Long-term efficacy and safety of alemtuzumab in participants with highly active MS: TOPAZ clinical trial and interim analysis of TREAT-MS real-world study

Abstract

Background: Alemtuzumab is a disease-modifying therapy for highly active relapsing-remitting multiple sclerosis (RRMS). Sustained efficacy up to 9 years was observed in the phase IIIb/IV open-label TOPAZ clinical trial and assessed in the real-world retrospective and prospective study, TREAT-MS.

Objectives: To examine long-term efficacy and safety of alemtuzumab in participants with multiple sclerosis (MS) and highly active disease (HAD) by combining up to 13 years of TOPAZ data and TREAT-MS interim data.

Design: TOPAZ: Randomized participants completing core CARE-MS I and II could receive additional alemtuzumab (12 mg/day, 3 consecutive days; ⩾12 months apart) for 11-13 years after initiating treatment. TREAT-MS: Participants from German MS clinics were observed for 4 years after last alemtuzumab treatment phase.

Methods: Efficacy outcomes (annualized relapse rate (ARR), change in Expanded Disability Status Scale (EDSS), 6-month confirmed disability worsening/improvement, magnetic resonance imaging), and adverse events (AEs) were examined. Primary HAD definition (⩾2 relapses in the year prior to baseline and ⩾1 gadolinium-enhancing lesion at baseline), and two alternative HAD definitions were assessed.

Results: More participants from CARE-MS I (28%) and II (24%) met primary HAD criteria than TREAT-MS (~14%). Mean ARR for alemtuzumab-treated HAD participants was significantly reduced in CARE-MS I and II (0.14 and 0.15, respectively, Years 3-13) and in TREAT-MS (0.24, >2 years). Stable/improved EDSS scores were achieved by 74% of HAD participants in CARE-MS I, 67% in CARE-MS II (both Year 11), and 79% in TREAT-MS (Year 3.6), with 6-month CDI achieved by about half at Year 11 (CARE-MS I, II). Annual treatment-emergent AE incidences declined in TOPAZ and were lower in TREAT-MS.

Conclusion: Sustained efficacy of alemtuzumab was observed for clinical and radiological outcomes in participants with HAD in the TOPAZ clinical trial and real-world TREAT-MS study with no new safety signals.

Trial registration: ClinicalTrials.gov (CARE-MS I, NCT00530348; CARE-MS II, NCT00548405; CARE-MS Extension Study, NCT00930553; TOPAZ, NCT02255656). Paul-Ehrlich-Institut (TREAT-MS, NIS 281).

Keywords: CARE-MS; RRMS; TOPAZ; TREAT-MS; alemtuzumab; highly active disease; multiple sclerosis.

Figure 1.

Disposition of CARE-MS I and CARE-MS II participants meeting HAD definition according to the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. Gd, gadolinium; HAD, highly active disease; IFNB-1a, interferon β-1a; SC, subcutaneous.

Figure 2.

ARRs for (a) CARE-MS I, (b) CARE-MS II, and (c) TREAT-MS participants with HAD treated with 12 mg alemtuzumab with the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. In TOPAZ (a and b), ARR was estimated through negative binomial regression with robust variance estimation. In TREAT-MS (c), post-baseline ARR was estimated by Poisson regression model adjusted for overdispersion, including the number of relapses as the dependent variable and observational time (years) as the independent variable after the start of alemtuzumab treatment and adjusted by subgroup; the mean observational year is shown. ^aBaseline ARR (mean (SD)) is the mean number of relapses for the past 1 year prior to the study. ^bMean (SD) observational time is 1.9 (0.4) years. ^cMean (SD) observational time at or after Y2 is 2.6 (1.2) years for relapses starting after Y2. **p ⩽ 0.01 for alemtuzumab-treated participants versus SC IFNB-1a over 0–2 years. ARR, annualized relapse rate; CI, confidence interval; HAD, highly active disease; IFNB-1a, interferon β-1a; SC, subcutaneous; SD, standard deviation; Y, Year.

Figure 3.

Percentage of HAD participants with improved or stable EDSS scores compared to baseline over time is shown for (a) CARE-MS I, (b) CARE-MS II, and (c) TREAT-MS, according to the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. Values may not sum appropriately due to rounding. Changes in EDSS scores were analyzed using ranked ANCOVA with adjustment for geographic region and baseline EDSS score. In TOPAZ (a and b), participants remained stable if −1 < CFB in EDSS < 1, worsened if CFB ⩾ 1, and improved if CFB ⩽ −1. In TREAT-MS (c), participants worsened if EDSS CFB ⩾ 1, were stable if −1 < CFB ⩽ 1, and improved if CFB < −1; the mean time from first to last observation is shown below the graph. *p < 0.05 relative to SC IFN-1B. ANCOVA, analysis of covariance; CFB, change from baseline; EDSS, Expanded Disability Status Score; Gd, gadolinium; HAD, highly active disease; IFNB-1a, interferon β-1a; SC, subcutaneous; Y, Year.

Figure 4.

