Alemtuzumab (Lemtrada) binds to the CD52 surface antigen found at high levels on T and B lymphocytes, and at lower levels on natural killer cells, monocytes and macrophages. This causes both antibody-dependent and complement-mediated cell lysis. The resultant depletion and repopulation of lymphocytes is thought to reduce the risk of MS relapse and ultimately delay disease progression.
Unlike existing MS treatments that require administration daily or several times a week, Lemtrada is given as a short course of intravenous infusions (12mg once daily for five days) followed 12 months later with a second short course (12mg once daily for three days).
Lemtrada must be administered where adequate facilities are available for the management of infusion-related, potentially anaphylactic reactions. Patients should receive pretreatment with corticosteroids, plus antihistamines and/or antipyretics if necessary.
Investigators assessed alemtuzumab for relapsing-remitting MS in three randomised, rater-blinded clinical trials: a 3-year phase II study in patients with early MS (CAMMS223, n=334); and two 24-month phase III studies in patients who had not received prior therapy (CARE-MS I, n=581) or had relapsed following first-line treatment (CARE-MS II, n=840).
In all studies, patients were randomised to receive subcutaneous interferon beta-1a (44 microgram three times a week) or annual cycles of intravenous alemtuzumab (12mg once daily for 5 days, followed 12 months later by a second 3-day course). The CAMMS223 and the CARE-MS II study also investigated alemtuzumab at a higher 24mg daily dose given in the same regimen as the 12mg dose. In the CARE-MS II study, however, dosing at this level was discontinued to aid recruitment, although data were included in the safety analysis.
The primary efficacy endpoints in all three studies were the percentage of patients with sustained (≥6 months) accumulation of disability (SAD) and the annualised relapse rate (ARR).
In the CAMMS223 study, alemtuzumab therapy was suspended before the planned study end date after 3 patients developed immune thrombocytopenic purpura, one of whom died. Analysis showed that alemtuzumab reduced the risk of 6-month SAD by 71% compared with interferon (HR 0.29, 95% CI 0.16-0.54, p<0.001). ARR was reduced by 74% in the alemtuzumab group compared with the interferon group (HR 0.26, 95% CI 0-16-0.41, p<0.001). There were no significant differences in outcomes between the alemtuzumab groups.
In the CARE-MS I study, in which patients were randomised to alemtuzumab or interferon beta in a 2:1 ratio, 22% (82) of patients who received alemtuzumab relapsed compared with 40% (75) of those given interferon, corresponding to a 54.9% reduction with alemtuzumab (rate ratio 0.45, 95% CI 0.32-0.63, p<0.0001). However, there was no significant difference in SAD between the two treatment arms.
In the CARE-MS II study, in which patients were randomised to alemtuzumab or interferon in 4:1 ratio, 35% (147) of patients in the alemtuzumab group experienced relapses compared with 51% (104) of those in the interferon group, corresponding to a 49.4% reduction with alemtuzumab (rate ratio 0.51, 95% CI 0.39-0.65, p<0.0001). SAD occurred in 13% (54) of patients treated with alemtuzumab versus 20% (40) of those who received interferon (HR 0.58, 95% CI 0.38-0.87, p=0.008).
The most common adverse events associated with alemtuzumab are rash, headache, pyrexia and respiratory tract infections. Severe autoimmune conditions, including thyroid disorders, nephropathy and immune thrombocytopenic purpura, have been reported in some patients. Individuals who are prescribed alemtuzumab should be warned of the risks before starting treatment and be given a patient alert card and patient guide; they must also be advised of the need to consent to follow-up for at least 48 months after the final dose.
In its most recent set of recommendations, the National Institute for Health and Care Excellence (NICE) has approved alemtuzumab for use on the NHS within its licensed indication.
Further information: Genzyme