Multiple Sclerosis
Figure 2: Change in Disability Scores from the CAMMS223 Trial
40 50 60 70
30 20 10
0
IFNβ-1a (n=104)
Decline
Alemtuzumab 12mg/day (n=107)
Alemtuzumab 24mg/day (n=108)
No change
Alemtuzumab pooled (n=215)
Improvement
Proportion of patients showing decline, no change or improvement in disability scores during treatment with interferon beta-1a (IFNβ-1a) (44μg continuously, subcutaneous injection) or alemtuzumab (12 or 24mg per day intravenous infusion*) in the CAMMS223 trial (three-year data). *Alemtuzumab dosing regimen is for five days initially, then for three days after 12 months. Source: CAMMS223 Trial Investigators, 2008.62
Figure 3: Kaplan–Meier Analysis of Sustained Accumulation of Disability in Patients on the CAMMS223 Trial
40 30 20 10 0 0 Number at risk:
SC IFNβ-1a Alem. 12mg/day Alem. 24mg/day
111 112 110
SC IFNβ-1a Alemtuzumab 24mg/day 94
106 107
86
105 105
81
101 102
74
100 99
68 96 96
60 90 93
35 64 73
Alemtuzumab 12mg/day Alemtuzumab pooled
Kaplan–Meier analysis of sustained accumulation of disability in patients treated with interferon beta-1a (IFNβ-1a) subcutaneous (SC) or alemtuzumab (alem.) (pooled 12 or 24mg dose groups) during the Campath-1H in Multiple Sclerosis (CAMMS223) trial and follow-up. Source: Coles et al., 2010.61
67 and 71, respectively (p<0.001, p=0.003 and p<0.001). From baseline to 36 months, all treatment groups were observed to have a lower volume of lesions, as measured by T2-weighted MRI. In addition, significant reductions in lesion load from baseline were observed at 12 months (p=0.01) and 24 months (p=0.005) in patients receiving alemtuzumab compared with IFNβ-1a. The changes in mean EDSS score from baseline at 36 months were -0.32, -0.45 and -0.39 for alemtuzumab 12 and 24mg per day and the pooled alemtuzumab analysis, respectively (p=0.006, p<0.001 and p<0.001 for changes from baseline) but was +0.38 for IFNβ-1a (p<0.001 for comparisons between alemtuzumab and IFNβ-1a). This indicates an unprecedented improvement in disability status for patients receiving alemtuzumab
86
32 62 72
Notable AEs occurring in both the alemtuzumab (pooled analysis) and IFNβ-1a groups were: autoimmune thyroid disorders (23 and 3%), idiopathic thrombocytopenic purpura (ITP) (3 and 1%) and infections (66 and 47%).62
6 12 18 24 Months 30 36 42 48
Three-year data for the CAMMS223 trial show that the overall proportion of patients receiving alemtuzumab who reported AEs was greater than the proportion receiving IFNβ-1a. In the alemtuzumab groups, the most common AEs reported were infusion-associated reactions (98.6%). These reactions were confined to the alemtuzumab group due to the method of administration. These reactions included rash (91.7%), headache (61.1%), pyrexia (37.5%), fatigue (27.8%), pruritus (25.0%) and nausea (24.1%).
but a deterioration for patients receiving IFNβ-1a. In addition, the proportion of patients observed to have improvements in disability scores was greater with alemtuzumab 12 and 24mg per day and pooled (54.2, 60.2 and 57.2%, respectively) than IFNβ-1a (33.7%) (see Figure 2).
The four-year follow-up of CAMMS223 patients show that the efficacy advantages of alemtuzumab compared with IFNβ-1a were sustained over long-term durations despite the fact that no further doses of alemtuzumab were given after two years and that the majority had not received a dose for three years.63
In the pooled alemtuzumab
groups, there was a 72% reduction in the risk of relapse and the proportion experiencing a relapse was approximately halved relative to the IFNβ-1a group. Annualised relapse rates were 0.1 for the pooled alemtuzumab groups and 0.34 for the IFNβ-1a group. With alemtuzumab there was a 73% reduction in the risk of SAD which is supported by the Kaplan–Meier analysis of SAD during the CAMMS223 study and through four-years of follow-up given in Figure 3. The percentage of patients with SAD was 9% for pooled alemtuzumab groups and 32% for the IFNβ-1a group. The significant improvement in disability for alemtuzumab was also maintained during four years of follow-up; the EDSS scores in the pooled alemtuzumab-treated patients improved by –0.43 (standard deviation [SD] = 1.04) whereas for IFNβ-1a the EDSS scores deteriorated by +0.25 (SD=0.96) (p<0.001). Therefore, the four-year data provide further evidence of the durability of benefit derived from alemtuzumab in producing clinically disease-free status and preventing clinical progression in a substantial majority of RRMS patients. This treatment effect is observed even in those patients who completed only two annual cycles of alemtuzumab during the first 12 months.64
Among the other events, the most frequent were influenza-like illness (4 versus 27%; p<0.001), fatigue (31 versus 30%), headache (31 versus 28%), pyrexia (11 versus 10%) and rash (26 versus 14%). Apart from influenza-like symptoms, the differences in incidence in these events between alemtuzumab- and IFNβ-1a-treated groups were not significant.62
The first case of ITP went unrecognised and following several weeks of typical symptoms, presented with a fatal cerebral haemorrhage. However, the other ITP cases were self-limiting or responsive to treatment, all patients achieved durable remission and no ITP was reported >16 months after treatment.65
It was previously hypothesised
that patients who had autoimmune AEs following alemtuzumab had a fundamentally different immune reconstitution and may be less likely to respond to treatment compared with patients without such events. The study data show that this is not the case; patients with autoimmune events through 36 months showed a 66% reduction in the risk of SAD (p=0.03) and a 78% reduction in risk of relapse
EUROPEAN NEUROLOGICAL REVIEW
% of patients with sustained accumulation of disability
% patients
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