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Long-term Experience of Glatiramer Acetate in Treating Multiple Sclerosis


acetate (GA; Copaxone®, co-polymer 1) was first tested in clinical trials in the mid-1980s and approved by the US Food and Drug Administration (FDA) for the treatment of RRMS in 1996; previously, therapies had been limited. GA is a mixture of synthetic peptides composed of random sequences of four amino acids (tyrosine, glutamate, alanine, and lysine) in a defined molar ratio with a length of 40–100 residues, and is structurally similar to myelin basic protein (MBP), a major component of myelin.14 administered as a daily subcutaneous (sc) injection (20 mg).


It is


Since its introduction, GA has been widely used as a first-line disease-modifying agent in RRMS. Extensive experience on its efficacy and safety has been gained in regular clinical use. A number of clinical studies and analyses have identified the short- and long-term benefits of GA (and other first-line disease-modifying agents such as interferon beta-1a [IFNβ-1a] and interferon beta-1b [IFNβ-1b]) in reducing relapses, disability progression, and the development of new magnetic resonance imaging (MRI) lesions. This article will review the long-term efficacy and safety data of GA.


Glatiramer Acetate Mechanism of Action The mechanism of action of GA differs from other available treatments for MS. It is thought to produce anti-inflammatory effects mainly by functional inhibition of MBP-reactive T lymphocytes and induction of T-helper 2 (Th2) lymphocytes in the CNS. The clinical immunomodulatory effect of GA was originally believed to result from a change in T-cell differentiation, cytokine secretion in CD4+ cells, and an increase in regulatory B-cell properties.15–17 Subsequent findings from clinical studies and animal models indicated that GA has more widespread immunomodulatory actions on cells of both the innate and adaptive immune systems.


GA has been demonstrated to downregulate the expression of interleukin (IL)-17 and IL-6 in animal models of MS and in peripheral blood mononuclear cells from patients with MS, modulating the inflammatory response from Th1 and Th17 cells.17–19


found to induce CD8+ T-cell responses in patients with MS.20


The secretion of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and insulin growth factor (IGF), may promote neuronal repair.23,24


Multiple Sclerosis Therapy with Glatiramer Acetate Clinical Trial Data


The first clinical study of GA was a double-blind, randomized, placebo-controlled Phase II trial of patients (n=50) with RRMS receiving either daily injections of 20 mg GA or placebo for two years. Two-year average relapse rates were 0.6 and 2.7 per patient in the GA and placebo groups, respectively.14


In the first Phase III multicenter, double-blind, placebo-controlled trial (n=251) of GA, patients were randomized to receive GA (n=125) or placebo (n=126) for two years. The primary endpoint was a difference in the MS relapse rate. The final two-year relapse rate was 1.19 ± 0.13 for patients receiving GA and 1.68 ± 0.13 for those receiving placebo,


US NEUROLOGY


Recent evidence suggests multiple mechanisms of action for GA that include possible neuroprotective and/or neuroregenerative effects.21,22


a 29 % reduction in favor of GA (p=0.007) (annualized rates [ARR] = 0.59 for GA and 0.84 for placebo). Furthermore, 33.6 % of patients receiving GA and 24.6 % receiving placebo were relapse-free. In an evaluation of disability as measured by the expanded disability status scale (EDSS), significantly more patients receiving GA showed improvement and more receiving placebo worsened (p=0.037).25


A blinded extension of this


study from one to 11 months (mean: 5.4 months GA group, 5.9 months placebo group) confirmed the sustained efficacy in terms of relapse rate and disability progression, high tolerance, and safety profile of GA.26


The trial was further extended as an open-label study,27 as discussed below


in the section entitled ‘Long-term Studies.’ This trial and its extension now constitute the longest continuous evaluation of a disease-modifying drug (DMD) in MS and show continued benefits in terms of decreased relapse rates, decreased disability progression, and decreased transition to SPMS.


Magnetic Resonance Imaging Studies


MRI provides a useful measure of inflammation and neurodegeneration in MS. MRI studies indicated that GA has a favorable effect on tissue disruption in MS lesions once they are formed.28


A large study in Europe and Canada randomized 239 patients with RRMS to either GA or placebo and obtained monthly brain MRI scans for nine months, followed by an open-label extension for nine months. The primary outcome measure, the mean number of gadolinium (Gd)-enhancing lesions, showed a 29 % reduction at nine months in the GA-treated group compared with placebo (p=0.003). Secondary outcomes, including the number of new enhancing lesions, the volume of enhancing lesions, and the changes in the volume and number of T2-weighted images, were also significantly reduced by treatment with GA.29


Compared with placebo,


GA reduced by 50 % the proportion of new MS lesions evolving into chronic black holes over an eight-month period (p=0.002).28


Furthermore, GA therapy has been


MRI lesion reduction is only a robust measure of treatment efficacy if the effect is homogeneous across patients. In an analysis of the European/Canadian trial data,29


lesion reduction owing to treatment


was estimated to range between 20 and 54 % in 95 % of the patients, indicating that GA has a homogeneous effect on MRI-measured disease activity in RRMS.30


The assessment of brain volume changes on MRI scans can provide a measure of progressive atrophy reflecting the neurodegenerative aspects of MS pathology. This was first demonstrated by use of the structural Image evaluation, using normalization, of atrophy (SIENA) technique to show less brain volume loss in GA-treated patients compared with placebo in the GA European/Canadian trial.31


Recent five-year data indicated that


GA (20 mg sc daily), low-dose IFNβ (Avonex®, 30 μg intramuscular [im] weekly), and high-dose IFNβ (Betaseron®, 250 μg sc every other day) significantly reduced the loss of brain volume in MS compared with no treatment (p<0.0001). The GA-treated group experienced a smaller loss in brain volume over five years, compared with the IFNβ-treated groups.32


In


the Rebif versus glatiramer acetate in relapsing MS disease (REGARD) trial, GA significantly reduced brain atrophy compared with IFNβ-1a.33


Although no significant difference in percentage brain volume change was found during the nine-month double-blind phase of the European/Canadian


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