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Multiple Sclerosis


Figure 1: Graph Depicting the Risk of Progressing to Clinically Definite Multiple Sclerosis with Glatiramer Acetate versus Placebo


HR 0.55 (95 % Cl 0.40–0.77); p=0.0005


55 50 45 40 35 30 25 20 15 10


0 5


0


Number at risk Glatiramer acetate


Placebo


243 238


Day 336 180


197 197


360


179 165


Placebo Glatiramer acetate


Kaplan–Meier curves with Cox’s proportional hazard ratio were used to model the amount of time for conversion to clinically definite multiple sclerosis (CDMS) for patients assigned to glatiramer acetate (GA) and placebo. There was a delay of 386 days (115 %) in conversion to CDMS for first-quartile patients receiving GA compared with those receiving placebo. CI = confidence interval; HR = hazard ratio. Source: Comi et al., 2009.35


trial, there was a significantly lower mean percentage brain volume change in GA patients during the open-label extension.29


Similarly, recent five-year


data from the study to evaluate early GA treatment in delaying conversion to clinically definite MS (CDMS) of subjects Presenting with CIS (PRECISE) trial have shown a reduction in brain atrophy after five years, although this was not observed in the initial randomized phase.34


Effect of Early Treatment with Glatiramer Acetate Early treatment with GA has been found to reduce the risk of developing CDMS compared with placebo. In the randomized, double-blind PRECISE trial (n=481), patients presenting with CIS with unifocal manifestation, a first event suggestive of MS, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either GA (n=243) or placebo (n=238) for up to 36 months, unless they converted to CDMS. The primary endpoint was time to CDMS, based on a second clinical attack. GA was found to reduce the risk of developing CDMS by 45 % compared with placebo (hazard ratio 0.55, 95 % confidence interval [CI] 0.40–0.77, p=0.0005). The time for 25 % of GA-treated patients to convert to CDMS was prolonged by 115 % compared with placebo, from 336 to 722 days (see Figure 1).35


Recently, five-year data from the PRECISE trial have been reported. Most of the patients from the randomized trial (85 %), entered the open-label phase of the study and 60 % completed an average of 4.3 years of follow-up. GA reduced the risk of conversion from CIS to CDMS by 41 % compared with placebo (hazard ratio 0.59, p=0.0005). The percentage of brain volume change during the entire observation period was significantly lower in patients treated early, an effect that was not seen in the earlier phase of the study.34


These findings have led to suggestions 128 Day 722 540 Days


166 136


124 98


78 55


22 15


720 900 1,080


that GA should be increasingly used for CIS patients with MRI results showing multifocal lesions.


Comparison of Glatiramer Acetate and Interferon Beta Treatments


Head-to-head comparison trials have so far shown largely similar efficacy between IFNβ treatments and GA. In the first multicenter, randomized parallel open-label trial to directly compare GA and IFNβ-1a in RRMS (n=764, REGARD trial), no significant differences were observed between the two drugs in the study endpoints, which included time to first relapse and change in the volume of T2 and contrast-enhancing MRI lesions.33


Similar clinical effects between GA and IFNβ-1b were also observed in the Betaferon efficacy yielding outcomes of a new dose (BEYOND) trial (n=2,244), in which outcome measures included relapse risk, the proportion of relapse-free patients, time to first relapse, disability accumulation, and most MRI parameters.36


A further head-to-head trial (Betaseron versus


copaxone in multiple sclerosis with triple-dose gadolinium and 3 Tesla MRI endpoints [BECOME] study, n=75) comparing IFNβ-1b and GA identified similar MRI clinical activity between the treatments.37


Switching from Other Therapeutic Agents to Glatiramer Acetate


Switching to GA may be beneficial in patients with RRMS who have an inadequate response to other first-line immunomodulatory therapy (IFNβ-1a or IFNβ-1b). A prospective, open-label study found that prior IFNβ-1b treatment does not negatively influence the efficacy, safety, or tolerability of subsequent GA therapy.38


In another study, patients


were switched from IFNβ-1a to GA because of persistent clinical disease activity or persistently unacceptable toxicity as determined by the treating neurologist. Switching from IFNβ-1a to GA reduced the mean ARR from 1.23 to 0.53 (p=0.0001).39


In a further study, in a patient


cohort three years after switching from IFNβ-1b to GA, the ARR fell by 57–78 %.40


The Coptimize study is a longitudinal study assessing disease course, characteristics, and reason for switching and has recruited RRMS patients switching from any MS drug to GA. To date, 144 clinics in 19 countries have contributed data from 637 patients. After 12 months of switching there was a 65 % reduction in ARR after switching to GA (n=155, p<0.0001) and EDSS was stable during the whole period.41


Some investigators have recently reported the successful switching to GA of MS patients who were receiving natalizumab and tested positive for John Cunningham (JC) virus antibodies.42


Changing therapy


maintained efficacy and no progressive multifocal leukoencephalopathy (PML) cases were reported following the switch. Further studies on a group of 35 patients switching from natalizumab to GA are in progress.


In an Italian study, 23 patients with RRMS who discontinued natalizumab after 12–18 months’ treatment were switched to GA 20 mg/day, which they received for at least six months to a maximum of 12 months.43


The


low ARR established during the natalizumab treatment was maintained during GA treatment (0.42 ± 0.7/year) and EDSS was stable in all patients. On MRI scanning, patients showed some evidence of disease


US NEUROLOGY


Patients with CDMS (%)


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