relapsing Multiple Sclerosis: Results from the 15-Year Analysis of the U.S. Prospective Open-label Study of Glatiramer Acetate,” a follow-up to the pivotal, Phase III trial, followed 100 ongoing Copaxone® (glatiramer acetate injection) patients starting in 1991. Patients' EDSS scores were evaluated every six months. Confirmed disability progression was defined as ‰¥1.0 EDSS point increase sustained for six months. Patients were classified as “stable/improved” if EDSS score changes were less or equal to 0.5 points. Proportions of patients who reached confirmed thresholds of EDSS 4, 6, or 8 while on Copaxone®, and Kaplan-Meier (KM) estimates of median times to these thresholds, were obtained. http://www.mscare.org/cmsc/Informs-Copaxone-Demonstrates-Robust-Long-Term-Efficacy-and-Safety.html
12. Wolinsky J, Narayana P, O'Connor P; et al. (2007). "Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial". Ann Neurol. 61 (1): 14–24. doi:10.1002/ana.21079. PMID 17262850. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
13. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf
14. http://www.medicalnewstoday.com/articles/90768.php
15. Lackner P., Part A., Burger C., Dietmann A., Broessner G., Helbok R., Reindl M., Schmutzhard E., Beer R. (2009) Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study. Malar J. 27;8(1):36

• Immunostimulants