Alemtuzumab effective in treating early MS but associated with autoimmunity

Key Points

A phase 2 study published in the New England Journal of Medicine reported that alemtuzumab was more effective than interferon beta-1a in treating early, relapsing-remitting multiple sclerosis (MS), but the agent was also associated with higher rates of autoimmunity, including cases of immune thrombocytopenic purpura (ITP).

In this blinded, randomized, 36-month trial, previously untreated patients with early, relapsing-remitting MS were randomized to 1 of 3 treatment groups: alemtuzumab 12 mg/d (n=113), alemtuzumab 24 mg/d (n=110), or interferon beta-1a 44 mcg (n=111). Alemtuzumab was administered via intravenous (IV) infusion on 5 consecutive days during Month 1 and on 3 consecutive days at Months 12 and 24; interferon beta-1a was administered via subcutaneous (SC) injection 3 times/wk after dose escalation. The coprimary end points were time to sustained accumulation of disability and rate of relapse. Secondary end points included the proportion of patients who did not have a relapse, changes in lesion burden, and brain volume. Baseline demographics were similar among the treatment groups.

In September 2005, the data and safety monitoring board recommended that alemtuzumab treatments be stopped based on 3 reports of ITP occurring in alemtuzumab-treated patients. Three additional reports of ITP in alemtuzumab-treated patients were received after treatment was halted. Investigators were able, however, to assess safety and efficacy end points as planned.

Alemtuzumab reduced the risk of sustained disability by 71% compared with interferon beta-1a (HR=0.29; 95% CI, 0.16–0.54; P<.001). In alemtuzumab-treated patients, the mean disability score on the Expanded Disability Status Scale (EDSS) was improved by 0.39 point, whereas the EDSS score worsened by 0.38 point among interferon beta-1a-treated patients (difference between treatment groups, 0.77; 95% CI, 0.48–1.06; P<.001). Alemtuzumab was associated with a 74% reduction in the rate of relapse compared with interferon beta-1a (HR=0.26; 95% CI, 0.16–0.41; P<.001). A total of 80% of alemtuzumab-treated patients and 52% of interferon beta-1a-treated patients remained relapse-free at 36 months (P<.001).

At 24 months, alemtuzumab was associated with a higher reduction from baseline in lesion volume compared with interferon beta-1a as measured by magnetic resonance imaging (MRI) (P=.005); at 36 months, the difference between alemtuzumab and interferon beta-1a was not significant. At 36 months, the reduction in brain volume from baseline was significantly lower in patients who were treated with alemtuzumab (–0.5%) than in those who received interferon beta-1a (–1.8%; P=.05). Brain volume was reduced from Month 12 to Month 36 by 0.2% in interferon beta-1a-treated patients and was increased by 0.9% in alemtuzumab-treated patients (P=.02).

The rate of serious adverse events was similar among the 3 treatment groups. Two deaths occurred during the study, both in alemtuzumab-treated patients. Three cases of cancer were reported in the alemtuzumab group, and 1 case of cancer was reported in the interferon beta-1a group. Serious infusion reactions and mild-to-moderate infections were more common in the alemtuzumab group; alemtuzumab-treated patients were also more likely to experience adverse events affecting the thyroid. One case of ITP was reported in an interferon beta-1a-treated patient (0.9%) compared with the 6 cases observed in alemtuzumab-treated patients (2.8%; P=.43).

The authors stated that although their study supports the efficacy of alemtuzumab in early relapsing-remitting MS, their results "raise the difficult issue of exposing young adults who have little disability to a drug having potentially serious adverse effects."

In an accompanying editorial, Stephen L. Hauser, MD, pointed out that currently available first-line agents are only modestly effective in early relapsing-remitting MS. He stated that safety concerns notwithstanding, the results of this study "clearly demonstrate the dramatic beneficial results of alemtuzumab on the rates of relapse and sustained disability and on MRI metrics of inflammation and atrophy progression in this cohort of patients with recent-onset, relapsing-remitting disease."

SOURCES

The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786–1801.

Hauser SL. Multiple lessons for multiple sclerosis [editorial]. N Engl J Med. 2008;359:1838–1841.