Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety

Abstract

Multiple sclerosis (MS) is an inflammatory condition of the CNS presumably induced by an environmental trigger(s) in a genetically susceptible individual. Inflammation is prominent and most susceptible to intervention early in MS, so early treatment with disease-modifying therapies is recommended to reduce relapses and new MRI activity (both markers of inflammation) with the goal of delaying disability progression. Unfortunately, the response to the disease-modifying therapies is variable and often falls short of stopping observable disease activity, so the search for more effective agents continues. Alemtuzumab is a monoclonal antibody against CD52 that has exhibited significant efficacy throughout its clinical trial program in MS; uniquely, some of the studies have demonstrated a sustained reduction in disability in MS patients. Countering this impressive efficacy is an associated high risk of autoimmune events (especially thyroid) and concerns for infection or malignancy given prolonged immunosuppression after treatment with alemtuzumab.

Keywords::

• alemtuzumab
• monoclonal antibody
• multiple sclerosis

Financial & competing interests disclosure

DE Jones has received research support from Biogen Idec and Genyzme; he has consulted for Biogen Idec, Genzyme and Novartis Pharmaceutical Company; he has Institutional contracts with Genzyme, Novartis Pharmaceutical Company and Biogen Idec. MD Goldman has received support from Biogen Idec, Novartis Pharmaceutical Company, NIH; Consulting for Concert Pharmaceuticals; Institutional Contracts: Biogen Idec, Novartis Pharmaceutical Company, Accorda Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Alemtuzumab is a monoclonal antibody against CD52, which causes rapid and profound lymphopenia. Differential recovery of lymphocyte subtypes may allow a reprogramming of the immune system and may partially explain the high risks of secondary autoimmune events.

• The clinical trials of alemtuzumab for multiple sclerosis (MS) suggest good efficacy in regard to relapse rate reduction and MRI progression. Although CARE-MS I did not meet its disability end point, many of the other trials with alemtuzumab did achieve it and actually suggest the possibility of sustained reduction of disability.

• The risk of secondary autoimmunity is high when giving alemtuzumab for MS, with most of the cases being autoimmune thyroid disease; unfortunately, the onset of this secondary autoimmunity is often years after dosing of alemtuzumab.

• The risk–benefit ratio of alemtuzumab for MS is complex, which may have been a factor in the US FDA’s initial decision not to approve alemtuzumab.