Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other immunostimulants.

ATC code: L03AX13

Mechanism of action
The mechanism by which glatiramer acetate exerts therapeutic effects in patients with 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-inflamatory 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.

Clinical efficacy and safety

Relapsing-Remitting Multiple Sclerosis
Evidence supporting the effectiveness of Copaxone 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 Copaxone 40 mg/ml (n=943) or placebo (n=461). Both treatment groups were comparable with respect to baseline demographics, MS disease characteristics and MRI parameters.
Patients had a median of 2.0 relapses in the 2 years prior to screening.
Compared to placebo, patients treated with Copaxone 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 Copaxone 20 mg/ml administered daily.


The following table presents the values for the primary and secondary outcome measures for the intent-to-treat population:

Adjusted Mean Estimates
Outcome Measure                         Copaxone                         P-Value Placebo
(40 mg/ml)
(N=461)
(N=943)
Annualized relapse rate (ARR)                           0.331             0.505       p<0.0001 Absolute Risk Difference*
-0.174 [-0.2841 to -0.0639]
(95% confidence intervals)
Cumulative number of new/enlarging T2
3.650             5.592       p<0.0001 lesions at months 6 and 12
Rate ratio** (95% confidence intervals)                0.653 [0.546 to 0.780] Cumulative number of enhancing lesions on
0.905             1.639       p<0.0001
T1-weighted images at months 6 and 12
Rate ratio** (95% confidence intervals)                0.552 [0.436 to 0.699] *Absolute risk difference is defined as the difference between the adjusted mean ARR of GA        40 mg TIW and adjusted mean ARR of Placebo.
** Rate ratio is defined as the ratio between GA 40 mg TIW and Placebo adjusted mean rates.

A direct comparison of the efficacy and safety between Copaxone 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.
Copaxone 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% of placebo- and Copaxone-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 Copaxone 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 Copaxone in patients with primary or secondary progressive disease.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
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.