Alemtuzumab Improves Sustained Accumulation of Disability Outcomes Using the SAD-Plus Assessment in RRMS Patients with Inadequate Efficacy Response to Prior Therapy

Background: Alemtuzumab was more effective than subcutaneous interferon beta-1a (SC IFNB-1a) in reducing the risk of sustained accumulation of disability (SAD) measured with the Expanded Disability Status Scale (EDSS) in CARE-MS II (NCT00548405). But EDSS alone may not be sensitive enough to detect meaningful changes in neurological function in some relapsing-remitting MS patients. Here, we present a novel composite endpoint that uses the EDSS, components of the MS Functional Composite, and the Sloan low-contrast visual acuity test to reexamine disability accumulation in CARE-MS II.

Objectives:  To examine alemtuzumab efficacy on SAD outcomes, as evaluated by the composite SAD-plus assessment, in the CARE-MS II study.

Methods:  Patients who participated in the 2-year, randomized, rater-blinded CARE-MS II study had active relapsing MS and ≥1 relapse on prior disease-modifying therapy. Patients received alemtuzumab 12 mg/day via intravenous infusions on 5 consecutive days at baseline and 3 consecutive days at month 12, or SC IFNB-1a 44 µg 3 times/week. SAD was defined as ≥1.0-point increase in EDSS score sustained over 6 months (≥1.5 point in patients with a baseline EDSS=0). Post hoc disability outcomes included the proportion of patients with worsening on the following measures sustained over 6 months: Timed 25-Foot Walk (T25FW; 20% increase from baseline), 9-Hole Peg Test (9-HPT; 20% increase from baseline), and Sloan visual acuity at 2.5% contrast (7-letter worsening). The proportion of patients with sustained worsening on any disability measure (T25FW, 9-HPT, Sloan, or SAD) was also assessed (SAD-plus endpoint).

Results: Compared with SC IFNB-1a (n=202), alemtuzumab treatment (n=435) led to significantly fewer patients with SAD (12.7% vs 21. 1%; P=0.0084), or sustained worsening on T25FW (10.6% vs 16.7%; P=0.0401), 9-HPT (5.4% vs 10%; P=0.0450), or Sloan (9.8% vs 18.2%; P=0.0068). The proportion of patients achieving the SAD-plus endpoint was significantly reduced by 37% with alemtuzumab vs SC IFNB-1a (33.6% vs 47.8%; P=0.0013).

Conclusions:  Alemtuzumab treatment was superior in reducing disability progression compared with SC IFNB-1a as measured by the SAD-plus composite endpoint encompassing EDSS-based SAD as well as ambulation, upper limb dexterity, and visual impairment. The SAD-plus endpoint is more sensitive to clinically meaningful impairments than EDSS-based SAD alone.

Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals.