TRANSFORMS was a 1-year, randomized, double blind, double-dummy phase 3 trial which compared the effect of 0

TRANSFORMS was a 1-year, randomized, double blind, double-dummy phase 3 trial which compared the effect of 0.5 mg and 1.25 mg doses of fingolimod to the effect of weekly intramuscular IFN–1a BMS-863233 (XL-413) on clinical and MRI measures in MS. 53 The primary outcome measure of the study was ARR. 0.02) as measured by the Losseff method on T1 weighted MRI.3,8 The alemtuzumab group experienced more auto-immune and infectious adverse events compared to those treated with IFN–1a. These included thyroid dysfunction in 23% versus 3%, immune thrombocytopenic purpura (ITP) in 2.8% versus 0.9% and infections in 66% versus 47% respectively.3 In the alemtuzumab arm, one patient developed listeria meningitis.4 One of the 6 patients in the alemtuzumab arm who developed BMS-863233 (XL-413) ITP died from brain hemorrhage. This led to drug suspension from September 2005 through May 2007.9 The successful phase 2 program led to the development of the parallel phase 3 clinical trials. The first phase 3 trial, CARE-MS I, was a 2-year randomized, rater-blinded, double-dummy, active comparator clinical trial studying the efficacy and safety of annual alemtuzumab (12 mg intravenously administered daily for 5 days during the first year and for 3 days in year 2) to subcutaneous IFN–1a 44 mcg 3 times weekly over the course of 2 years in treatment na?ve patients with RRMS. Co-primary outcomes were ARR and time to 6-month SAD. The first primary endpoint was met with a 55% reduction in ARR with alemtuzumab treatment compared to treatment with IFN–1a ( 0.0001).10 The second primary endpoint, time to 6-month SAD, did not demonstrate a statistically significant between-group difference. At two years, 8% of patients treated with alemtuzumab had sustained increase in EDSS compared to 11% of patients treated with IFN–1a (= 0.22).10 This finding may be explained by the relatively young patient population who were very early in the course of their disease during the study period. Further studies of alemtuzumab carried out for a longer duration may be able to detect a difference in SAD. The second phase 3 trial coined, CARE-MS II, utilized G-CSF the same design as CARE-MS I, however, in this trial enrollment criteria required that patients have had at least 2 relapses within 2 years prior to entering the trial with at least 1 relapse within the year prior to enrollment and 1 relapse while on a MS disease-modifying therapy. Co-primary endpoints were the same BMS-863233 (XL-413) as CARE-MS I, and this trial met both of its primary endpoints with a 49% relapse rate reduction compared to IFN–1a treated patients ( 0.0001) and a 42% reduction in 6 month SAD favoring the alemtuzumab arm (= 0.0084).11 Auto-immune thyroid disorders developed in 16% and ITP occurred in 1% of patients in the alemtuzumab arm. Safety Patients treated with alemtuzumab in CAMMS and CARE MS trials experienced significantly more infusion related reactions and drug-induced autoimmunity compared to those treated with IFN–1a. Infusion associated reactions include fever, headache, malaise and/or urticarial rash, fortunately, these symptoms are largely prevented by pre-treatment with corticosteroids.12 Drug-induced autoimmunity with alemtuzumab, most commonly involves thyroid dysfunction and occurs in 20%C30%.4,5 Additionally, there have been a few cases of Goodpastures disease.5 The most serious auto-immune condition which has occurred with alemtuzumab is idiopathic thrombocytopenic purpura (ITP). The index patient in the CAMMS-223 died secondary to ITP when early signs were not reported. A monitoring risk management program is now in place for all patients treated with alemtuzumab to identify early signs of ITP.4 Daclizumab Daclizumab is a humanized monoclonal antibody against the subunit, CD25, of the IL-2 receptor on T cells, B cells, macrophages and natural killer cells.13 Interleukin-2 plays a key role in T cell activation and proliferation. Cluster of differentiation-25 (CD-25) blockade selectively inhibits activated T cells which play an important role in the pathogenesis of auto-immune disease and therefore, this drug is of interest in the treatment of MS. In addition, daclizumab has been shown to increase the quantity of CD56bright natural killer (NK) cells (a regulatory subset of NK cells) which down regulate adaptive T cell responses.14 Administration.