Multiple sclerosis is unique among neurological diseases in that there are currently eight treatments for this one condition that have received approval by the U.S. Food and Drug Administration (FDA). Five of these drugs require subcutaneous or intramuscular injection, two are administered intravenously, and fingolimod, the newest agent on the block, is given orally. None are considered curative, but these disease-modifying therapies (DMT) have led to a reduction in relapse rates and the progression of disability.
Despite this progress, each of the drugs comes with side effects, including flu-like symptoms with the interferons, lipoatrophy with glatiramer, progressive multifocal leukodystrophy (PML) with natalizumab, and congestive heart failure or leukemia with mitoxantrone. As the first oral agent for MS, fingolimod created great expectations prior to FDA approval. Its popularity, however, has been surprisingly limited, presumably due to the potential for unknown long-term risks. The occur rence of PML with natalizumab demonstrated to MS neurologists and patients the potential risks associated with new drugs.
Additional DMTs in the pipeline may increase MS-management effectiveness in coming years, although safety will continue to be a major consideration in the use of these drugs. For instance, oral cladribine was on the verge of FDA approval in early March when the agency referred the drug back for more safety studies. This drug is already used in intravenous form for the management of hairy cell leukemia, but it is being studied for use with remitting relapsing MS because of its apoptotic effects on lymphocytes. If cladribine is ultimately approved for use, the risk of infection and neoplasms may limit its use.
Other oral agents being studied include:
- Teriflunomide: A metabolite of leflunomide, a drug used for the treatment of rheumatoid arthritis, that inhibits pyrimidine synthesis in rapidly dividing cells
- Laquinomod: An agent that reduces inflammatory cytokines by shifting Th1 to Th2 lymphocytes
- Dimethyl fumaric acid: An immunoprotective against oxidative stress-induced cell death in nerve cells
- Firategrast: An oral alpha-4 integrin antagonist that is similar to natalizumab, has not associated with PML in a phase II study.
Additional drugs in the MS pipeline include:
- Alemtuzumab, which binds to CD52 on T and B cells. It is used for the treatment of chronic lymphocytic leukemia. Immune thrombocytopenic purpura, immune-medicated thyroiditis and Goodpasteur’s syndrome may limit its use.
- Rituxumab, which depletes CD20 B cells, is used for the treatment of non- Hodgkin’s lymphoma, diffuse B cell lymphoma and rheumatoid arthritis. A trial of rituximab failed to achieve its primary outcome measure in the treatment of primary progressive MS.
- Daclizumab is an anti-CD25 monoclonal antibody that leads to an increase in natural killer cells. It is associated with risk of infections.
- Ocrelizumab is an anti-CD20 monoclonal antibody that has shown a reduction in annualized relapse rate and gadolinium- enhancing lesions in phase II studies. Adverse reactions include systemic inflammatory response syndrome and infusion reactions.
Potential drug combinations under consideration have included glatiramer plus interferon (“Combi-Rx” study) and simvastatin plus interferon beta-1-a (“SIMCOMBIN” study). The latter was reported to be ineffective against MS.
Emerging therapies in MS will offer patients and their neurologists an ever expanding choice of mechanism of action and consideration of adverse effects. As additional DMTs become available, it is important to develop algorithms for choosing a particular therapy, and to balance the risk and potential benefit of each therapy for each patient. One day, it may become possible to use the advances of personalized medicine to help patients choose the drug that is best for them.
