Objective: Presentation of top line clinical efficacy and safety results from phase 3 pivotal study: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I)
Background: Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Alemtuzumab was significantly more effective than subcutaneous interferon-beta-1a (SC IFNB-1a) in a phase 2 trial (CAMMS223) with relapsing-remitting multiple sclerosis (RRMS) patients. CARE-MS I is a phase 3 trial designed to confirm the efficacy and safety of alemtuzumab versus SC INFB-1a.
Methods: CARE-MS I is a 2-year, randomised, rater-blinded, active-comparator, global trial comparing the safety and efficacy of alemtuzumab to IFNB-1a in active, treatment-naïve RRMS patients. Patients received 2 annual short cycles (5 days and 3 days) of 12 mg/day intravenous alemtuzumab or 44 mcg SC IFNB-1a 3 x weekly for 24 months. Entry criteria included: age 18-50 years; MS symptom onset <= 5 years; baseline Expanded Disability Status Score (EDSS) <=3; 2 or more relapses in the 24 months prior to study entry; and at least 1 attack in the 12 months prior to study entry. The primary efficacy endpoints are relapse rate and time to sustained accumulation of disability (SAD). SAD is defined as an >=1 point increase in EDSS lasting >=6 months (or >=1.5 point increase if baseline EDSS <1). Blinded raters assessed EDSS quarterly, and relapses as needed. Safety was assessed continuously. The protocol included a safety education and monitoring program for early detection of identified secondary autoimmune disorders as part of a proactive risk mitigation strategy.
Alemtuzumab reduced the annualised relapse rate compared to IFNβ-1a by 55% (P<0.0001). 8% alemtuzumab and 11% IFNβ-1a treated subjects showed disability progression (confirmed at 6 months). This was not statistically significant (P=0.22) due to the unexpected low rate of sustained disability in IFNβ-1a treated arm. There was a significant slowing in brain atrophy on alemtuzumab vs. IFNβ-1a ; brain volume change -1.5% IFNβ-1a vs -0.8% alemtuzumab.
Headline adverse events:
No alemtuzumab treatment discontinuations occurred due to adverse events. 18% of subjects developed autoimmune thyroid disease with alemtuzumab compared to 6% on IFNβ-1a. 0.8% of subjects treated with alemtuzumab developed autoimmune thrombocytopenia (3 cases). 67% of subjects developed infections (1.9% serious) on alemtuzumab compared to 46% (1.1% serious) on IFNβ-1a. There were 2 cases of thyroid carcinoma with alemtuzumab.
Conclusions: CARE-MS confirmed alemtuzumab’s ability to reduce relapses compared to IFNβ-1a. It did not slow the progression of diability compared to IFNβ-1a due to low event rate.
“Some people felt let down by these results after the hype of the phase 2 results. Not me. I still think Alemtuzumab is the most effective treatment in late stage development, but it comes with risks that for some will be worth taking. The fact that the trial did not show an impact on disability progression is not important; the subjects in this study were very early in the course of the disease.”
“More worrying was the reporting of two thyroid cancers in Alemtuzumab treated subjects. It seems likely that one of the cancers pre-dated the trial as the subject had a thyroid nodule documented before entering the study. Fortunately, both were detected early and excised.”
“After my experience with Cladribine and the regulatory decisions concerning the cancer risk associated with this drug I sincerely hope the regulators don’t take the same view in relation to these cancers!”