The monoclonal antibody alemtuzumab reduced disease progression and accumulation of disability versus interferon in phase 3 clinical trials.
Results of a pair of phase 3 clinical trials reported simultaneously online in Lancet may prove life-changing for patients with relapsing-remitting multiple sclerosis (MS). The two head-to-head studies showed that the monoclonal antibody alemtuzumab significantly reduced relapse rates relative to interferon beta 1a both in those who did not respond to first-line MS therapy and in treatment-naive patients. The drug was originally approved to treat B-cell chronic lymphocytic leukemia.
CARE-MS I1 enrolled 563 patients who had not yet received any MS treatment. The 2 primary endpoints were annualized relapse rate and development of 6-month sustained disability progression. Patients were followed for 2 years from baseline.
The annualized relapse rate in those given alemtuzumab was approximately 20% (0.18 [95% CI, 0.13 to 0.23]). By comparison, the relapse rate in interferon recipients was nearly 40% (0.39 [95% CI, 0.29 to 0.53]).
There was a nonsignificant trend favoring alemtuzumab in accumulation of disability. This endpoint was seen in 8% of patients receiving alemtuzumab compared with 11.1% of the interferon group (P = .22).
Disease progression, as judged by MRI scan, favored alemtuzumab. The percentage of new or enlarging T2-hyperintense lesions was 48% among alemtuzumab recipients and 58% among interferon recipients (P = .01). At the same time, the median change in total T2 lesion volume was −6.5% with interferon and −9.3% with alemtuzumab (P = .31).
Approximately 74% of patients in the alemtuzumab group were judged to be clinically disease-free at the 2-year evaluation compared with 56% of the interferon group (OR = 2.36; 95% CI, 1.62 to 3.43; P < .0001).
Alemtuzumab After First-Line Treatment
Patients enrolled in the CARE-MS II2 study had at least 1 relapse while receiving interferon or glatiramer. Trial design was similar to that of the first study; however, 2 dosing regimens with alemtuzumab (12 and 24 mg) were tested along with interferon beta 1a.
Results were similar to those in the CARE-MS I. In the treatment-naive population, annualized relapse rates were cut in half with alemtuzumab (12 mg): 0.26 (95% CI, 0.21 to 0.33) versus 0.52 (95% CI, 0.41 to 0.66) with interferon.
In contrast to CARE-MS I findings, however, the difference in the proportion of patients who experienced 6-month disability progression achieved statistical significance: 12.7% with alemtuzumab at 12 mg versus 21.3% in the interferon group (P = .0084).
MRI outcomes in CARE-MS II also were similar to those seen in the first study. Significant advantages were seen for alemtuzumab (12 mg) in the proportion of patients with new or enlarging T2 lesions and with gadolinium-enhancing lesions at the 2-year evaluation.
In both studies, brain atrophy was significantly slowed with alemtuzumab, although it was not stopped.
At the 2-year evaluation, 60% of CARE-MS II patients treated with alemtuzumab 12 mg were clinically disease-free compared with 41% of the interferon group (P < .0001).
Alemtuzumab is the first MS therapy to show improved efficacy on clinical endpoints against an active comparator in phase 2 and phase 3 trials. The drug is not without significant adverse effects, however: the most common are infusion-associated adverse effects (headache, rash, pyrexia, nausea, and urticaria) and infections. The most common infections involved the upper respiratory tract and urinary tract; oral herpes was also common. Most of these adverse effects have been moderate and have responded to standard treatments. Autoimmune thyroid-related adverse events were seen in 18% of alemtuzumab-treated patients; also, in approximately 1% of patients in each study, immune thrombocytopenia developed during the study period. Cases of autoimmunity were detected and managed using conventional therapies. Monitoring programs to ensure early detection and management of such adverse effects are planned.
1. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
[early online publication, November 1, 2012]. Lancet. Full article available here.
2. Coles AJ, Twyman CL, Arnold Dl, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. [early online publication, November 1, 2012]. Lancet. Full article available here.