Compared with interferon beta-1a, alemtuzumab▼ reduced the annualised risk of relapse and sustained disability over 36 months in patients with previously untreated early relapsing-remitting multiple sclerosis (RRMS). However, treatment in the alemtuzumab▼ groups was stopped prematurely due to the development of immune thrombocytopenic purpura in three patients, one of whom died.
Despite the publicity surrounding this drug in MS, alemtuzumab▼ is not likely to reach the market for several years. The longer term effects of this drug, particularly the development of toxic adverse effects, will require extensive evaluation by regulators. Patients with MS who require further information about trials or management of their condition are advised to contact their local specialist.
What is this about?
Multiple sclerosis (MS) usually starts as a relapsing-remitting condition, but most patients eventually develop progressive neurological deficits without further relapses. Alemtuzumab▼ is a monoclonal antibody that causes sustained depletion of T-cells and hence may have a role in the treatment of multiple sclerosis.
This phase II, single-blind randomised trial assessed patients with early relapsing-remitting MS who had not received previous therapy and had a score of ≤ 3.0 on the 10-point Expanded Disability Status Scale (EDSS). 113 and 110 patients respectively were randomised to alemtuzumab▼ 12mg and 24mg daily for five days given by intravenous infusion after enrolment and in two further cycles at 12 and 24 months. 111 patients were given subcutaneous interferon beta-1a three times weekly. EDSS scores were determined by a neurologist who was blind to treatment allocation. A sustained accumulation of disability was defined as an increase of at least 1.5 points for patients with a baseline score of 0 and of at least 1.0 points for patients with a baseline score ≥ 1.0. No differences in outcomes were seen for the different doses of alemtuzumab▼ so pooled results are quoted here.
The sustained accumulation of disability was 9.0% with alemtuzumab▼ and 26.2% with interferon beta-1a; hazard ratio (HR) 0.29, 95% confidence interval (CI) 0.16 to 0.54, P<0.001. Six patients would need to be treated with alemtuzumab▼ rather than interferon for 36 months to avoid one sustained disability event. Alemtuzumab▼ also reduced the annualised rate of relapse compared to interferon: HR 0.26, 95% CI 0.16 to 0.41, P<0.001.
Serious adverse events happened in 22.4% of the interferon and 23.6% of the alemtuzumab▼ patients but more patients in the interferon group stopped treatment due to adverse events (12.1% vs. 1.4%, P<0.001). Infusion-related reactions were seen in 98.6% of alemtuzumab▼ patients (e.g. rash, pyrexia). Thyroid autoimmunity has been seen previously with alemtuzumab▼. In this trial, autoimmune thyroid disorders were seen in 22.7% of alemtuzumab▼ patients compared to 2.8% of the interferon group. Immune thrombocytopenic purpura (ITP) developed in six patients taking alemtuzumab▼ and in one patient administered interferon beta (P=0.43). The trial was not powered to show differences in rare adverse events such as opportunistic infections but profound T-cell depletion is likely to increase the risk of such infections.
In September 2005 the monitoring committee recommended that the alemtuzumab▼ arms of the trial be stopped due to the reports of ITP, therefore 72% of patients receiving that drug did not receive their third cycle of treatment.
This was a phase II trial, so alemtuzumab▼ is not likely to reach the market for several years. Longer-term trials are necessary to demonstrate safety and sustained effectiveness. It is not yet known if early treatment with alemtuzumab▼ may protect against the development of disability many years later and the toxic adverse effects may dampen enthusiasm. Patients with MS who require further information about trials or management of their condition are advised to contact their local specialist.
The trial was supported by Genzyme and Bayer Schering Pharma.
Further information on the management of MS can be found on the NICE website.