AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.
Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.
In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).
At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).
Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.
The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).
SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.
"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."
However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).
Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.
A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).
Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.
"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.
In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."
Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.