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Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism(s) by which glatiramer acetate exerts its therapeutic effects in relapsing forms of MS is not fully elucidated, but is presumed to involve modulation of immune processes. Studies in animals and MS patients suggest glatiramer acetate acts on innate immune cells, including monocytes, dendritic cells and B cells, which in turn modulate adaptive functions B and T cells inducing anti-inflammatory and regulatory cytokine secretion. Whether the therapeutic effect is mediated by the cellular effects described as previously mentioned is not known because the pathophysiology of MS is only partially understood.
Clinical efficacy and safety: Relapsing-Remitting Multiple Sclerosis: Evidence supporting the effectiveness of glatiramer acetate 40 mg/ml injection administered subcutaneously three times a week in decreasing the frequency of relapses derives from one 12-month placebo-controlled study.
In the pivotal clinical trial Relapsing-Remitting Multiple Sclerosis was characterized by either at least one documented relapse in the last 12 months, or at least two documented relapses in the last 24 months, or one documented relapse between the last 12 and 24 months with at least one documented T1-gadolinium enhancing lesion on magnetic resonance imaging performed the last 12 months.
The primary outcome measure was the total number of confirmed relapses. Secondary MRI outcomes included the cumulative number of new/enlarging T2 lesions and the cumulative number of enhancing lesions on T1-weighted images, both measured at months 6 and 12.
A total of 1404 patients were randomized in a 2:1 ratio to receive either glatiramer acetate 40 mg/ml (n=943) or placebo (n=461). Both treatment groups were comparable with respect to baseline demographics, MS disease characteristics and magnetic resonance imaging (MRI) parameters. Patients had a median of 2.0 relapses in the 2 years prior to screening.
Compared to placebo, patients treated with glatiramer acetate 40 mg/ml three times per week had meaningful and statistically significant reductions in the primary and secondary outcome measures which are consistent with the treatment effect of glatiramer acetate 20 mg/ml administered daily.
The following table presents the values for the primary and secondary outcome measures for the intent-to-treat population: (See Table 1.)
Click on icon to see table/diagram/imageA direct comparison of the efficacy and safety between glatiramer acetate 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.
Glatiramer acetate 40 mg/ml: The proportion of patients with 3-month confirmed disability progression (CDP) was an exploratory endpoint in a 12-month placebo-controlled study (GALA). Three-month CDP was experienced by 3% and 3.5% placebo- and glatiramer acetate-treated patients, respectively (odds ratio, OR [95% CI]: 1.182 [0.661, 2.117] (p=0.5726). Including the open-label extension of the study (up to 7 years), time to 6-month CDP was an exploratory endpoint. The hazard ratio (HR) [95% CI] for the intent to treat cohort, comparing the early start glatiramer acetate group to the delayed start group was 0.892 [0.688, 1.157] (p=0.3898).
There is currently no evidence for the use of glatiramer acetate in patients with primary or secondary progressive disease.
Pharmacokinetics: Pharmacokinetic studies in patients have not been performed. In vitro data and limited data from healthy volunteers indicate that with subcutaneous administration of glatiramer acetate, the active substance is readily absorbed and that a large part of the dose is rapidly degraded to smaller fragments already in subcutaneous tissue.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, beyond the information included in other sections of the SmPC. Due to the lack of pharmacokinetic data in humans, margins of exposure between humans and animals cannot be established.
Immune complex deposition in the glomeruli of the kidney was reported in a small number of rats and monkeys treated for at least 6 months. In a 2 years rat study, no indication of immune complex deposition in the glomeruli of the kidney was seen.
Anaphylaxis after administration to sensitised animals (guinea pigs or mice) was reported. The relevance of these data for humans is unknown.
Toxicity at the injection site was a common finding after repeated administration in animals.
In rats, a slight but statistically significant reduction in body weight gain of offspring born to dams treated during pregnancy and throughout lactation was observed at subcutaneous doses ≥ 6mg/kg/day (2.83-times the maximum recommended human daily dose for a 60 kg adult based on mg/m2) in comparison to control. No other significant effects on offspring growth and behavioral development were observed.
