Glatiramer acetate

Overview
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.

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. 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.

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.

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, and Argentina.

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 are defined as 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.

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 (the 9006 trial; Cohen JA et al. Neurology. 2007;68:939-944). 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.

Efforts are continuing towards the launch of glatiramer acetate in additional international markets, as well as towards broadening its indications and usage within the MS population. To this end, an extensive Medical Operating plan, consisting of various clinical trials, is 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. Recent results from some of the latter studies reveal a very good effect of glatiramer acetate in highly active patients.

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