Using four definitions of highly active disease (HAD) with varying criteria, alemtuzumab improved outcomes in patients with HAD, and efficacy was maintained over 9 years in highly active relapsing-remitting multiple sclerosis. |
Efficacy in the HAD population was generally consistent with and similar to the overall Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) population. |
No new safety signals were seen in alemtuzumab-treated patients with HAD over 9 years. |
1 Introduction
2 Methods
2.1 Design of CARE-MS Core Studies and Extension Studies
2.2 Clinical Efficacy Assessments
2.3 Safety Monitoring
2.4 HAD Definitions and Analyses
2.5 Statistical Analyses
2.6 Standard Protocol Approvals, Registrations, and Patient Consents
3 Results
3.1 Patients and Baseline Characteristics: Primary HAD Definition
Baseline characteristic | Alemtuzumab-treated HAD patients | |
---|---|---|
CARE-MS I (N = 105) | CARE-MS II (N = 103) | |
Age (years) | 32.1 (8.0) | 32.7 (7.7) |
Female, n (%) | 69 (66) | 69 (67) |
EDSS score | 2.0 (0.8) | 2.6 (1.2) |
Years since initial relapse | 1.7 (1.4) | 4.0 (2.6) |
Number of relapses in prior 1 year | 2.3 (0.6) | 2.4 (0.8) |
Number of relapses in prior 2 years | 2.9 (1.0) | 3.4 (1.4) |
Gd-enhancing lesion count | 5.6 (7.1) | 5.2 (6.2) |
Patients with Gd-enhancing lesions, n (%) | 105 (100) | 103 (100) |
T2-hyperintense lesion volume (cm3) | 9.9 (10.1) | 12.1 (12.2) |
Brain parenchymal fraction | 0.82 (0.02) | 0.82 (0.02) |
Number of previous DMTs received, n (%) | ||
0 | 105 (100) | 0 |
1 | – | 69 (67) |
2 | – | 26 (25) |
3 | – | 5 (5) |
≥ 4 | – | 3 (3) |
Previous DMTs received, n (%) | ||
IFNB-1a | – | 59 (57) |
IFNB-1b | – | 32 (31) |
Glatiramer acetate | – | 42 (41) |
Natalizumab | – | 7 (7) |
Immunoglobulin | – | 3 (3) |
Azathioprine | – | 4 (4) |
3.2 Efficacy: Primary HAD Definition
3.3 Sensitivity Analyses of Efficacy: Alternative Definitions of HAD
Parameter | Alemtuzumab-treated patients | |||
---|---|---|---|---|
Primary HAD definition (N = 208)a | Alternative HAD definition 1 (N = 438)b | Alternative HAD definition 2 (N = 174)c | Alternative HAD definition 3 (N = 180)d | |
Proportion of the overall pooled CARE-MS alemtuzumab-treated population satisfying each HAD definition (%) | 26 | 54 | 21 | 22 |
Proportion of patients who received neither additional alemtuzumab nor another DMT in the extensions (%) | 50 | 50 | 41 | 40 |
Proportion of patients who received additional alemtuzumab (%) | 48g | 48h | 55i | 55j |
3 total courses, % | 26g | 25h | 26i | 29j |
4 total courses, % | 14g | 15h | 18i | 16j |
5 total courses, % | 5g | 4h | 8i | 7j |
6 total courses, % | 2g | 2h | 1i | 2j |
7 total courses, % | 0.5g | 0.5h | 2i | 1j |
8 total courses, % | 0.5g | 0.2h | 0 | 0.6j |
ARR over Y3–9 (95% CI) | 0.16 (0.13–0.19) | 0.18 (0.16–0.21) | 0.17 (0.14–0.21) | 0.17 (0.14–0.21) |
Proportion of patients relapse-free over Y3–9 (%) (95% CI)e | 53 (45–61) | 51 (46–57) | 47 (39–56) | 47 (38–56) |
Mean EDSS score change over Y0–9 (95% CI) | 0.17 (− 0.06 to 0.39) | 0.19 (0.04–0.34) | 0.28 (0.01–0.55) | 0.33 (0.03–0.63) |
Proportion of patients with improved or stable EDSS over Y0–9f (%) | 72 (improved 25; stable 47) | 71 (improved 22; stable 50) | 70 (improved 22; stable 48) | 66 (improved 22; stable 44) |
Proportion of patients free of 6-month CDW over Y0–9 (%) (95% CI) | 62 (54–69) | 64 (59–69) | 59 (51–66) | 56 (48–64) |
Proportion of patients with 6-month CDI over Y0–9 (%) (95% CI) | 50 (41–59) | 46 (40–52) | 49 (40–59) | 51 (42–60) |
Proportion of patients free of MRI disease activity in Y9 (%) (95% CI)e | 69 (61–77) | 69 (63–74) | 57 (48–66) | 69 (60–78) |
Proportion of patients with NEDA in Y9 (%) (95% CI)e | 62 (54–70) | 61 (56–67) | 53 (44–63) | 59 (49–69) |
Proportion of patients with cumulative NEDA over Y3–9 (%) (95% CI)e | 18 (11–25) | 20 (15–26) | 9 (3–15) | 10 (3–17) |
Median BPF change over Y0–9 (%) (95% CI) | − 2.15 (− 2.65 to − 1.78) | − 1.77 (− 2.02 to − 1.55) | − 2.40 (− 2.80 to − 2.05) | − 1.80 (− 2.20 to − 1.35) |
3.4 Safety: Primary HAD Definition
AEs, n (%) | Alemtuzumab-treated HAD patients over years 0–9 | |
---|---|---|
CARE-MS I (N = 105) | CARE-MS II (N = 103) | |
Any AE | 104 (99.0) | 103 (100.0) |
Serious AEs | 40 (38.1) | 41 (39.8) |
Infections | 89 (84.8) | 93 (90.3) |
Serious infections | 7 (6.7) | 9 (8.7) |
Autoimmune AEsa | ||
Thyroid AEs | 51 (48.6) | 45 (43.7) |
Serious thyroid AEs | 5 (4.8) | 7 (6.8) |
ITP | 3 (2.9) | 0 |
Nephropathies | 1 (1.0) | 1 (1.0) |
Malignancies | 3 (2.9) | 0 |
Deaths | 1 (1.0) | 2 (1.9) |