Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS

$\textbf{Objective:}$ To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). $\textbf{Methods:}$ The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). $\textbf{Results:}$ Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies ($p$ < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions ($p$ < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes ($p$ = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I ($p$ < 0.0001) and II ($p$ = 0.012) vs SC IFN-β-1a. $\textbf{Conclusions:}$ Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS. $\textbf{ClinicalTrials.gov identifier:}$ NCT00530348 and NCT00548405. $\textbf{Classification of evidence:}$ The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.Dr. Havrdova was supported by the Czech Ministry of Education, PRVOUK-P26/LF1/4. The CARE-MS studies were funded by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. METHODS CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. RESULTS Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CONCLUSION CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab.

To examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS. Patients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity. Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes. Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response

Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]). Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years). Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22–0.24 vs. 0.38–0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%–92% vs. 62%–88%; achievement of 6-month confirmed disability improvement [CDI]: 20%–31% vs. 13%–25%), increased proportions free of MRI disease activity (70%–86% vs. 42%–63% per year), and slowed brain volume loss (BVL; –0.45% to –0.87% vs. –0.50% to –1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%–2.2% vs. >45 years: 8.1%) and deaths (0%–1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts. Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies.

Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses. Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown