Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Abstract

Background and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation).

Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)].

Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent.

Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course.

Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Keywords: Alemtuzumab; disease-modifying therapy; follow-up studies; interferon beta-1a; multiple sclerosis; relapsing-remitting.

Figure 1.

Disposition of participants from the 2-year core CARE-MS II study through to the CARE-MS and TOPAZ extension studies. ^aReasons included lost to follow-up, physician’s decision, withdrawal of patient’s consent, study terminated by the sponsor or other, non-specified reasons. ^bAll participants initially randomized to receive SC IFNB-1a in the core study received two courses of alemtuzumab in the CARE-MS extension. DMT, disease-modifying therapy; SC IFNB-1a, subcutaneous interferon beta-1a.

Figure 2.

(a) Total number of alemtuzumab courses during the CARE-MS II core study and CARE-MS and TOPAZ extension studies. Participants in the IFN-alemtuzumab group were eligible to receive SC IFNB-1a during Years 1–2 and alemtuzumab during Years 3–11. (b and c) Receipt of alemtuzumab courses 3–8 by study year for participants in the CARE-MS (Years 3–6) and TOPAZ (Year 7–13) extension studies in the (b) alemtuzumab-only group (n = 393) and (c) IFN-alemtuzumab group (n = 143). SC IFNB-1a, subcutaneous interferon beta-1a.

Figure 3.

Changes in clinical outcomes among participants from CARE-MS II. (a) ARR was estimated using a negative binomial model. (b) Mean EDSS score from baseline to Year 11 and the percentage of participants for whom EDSS score was stable (⩽0.5-point change in either direction) or improved (⩾1.0-point decrease) relative to baseline. (c) Proportion of participants free of 6-month CDW, defined as ⩾1.0-point increase in EDSS score or ⩾1.5-point increase if the baseline EDSS score was 0, confirmed over 6 months. (d) Proportion of participants with 6-month CDI, defined as ⩾1.0-point decrease in EDSS score from baseline (assessed only in participants with baseline EDSS ⩾2.0), confirmed over 6 months. ^aKaplan–Meier estimates. ARR, annualized relapse rate; CDI, confirmed disability improvement; CDW, confirmed disability worsening; CI, confidence interval; EDSS, Expanded Disability Status Scale; SC IFNB-1a, subcutaneous interferon beta-1a; SE, standard error.

Figure 4.

MRI lesion outcomes through Year 11 among participants from CARE-MS II. (a and b) Freedom from MRI disease activity each year for participants who received (a) alemtuzumab-only and (b) SC IFNB-1a in Years 0–2, then alemtuzumab in Years 3–11. (c) Freedom from MRI disease activity, Gd-enhancing lesions, and new/enlarging T2 lesions. MRI disease activity was defined as new Gd-enhancing T1 lesions on current MRI or new/enlarging T2 hyperintense lesions since the last MRI. The percentage of participants free of MRI disease activity was based on the average percentages and the distribution range (minimum, maximum) during both the core study (Years 1–2) and extension studies (Years 3–11). CI, confidence interval; Gd, gadolinium; SC IFNB-1a, subcutaneous interferon beta-1a; MRI, magnetic resonance imaging.

Figure 5.

Brain volume loss through Year 11 in participants from CARE-MS II who received (a) alemtuzumab-only and (b) SC IFNB-1a in Years 0–2, then alemtuzumab in Years 3–11. BPF, brain parenchymal fraction; CI, confidence interval; SC IFNB-1a, subcutaneous interferon beta-1a.