MS Speaks

Journal Watch (November 16, 2014) also has an article on this new option but it is mainly a summary of the Boston Globe article. It refers to an article in the New England Journal of Medicine in 2012, providing information on clinical trial results along with a comment:

December 4, 2012

Pivotal Trials of Alemtuzumab in MS

Samia J. Khoury, MD reviewing Cohen JA et al. Lancet 2012 Nov 24. Coles AJ et al. Lancet 2012 Nov 24.

Two randomized trials provide evidence on alemtuzumab's efficacy and safety in treating multiple sclerosis — one in treatment-naive patients, the other in patients who relapsed on standard treatment.

Alemtuzumab is a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes. It is FDA approved for treatment of B-cell leukemia but not for treatment of multiple sclerosis (MS). Researchers conducted two multicenter, phase III, manufacturer-funded, 2-year trials of alemtuzumab to treat early relapsing–remitting MS.

In the trial by Cohen and colleagues, the investigators randomized 581 treatment-naive patients in a 2:1 ratio to intravenous alemtuzumab (12 mg daily for 5 days at baseline, then daily for 3 days at 12 months) or subcutaneous interferon beta-1a (IFNβ-1a; 44 μg 3 times per week). Coprimary endpoints were relapse rate and time to 6-month sustained accumulation of disability. Relapses occurred in 22% of the alemtuzumab group versus 40% of the IFNβ-1a group (P<0.0001), a 54.9% improvement. Sustained disability accumulation occurred in 8% of the alemtuzumab group versus 11% of the IFNβ-1a group (hazard ratio, 0.70). Most alemtuzumab recipients (90%) had infusion-associated reactions, 3% of which were serious. Thyroid-associated adverse events occurred in 18% of alemtuzumab recipients and immune thrombocytopenia in 1%. Two alemtuzumab recipients developed thyroid papillary carcinoma. One patient died after discontinuing corticosteroids for presumed autoimmune pancytopenia.

The trial conducted by Coles and colleagues included 840 patients with at least one relapse with interferon beta or glatiramer therapy, who were randomized 1:2:2 to receive 44 μg of subcutaneous IFNβ-1a, 12 mg of intravenous alemtuzumab, or 24 mg of alemtuzumab, following the same regimen as in the first trial, with the same coprimary endpoints. The 24-mg alemtuzumab group stopped recruitment mid-study to increase recruitment in the 12-mg group; outcomes are reported only for the 12-mg group. Relapses occurred in 35% of the alemtuzumab group versus 51% of the IFNβ-1a group (P<0.0001), a 49.4% improvement. Sustained disability accumulation occurred in 13% of the alemtuzumab group versus 20% of the IFNβ-1a group (HR, 0.58). The rate of infusion-associated reactions was 90% among the alemtuzumab recipients, and 77% had infections (mostly mild-to-moderate) compared with 66% in the IFNβ-1a group. Thyroid disorders occurred in 16% of alemtuzumab recipients and immune thrombocytopenia in 1%.

COMMENT

The findings of these two phase III trials confirm the previously reported beneficial effects of alemtuzumab against an active comparator. Alemtuzumab is the only drug shown to have superiority over IFNβ-1a in disability outcomes in a monotherapy phase III trial. However, the effectiveness comes at the price of increased autoimmunity during immune reconstitution. The significant risk for autoimmunity and the high rate of infusion-related reactions decrease the attractiveness of alemtuzumab for treatment-naive patients. It would likely be prescribed for patients with active disease who have failed interferon or glatiramer acetate therapy, especially those who are JC virus antibody–positive (and therefore at increased risk for progressive multifocal leukoencephalopathy from natalizumab; JW Neurol May 29 2012).

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Dr. Khoury is the Jack, Sadie, and David Breakstone Professor of Neurology, Harvard Medical School, and Co-Director of the Partners MS Center, Brigham and Women's Hospital, Boston.

- See more at: http://www.jwatch.org/jn201212040000001/2012/12/04/pivotal-trials-alemtuzumab-ms#sthash.06PlclrW.dpuf