Mechanism of Action

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 allergic 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.

Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally occurring immune responses. Results of a limited battery of tests designed to evaluate this risk produced no finding of concern; nevertheless, there is no logical way to absolutely exclude this possibility (see PRECAUTIONS).

Pharmacokinetics

Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support the assumption that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Nevertheless, larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

Clinical Trials

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.)

One trial was performed at a single center. It enrolled 50 patients who were randomized to receive daily doses of either glatiramer acetate, 20 mg subcutaneously, or placebo (glatiramer acetate, n=25; placebo, n=25). Patients were diagnosed with RR MS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair.

Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours).

The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: 1) the frequency of attacks during the trial, and 2) the change in the number of attacks compared with the number which occurred during the previous 2 years.

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