Percentage of HAD participants free of 6-month CDW over time is shown for (a) CARE-MS I, (b) CARE-MS II, and (c) TREAT-MS with the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. In TOPAZ (a and b), baseline was based on the core study; CDW was defined as an EDSS increase of at least 1.0 point (or ⩾1.5 points if baseline EDSS = 0) confirmed over 6 months. In TREAT-MS (c), CDW was defined as an increase from baseline of at least 1.5 points if the baseline EDSS score was 0, of at least 1 point if the baseline EDSS score was 1–5, or at least 0.5 points if the baseline EDSS score was >5.0 confirmed over 6 months. CDW, clinical disease worsening; EDSS, Expanded Disability Status Scale; Gd, gadolinium; HAD, highly active disease; Y, year.

Figure 5.

Percentage of HAD participants achieving 6-month CDI over time for (a) CARE-MS I, (b) CARE-MS II, and (c) TREAT-MS with the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. In TOPAZ (a and b), CDI was defined as a decrease in EDSS score of at least 1.0 point from core study baseline confirmed over 6 months (only applicable to participants with a baseline EDSS score ⩾2.0). In TREAT-MS (c), CDI was defined as a decrease from baseline of ⩾1.5 points if the baseline EDSS score was 0, of ⩾1.0 point if the baseline EDSS score was 1–5, or of ⩾0.5 points if the baseline EDSS score was >5.0 confirmed over 6 months. CDI, clinical disease improvement; EDSS, Expanded Disability Status Scale; Gd, gadolinium; HAD, highly active disease; Y, Year.

Figure 6.

Percentage of participants with HAD free of MRI disease activity for (a) CARE-MS I and (b) CARE-MS II is shown with the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. Free from MRI disease activity is defined as having no new Gd-enhancing T1 lesions on the current MRI and no new/enlarging T2 hyperintense lesions since the last MRI. Proportions of participants free of MRI disease activity, new Gd-enhancing T1 lesions, new/enlarging T2 hyperintense lesions, and new T1 hypointense lesions were evaluated using logistic regression models adjusted for baseline values, with 95% CIs obtained by normal approximation to the binomial distribution. ***p < 0.001 and ****p < 0.0001 for alemtuzumab-treated participants with HAD versus SC IFNB-1a. CI, confidence interval; Gd, gadolinium; HAD, highly active disease; MRI, magnetic resonance imaging; MS, multiple sclerosis; SC, subcutaneous; Y, Year.

Figure 7.

Percentage of participants with HAD achieving NEDA-3 for (a) CARE-MS I and (b) CARE-MS II with the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. NEDA-3 is defined as having no clinical or MRI disease activity. CI, confidence interval; HAD, highly active disease; NEDA, no evidence of disease activity; SC, subcutaneous; Y, year.

Figure 8.

Median annualized PBVC with 95% CI for (a) CARE-MS I and (b) CARE-MS II participants with HAD according to the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. Annualized percent brain volume change PBVC = (% change from baseline in BPF from drug start to last BPF measure divided by the number of days of follow-up between drug start and last BPF measure) multiplied by 365. BPF, brain parenchymal fraction; CI, confidence interval; HAD, highly active disease; IFNB-1a, interferon β-1a; PBVC, percent brain volume change; SC, subcutaneous.

Figure 9.

Mean VAS (SD) scores for participants with HAD from (a) CARE-MS I, (b) CARE-MS II, and (c) TREAT-MS according to the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. VAS relates to the current state of health of the respondent. The respondent marks the current assessment of their own health on a thermometer scale from 0 to 100. In TOPAZ, a mixed model for repeated measures analysis of changes from core baseline was used over 72 months in QoL Assessment: EQ-5D. Changes from core baseline and treatment differences were estimated using an unstructured covariance model with a time by treatment interaction and covariate adjustment for treatment, time, geographic region, and core baseline score. **p < 0.01 for participants with HAD treated with alemtuzumab versus SC IFNB-1a. BL, baseline; Gd, gadolinium; HAD, highly active disease; IFNB-1a, interferon β-1a; MS, multiple sclerosis; QoL, quality of life; SC, subcutaneous; SD, standard deviation; VAS, Visual Analogue Scale; Y, Year.

Figure 10.

Mean (SD) scores for work and household productivity for participants with HAD according to the following criteria: ⩾2 relapses in the year prior to baseline and ⩾1 Gd-enhancing lesion at baseline. Participants completed the following questionnaires: HRPQ for TOPAZ (CARE-MS I and II) and WPAI for TREAT-MS. (a) Household productivity hours lost due to MS over time, pooled CARE-MS I and II. (b) Percentage of the impact on work output for household chores over time, pooled CARE-MS I and II. (c) Percentage of work time missed due to MS, TREAT-MS. (d) Percentage of impairment while working due to MS, TREAT-MS. (e) Percentage of activity impairment due to MS. Gd, gadolinium; HAD, highly active disease; HRPQ, health-related productivity questionnaire; MS, multiple sclerosis; SD, standard deviation; WPAI, work productivity and activity impairment; Y, Year.

Figure 11.

Three different definitions of HAD were applied to the core CARE-MS I and II populations, resulting in three groups of HAD participants. Some participants met more than one definition and were included in more than one group. Gd, gadolinium; HAD, highly active disease.