Glatiramer acetate

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Glatiramer Acetate is the generic name for the drug Copaxone or Copolymer 1, developed by Teva Pharmaceuticals. It is an immunomodulator, licensed in much of the world for reduced frequency of relapses in relapsing-remitting multiple sclerosis. Copaxone is administered by subcutaneous injection at a dose of 20 mg per day. It is a non-interferon and non steroidal medication.

[edit] How Glatiramer Acetate Works

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.[1] 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.[2]

[edit] Development

Glatiramer acetate was originally discovered by Professor Sela, Professor Arnon and Dr. Teitelbaum at the Weizmann Institute of Science in Israel. The efficacy and safety of glatiramer acetate were demonstrated in three main clinical trials: The first trial, led by Professor M. 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.

[edit] 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.

[edit] Side Effects

Injection Site Reaction - Upper Left Arm

Side effects generally include a lump at the injection site (injection site reaction), aches, fever, chills and are generally mild in nature. Occasionally a reaction occurs minutes after injection in which there is flushing, shortness in breath, anxiety & rapid heartbeat. These side effects subside within thirty minutes. Over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, 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.^[1]

[edit] 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).^[2] A comparative trial of the approved 20 mg dose and the 40 mg dose showed no significant difference in efficacy between these doses^[3].

However, a 2004 Cochrane Medical review^[4] 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."

In its pivotal trial ^[5] 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).

As a result^[6], the FDA marketing label for Copaxone does not have an indication for reducing the progression of disability.

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.^[7]

Various clinical trials in glatiramer acetate are on-going. This includes studies with a higher dose of glatiramer acetare ( 40 mg - the FORTE study); studies in Clinically Isolated Syndrome patients (the PreCISe study) as well as numerous combination and induction protocols, in which glatiramer acetate is given together with or following another active product.

[edit] Etymology

The proper name of the drug is derived from its component amino acids: glutamic acid, lysine, alanine, and tyrosine.

[edit] References

1. ^ FDA Copaxone Label: http://www.fda.gov/cder/foi/label/2001/20622s15lbl.pdf
2. ^ http://www.copaxone.com/pdf/PrescribingInformation.pdf
3. ^ the 9006 trial; Cohen JA et al. Neurology. 2007;68:939-944)
4. ^ Cochrane Medical review of Copaxone - http://www.cochrane.org/reviews/en/ab004678.html
5. ^ FDA marketing label - http://www.copaxone.com/pdf/PrescribingInformation.pdf
6. ^ Copaxone marketing materials - http://www.copaxone.com/NewlyDiagnosed/pivotTrial.aspx
7. ^ 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.