Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients

Abstract

Objective: To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.

Methods: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.

Results: Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.

Conclusions: In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.

Classification of evidence: This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.

Figure 1. Expanded Disability Status Scale (EDSS)–based improvement or worsening

(A) Distribution of confirmed EDSS change from baseline to month 24 shown in half-point increments for alemtuzumab patients compared with subcutaneous interferon-β-1a (SC IFN-β-1a) patients. (B) Odds for improvement vs remaining stable or worsening with respect to the different functional systems of the EDSS at month 24. CI = confidence interval; OR = odds ratio of being improved vs stable or worsened.

Figure 2. Proportions of patients demonstrating 6-month confirmed disability improvement (CDI)

Kaplan-Meier estimates of risk for 6-month CDI with stratification by baseline Expanded Disability Status Scale (EDSS). Only patients with baseline EDSS ≥2.0 were included in the analyses of CDI; 154 (alemtuzumab, n = 105; subcutaneous interferon-β-1a [SC IFN-β-1a], n = 49) patients were excluded from the analysis for not meeting this criterion.

Figure 3. Multiple Sclerosis Functional Composite (MSFC)–based disability outcomes

(A) Patients with ≥15% worsening in MSFC score^a and mean (95% confidence interval [CI]) changes in (B) 9-Hole Peg Test, (C) Timed 25-Foot Walk, (D) Paced Auditory Serial Addition Test–3 (PASAT-3), and (E) 4-dimensional composite score, MSFC plus Sloan low-contrast letter acuity (SLCLA) (1.25% contrast). ^a Increase from baseline of ≥15% on ≥1 component sustained for at least 6 months. p Values are from proportional hazards regression with robust variance estimation and covariate adjustment for geographic region. Changes from baseline on MSFC Z scores analyzed using Wei-Lachin test and mixed model for repeated measures analyses with a time by treatment interaction and covariate adjustment for geographic region and baseline score. Wei-Lachin test statistics were 2.87 (9-Hole Peg Test), 1.61 (Timed 25-Foot Walk Test), 1.44 (PASAT-3), and 2.57 (MSFC + SLCLA). The Sloan chart was not administered to patients at Russian and Ukrainian sites because Sloan charts use Latin alphabetic characters that may have been unfamiliar to individuals in these countries (alemtuzumab, n = 47; subcutaneous interferon-β-1a [SC IFN-β-1a], n = 23). *p < 0.001 and **p < 0.05, between-treatment differences; †p < 0.05, within-treatment change from baseline.