Enduring Clinical Value of Copaxone® (Glatiramer Acetate) in Multiple Sclerosis after 20 Years of Use
Table 1
Long-term data and real-world data for GA in MS.
Study overview
Study
Design (Jadad score)
Treatment
Patients
Duration, percent withdrawals
Key data
Comment
Reference
Pivotal studies
US Glatiramer Acetate Trial
Multicenter, randomized, PBO-controlled (5)
GA 20 mg SC QD vs PBO
Relapsing-remitting MS n=251
2 y, GA: 15.2 PBO: 13.5
29% reduction in ARR vs PBO: 0.59 vs 0.84 (p=0.007) Little difference between groups in progression to sustained disability (EDSS) Injection-site reaction most common AE
(i) US registration trial (ii) MRI endpoints not assessed
29% reduction in total no. of T1-weighted enhancing lesions (mean reduction between groups: -10.8, p=0.003; GA: 25.96 vs PBO: 36.80) Consistent significant differences favoring GA across MRI endpoints: no. of new enhancing lesions, monthly change in enhancing lesion volume, change from baseline at 9 months in T2 lesion volume, no. of new lesions on T2-weighted imagesTreatment effects increased over time33% reduction in ARR for GA vs PBO: 0.81 vs 1.21 (p=0.012) No unanticipated AEs reported
(i) Study designed to assess effect of GA on MRI-measured disease activity and burden (monthly MRI scans); patients had to have ≥1 enhancing lesion (lesion levels relatively high at baseline)
Relapsing-remitting MS (n=232 received ≥1 dose [mITT]) (n=100 ongoing at 15 y; 74 ongoing at 20 y)
20 y, 15 y: 57 20 y: 68
15-y timepoint Ongoing patients: Mean GA exposure: 13.6 y; mean disease duration: 22 yARR reduced from 1.12 before starting GA therapy to 0.25 at 15-y timepoint57% had stable/improved EDSS scores (change ≤0.5 points) 65% had not transitioned to secondary progressive MS82% remained ambulatory without mobility aidsSafety consistent with previous shorter-term studies20-y timepoint Mean GA exposure: 19.3 y; mean disease duration: 27.3 yCumulative ARR: 0.224.3% relapse free through entire observation period53% had not transitioned to secondary progressive MS79.5% remained ambulatory without mobility aids (EDSS <6)
(i) Consistent low relapse rate and slow progression of disability (ii) Limitations of this study should be considered, e.g., prospective; patients with more aggressive disease may have dropped out (41% of withdrawals were owing to perceived disease progression or request to switch treatment); patients who remained in study may have had relatively mild MS (iii) Most common reason for drop-out from study was FDA approval of Betaseron® and desire to switch to an “FDA-approved” treatment (iv) No long-term safety issues identified (v) Only study of MS therapy with ≥10 y of continuous monitoring
GA 20 mg SC QD (cross-over phase for PBO patients)
n=224
9 mo, GA: 4.0
Reduction in mean no. of Gd+ lesions was 46.5% for those receiving GA for full 18 mo vs 54% for those receiving GA after PBO35% fewer enhancements with continuous GA treatment (p=0.03) Corresponded to a mean of 6.6 fewer Gd+ lesions and 5.3 fewer new T2 lesions on quarterly scans for patients always receiving GA (e.g., during double-blind period and ongoing) vs those randomized to a delayed start (PBO during double-blind period)
(i) Reproducible reductions in mean no. of Gd+ lesions for patients originally receiving PBO and reductions maintained for those receiving GA for 18 months
Long-term follow-up group n=142 (73 received GA from study start)
5 y, GA: 34
Mean follow-up: 5.8 ySimilar MRI measures at 5 y between patients always receiving GA and those originally assigned to PBO (i.e., delayed start to GA) Fewer patients receiving GA required unilateral walking aids (6.9% vs 18.8% of those receiving PBO in double-blind phase of study) Percentage brain volume change at baseline and long-term follow-up significantly correlated with lesion load at entry
(i) Support for efficacy of early intervention (ii) Differences in trial design vs US extension study, i.e., patients in this trial had more aggressive MS (iii) High drop-out rate, which was related to the FDA/EMA approval of Betaseron® (as indicated above)
GA 20 mg SC QD, IFNβ-1b 250 μg SC EOD; IFNβ-1a 30 μg IM QW, untreated
Treatment-naïve, relapsing-remitting MS n=275
5 y
Significantly lower percentage change in brain volume loss from baseline to 5 y for GA -2.27% vs IFNβ-1a -2.62% and IFNβ-1b -3.21% (p<0.01) Reduced brain volume loss for all active treatments vs untreated (p<0.0001)
(i) GA-treated group experienced least loss of brain volume over 5 y (ii) Superior efficacy of GA vs IFNβ-1a/b in slowing brain volume loss (iii) Study supports the importance of long-term observations for robust data on brain volume loss
Multicenter, non-interventional, retrospective cohort study
IFNβ-1a 30 μg IM, IFNβ-1a 22/44 μg SC, IFNβ-1b 250 μg SC, GA 20 mg SC at standard doses
Relapsing-remitting MS or CIS n=546
2 y
Comparable ARR at 1 y and 2 yYear 1 (% patients with ≥1 relapse): GA: 18%, IFNβ: 16–24%Year 2: GA: 22% vs IFNβ: 23–27%EDSS changes between Year 1 and Year 2 were comparable between groups
(i) Patient cohorts were not matching at baseline (ii) Not stated in study report whether the study was powered to demonstrate EDSS change
ARR ranged from 1.5 pretreatment to 0.2–0.3 over 9 y of treatment89.9% patients free from disability progression at Year 5 and 85.7% remained so at Year 975.2% of patients showed long-term absence of disability progression for ≥5 consecutive years92.6% remained ambulatory without mobility aidsReductions in Gd+ T1-weighted lesions (p<0.5) and no. of new T2 lesions (p=NS) from baseline to last follow-up
(i) Consistent with decline in disability progression in pivotal study extensions (detailed above) (ii) Value of data from later years reduced due to decreasing patient numbers in Years 7–9 (Year 7 n=61, Year 9 n=21) (iii) Supports long-term sustained efficacy for GA in stabilizing disease (low ARR and disability [EDSS] progression) (iv) Safety data not reported (v) Supports long-term patient acceptance of injectable therapy
Propensity score-matched analysis of MSBase registry
IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b, GA
n=3326
Median follow-up: 3.7 y (IQR 2.2–6.3 y)
Lower relapse rate with GA treatment vs IFNβ-1a IM or IFNβ-1b (observed mean differences 0.15–0.16; p<0.001) Higher proportion of relapse-free patients with GA vs IFNβ-1a IM or IFNβ-1b (hazard ratio 1.36 and 1.48, respectively; p≤0.02) No differences in 1-y confirmed progression of disability over 10 y
(i) Higher proportion of patients were relapse-free with GA treatment compared with IFNβ-1a/b (ii) Safety data not reported
