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A New Monoclonal Antibody in the Fight Against Multiple Sclerosis: Alemtuzumab
Abstract & Commentary
By Nancy Nealon, MD, Assistant Professor, General Neurology, Weill Cornell Medical College; Judith Jaffe Multiple Sclerosis Center, New York, NY. Dr. Nealon reports that she serves on the speaker's bureau for Biogen Idec.
Synopsis: The monoclonal antibody alemtuzumab, that targets the CD52 receptor on lymphocytes, reduced acute exacerbations and early disability by 70%.
Source: The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008:359:1786-801
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of unknown etiology, with both genetic and environmental risk factors. Current disease-modifying therapies decrease the acute inflammatory activity, decrease relapses, and slow short-term disability progression. But all patients do not respond to the currently approved medications, and most patients develop disability over time. Better understanding of the disease process and more effective medications are needed.
Alemtuzumab is a monoclonal antibody that targets the CD52 receptor on lymphocytes and monocytes. Annual IV administration depletes T lymphocyte counts for more than a year. B lymphocytes begin to recover about three months after the infusion. Early reconstitution of B lymphocytes may be the mechanism that explains new autoimmunity side-effects described with this drug.
The CAMMS223 trial investigators reported the results of a phase 2, randomized, controlled trial, that enrolled 334 treatment-naïve MS patients. The subjects were recently diagnosed patients with disease duration of less than three years and Expanded Disability Status Scale (EDSS) < 3. One third of patients received 12 mg of alemtuzumab, once yearly; one third received 24 mg, once yearly; and one third received interferon beta 1a, 44 micrograms, subcutaneous, three times per week for 36 weeks. The interferon arm is the current standard of care for early relapsing–remitting patients. Co-primary outcome measures of efficacy were time to sustained development of disability and relapse rate. Patients receiving either dose of alemtuzumab had the same response and side-effect profile, so the two groups were combined. Alemtuzumab decreased the risk of sustained disability by 71% and reduced the risk of relapse by 74%, compared to high-dose interferon beta 1a. Secondary end points included MRI measures of lesion burden measured by T2-weighted MRI scans, and showed a reduced lesion burden in the alemtuzumab group compared to the interferon-treated patients. A dramatic finding was the change in brain volume between treatment groups. Patients on alemtuzumab had an increase in brain volume on T1 images in scans from month 12 to month 36, while brain volume decreased in patients treated with beta interferon.
Serious toxicity occurred from new autoimmunity disorders. Twenty-five percent (25%) of patients on alemtuzumab developed thyroid antibodies and hyperthyroidism Four patients needed thyroid ablation by radioactive iodine, and 24 required antithyroid medications. Three percent (3%) of patients on alemtuzumab developed idiopathic thrombocytopenic purpura (ITP), and one had a fatal cerebral hemorrhage. The other patients with ITP recovered after steroid therapy and one, after treatment with rituximab. No serious opportunistic infections occurred during the trial.
The study design of the CAMMS223 trial was developed from earlier use of alemtuzumab in small groups of secondary progressive and relapsing–remitting patients. MS is a chronic disease with an early relapsing–remitting phase causing minimal disability in 85% of patients. However, most patients enter a secondary progressive phase with increasing disability, and by 15–20 years after onset of disease, 50% of patients need a cane to ambulate. Axonal injury and loss causes long-term disability in these patients. Brain atrophy measurements are used as a surrogate marker for axonal loss, and disability in MS correlates better with brain atrophy than T-2 lesion load. Newer MRI techniques (MR spectroscopy, diffusion tensor imaging, functional imaging) and optical coherence tomography of the optic disc document axonal loss early in the disease process.
Current disease-modifying agents have decreased inflammation and relapse rate by one third, but the relationship to axonal loss and long-term disability is unknown.
If axons degenerate as a result of earlier inflammatory activity, early aggressive suppression of inflammation may prevent disease progression. If inflammatory activity and axonal loss are independent disease mechanisms, decreasing inflammation may slow the disease course but will not change the secondary progressive phase. Alemtuzumab suppressed inflammation in secondary progressive patients in a study by Coles.1 It also reduced new gadolinium lesions by 90% over a period of 18 months, but failed to prevent progression of brain atrophy or disability as measured by the EDSS. Open-label use of alemtuzumab in 25 relapsing–remitting patients suggested disease stabilization. The idea that suppressing inflammation closer to disease onset might prevent progression led to the use of intense immunosuppression in newly diagnosed patients. In the CAMMS223 trial, alemtuzumab suppressed inflammatory activity and relapse rate in recently diagnosed patients with MS by 70% compared to high-dose interferon. Disability did not progress as measured by EDSS. More importantly, cerebral volume increased from months 12–36 in patients treated with alemtuzumab but not with beta interferon. This implies that early aggressive treatment of the inflammatory component of the disease may prevent axonal loss later on. These findings support the hypothesis that the early inflammatory lesions in MS may result in secondary axonal degeneration. Treating patients with intense immunosuppression at disease onset may be necessary to prevent later degeneration.
However, treating patients early with more potent monoclonal antibodies like alemtuzumab exposes active young patients to more serious, potentially life-threatening toxicity. Patients need to be aware of the risk/benefit ratios involved in these treatments. Longer follow-up will show whether this early treatment retains its efficacy. Continued surveillance is necessary for opportunistic infections, other autoimmune problems, and malignancy risk.
1. Coles AJ. The window of therapeutic opportunity in multiple sclerosis. J Neurol 2006:98-108.