Glatiramer acetate

Glatiramer acetate (GA) (Copaxone, Teva Neuroscience North America / Teva Pharmaceuticals) is a first-line therapy for relapsing forms of MS and CIS. GA contains an incalculable number of active amino acid sequences and is composed of a large number of synthetic peptides. The usual dose of GA is 20 mg subcutaneously once a day.

The mechanism of action (MOA) of GA is not completely understood, but consists of an antigen-presenting cell (APC) incorporating peptides of GA and presenting them to a lymphocyte, similar to the process of a vaccine. This process creates a unique population of lymphocytes circulating in the blood which are responsive to GA. It inhibits the multiplication of human lymphocytes that are capable of reacting to myelin basic protein. Researchers have been able to show that GA binds directly to the portion of the APC that is required to stimulate the T lymphocyte, thus blocking direct immunologic attack. It was in the late 1980s that the immunologic concept of Th1 (proinflammatory) and Th2 (anti-inflammatory) lymphocytes gained momentum. These two types of lymphocytes can be identified by the chemicals that they manufacture and then secrete. These chemicals are known as cytokines, and can be divided into inflammatory and proinflammatory. In 1997, Aharoni and colleagues published a paper that described how GA could stimulate the production of Th2 (anti-inflammatory) cells that inhibited the inflammatory response by secreting anti-inflammatory cytokines [Aharoni et al. 1997]. The GAs' effect begins in the peripheral tissues in a population of specific lymphocytes which circulate in the blood and are capable of migrating into the CNS tissue by crossing the blood-brain barrier (BBB). These cells then encounter fragments of several myelin proteins that stimulate the glatiramer cells to multiply and begin to produce anti-inflammatory cytokines. Since the glatiramer-activated lymphocytes can suppress inflammation under way in the diseased area of CNS tissue, this process has been given the name bystander suppression [Johnson, 2010]. To date, data suggest that GA treatment is associated with a broader immunomodulatory effect on cells of not only the innate but also the adaptive immune system. Recent investigations indicate that GA treatment may also promote regulatory B-cell properties [Lalive et al. 2011].

GA has a relatively narrow adverse effect profile. Most frequently patients complain of mild pain and pruritis at the injection site. Lipoatrophy and skin site reactions are also seen and may lead to discontinuation of therapy. A transient reaction called immediate postinjection reaction consists of chest tightness, flushing and dyspnea beginning soon after the injection and lasting no longer than 20 min. If no history or evidence of coronary artery disease, the patient can be reassured that such a reaction is benign [DiPiro et al. 2005].

Multicenter trials with GA have demonstrated statistically significant reductions in mean ARR that are comparable to those of the IFNs [DiPiro et al. 2005]. In two recent studies the efficacy of GA was compared with high-dose/high-frequency IFN-β. In the Rebif versus Glatiramer Acetate in Relapsing MS Disease (REGARD) study [Mikol et al. 2008], subcutaneous IFN-β1a was compared with GA, and in the Betaseron/Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study [O'Connor et al. 2009], subcutaneous IFN-β1b was compared with GA. In both trials, there was no significant difference between IFN and GA in the primary endpoints or in any clinical endpoints, although some differences in magnetic resonance imaging (MRI) measures of disease activity have been claimed.

The results from a 15-year analysis of the US prospective open-label study of GA indicate that long-term continuous use is safe. It also indicates that the majority of patients continuing on GA therapy in the study have had few relapses and minimal disease progression. Of the initial 232 patients that received at least one GA dose since study initiation in 1991, only 100 (43%, ongoing cohort) patients continued. Of the 100 patients receiving continuous GA as sole immunomodulatory therapy for 15 years (mean disease duration of 22 years and mean patient age of 50 years) have not transitioned to SPMS, 57% have retained stable or improved the Expanded Disability Status Scale (EDSS) scores over the course of the study and 82% remain ambulatory without mobility aids. There was no occurrence of any unforeseen adverse events in patients receiving GA therapy. The study will continue for 20 years of prospective follow up [Ford et al. 2010].