Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Other immunostimulants
ATC code: L03AX13
The mechanism by which glatiramer acetate exerts 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 of B and T cells inducing anti-inflammatory and regulatory cytokine secretion. Whether the therapeutic effect is mediated by the cellular effects described above is not known because the pathophysiology of MS is only partially understood.
A total of 269 patients have been treated with glatiramer acetate in three controlled trials. The first was a two-year study involving 50 patients (glatiramer acetate n=25, placebo n=25) who were diagnosed with relapsing-remitting MS by the then-applicable standard criteria, and who had at least two attacks of neurological dysfunction (exacerbations) during the preceding two years. The second study applied the same inclusion criteria and included 251 patients treated for up to 35 months (glatiramer acetate n=125, placebo n=126). The third study was a nine-month study involving 239 patients (glatiramer acetate n=119, placebo n=120) where inclusion criteria were similar to those in the first and second studies with the additional criterion that patients had to have at least one gadolinium-enhancing lesion on the screening MRI.
In clinical trials in MS patients receiving glatiramer acetate, a significant reduction in the number of relapses, compared with placebo, was seen.
In the largest controlled study, the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 under glatiramer acetate.
Exposure data are available for up to twelve years in 103 patients treated with glatiramer acetate.
Glatiramer acetate has also demonstrated beneficial effects over placebo on MRI parameters relevant to relapsing-remitting MS.
Glatiramer acetate 20 mg/mL: In the controlled study 9001/9001E, which enrolled 251 patients, who were followed for up to 35 months (including a blinded phase extension 9001E of the 9001 study), the cumulative percentage of patients who developed 3-month confirmed disability progression was 29.4% for placebo and 23.2% for Glatiramer acetate-treated patients (p=0.199).
There is no evidence that glatiramer acetate treatment has an effect on relapse duration or severity.
There is currently no evidence for the use of glatiramer acetate in patients with primary or secondary progressive disease.
Single Clinical Event Suggestive of MS:
One placebo-controlled study involving 481 patients (glatiramer acetate n=243, placebo n=238) was performed in patients with a well-defined, single, unifocal neurological manifestation and MRI features highly suggestive of MS (at least two cerebral lesions on the T2-weighted MRI above 6 mm diameter). Any disease other than MS that could better explain signs and symptoms of the patient had to be excluded.
The placebo-controlled period was followed by an open label treatment: Patients who either presented with MS symptoms or were asymptomatic for three years, whichever came first, were assigned to active drug treatment in an open-label phase for an additional period of two years, not exceeding a maximal total treatment duration of 5 years. Of the 243 patients initially randomised to glatiramer acetate, 198 continued glatiramer acetate treatment in the open-label phase. Of the 238 patients initially randomised to placebo, 211 switched to glatiramer acetate treatment in the open-label phase.
During the placebo-controlled period of up to three years, glatiramer acetate delayed the progression from the first clinical event to clinically definite multiple sclerosis (CDMS) according to Poser criteria in a statistically significant and clinically meaningful manner, corresponding to a risk reduction of 45% (Hazard Ratio = 0.55; 95% CI [0.40; 0.77], p-value=0.0005). The proportion of patients who converted to CDMS was 43% for the placebo group and 25% in the glatiramer acetate group.
The favourable effect of treatment with glatiramer acetate over placebo was also demonstrated in two secondary MRI endpoints, i.e. number of new T2 lesions and T2 lesion volume.
Post-hoc subgroup analyses were performed in patients with various baseline characteristics to identify a population at high risk to develop the second attack. For subjects with baseline MRI with at least one T1 Gd-enhancing lesion and 9 or more T2 lesions, conversion to CDMS was evident for 50% of the placebo subjects vs. 28% of the glatiramer acetate subjects in 2.4 years. For subjects with 9 or more T2 lesions at baseline, conversion to CDMS was evident for 45% of the placebo subjects vs. 26% on glatiramer acetate in 2.4 years. However, the impact of early treatment with glatiramer acetate on the long term evolution of the disease is unknown even in these high-risk subgroups as the study was mainly designed to assess the time to the second event. In any case, treatment should only be considered for patients classified at high risk.
The effect shown in the placebo-controlled phase was sustained in the long-term follow-up period of up to 5 years. The time progression from the first clinical event to CDMS was prolonged with earlier glatiramer acetate treatment as compared to delayed treatment, reflecting a 41% risk reduction with earlier versus later treatment (Hazard Ratio = 0.59; 95% CI [0.44; 0.80], p-value=0.0005). The proportion of subjects in the Delayed Start group who progressed was higher (49.6%) compared to those in the Early Start group (32.9%).
A consistent effect in favour of early treatment over delayed treatment across time was shown for the annualised number of lesions over the entire study period in new T1 Gd-enhancing lesions (reduced by 54%; p<0.0001), new T2 lesions (reduced by 42%; p<0.0001) and new T1 hypointense lesions (reduced by 52%; p<0.0001). An effect in reductions in favor of early versus delayed treatment was also observed for the total number of new T1 Gd-enhancing lesions (reduced by 46%; p=0.001), T1 Gd-enhancing lesions volume (a mean difference of -0.06 ml; p<0.001), as well as the total number of new T1 hypointense lesions (reduced by 46%; p<0.001) measured over the entire study period.
No appreciable differences between the Early Start and Delayed Start cohorts were observed for either hypointense T1 lesion volume or brain atrophy over 5 years. However, analysis of brain atrophy at last observed value (adjusted to treatment exposure) showed a reduction in favour of early treatment with glatiramer acetate (the mean difference of percent change in brain volume was 0.28%; p=0.0209).
Brabio 20 mg/mL solution for injection, pre-filled syringe is a hybrid medicinal product. Detailed information is available on the MRI product index; http://mri.medagencies.org/Human/.
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.
Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotocixity, 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 behavioural development were observed.
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