Treatment Options for Multiple Sclerosis: Current and Emerging Therapies

Kristen M. Gawronski, Pharm.D.; Michelle M. Rainka, Pharm.D.; Malti J. Patel, M.D.; Francis M. Gengo, Pharm.D., FCP

Disclosures

Pharmacotherapy. 2010;30(9):916-927. 

In This Article

Current Therapies

Six drugs are currently approved for the treatment of RRMS. These include two forms of interferon β (β-1a [intramuscular and subcutaneous formulations] and β-1b), glatiramer acetate, natalizumab, and mitoxantrone. All of these drugs are administered parenterally, by injection or infusion; thus, compliance may be an issue for patients.[4]

Interferon β and glatiramer acetate are considered first-line disease-modifying agents for the treatment of RRMS, as they have been shown to have comparable efficacy for decreasing relapses by approximately 30%.[5] No significant differences have been determined between either agent with regard to relapse rate, disability progression, or MR imaging outcomes including lesion number or volume.[6] Based on the similar efficacies of these agents, selection is typically based on comorbid conditions, adverse-effect profile, and patient preference.

Interferon β

Interferon β, a first-line treatment for multiple sclerosis, is available as interferon β-1a or β-1b. Interferon β-1a may be administered by using an intramuscular formulation, given once/week, or a subcutaneous formulation, given 3 times/week. Interferon β-1b is available as a subcutaneous formulation, given every other day. Although the exact mechanism of action is unknown, it is proposed that interferon β works by suppressing T-helper cell response, reducing T-cell migration across the blood-brain barrier.[2,4] Common adverse effects of interferon therapy include flulike symptoms after injection, depression, and liver enzyme level abnormalities.[6]

Glatiramer Acetate

Glatiramer acetate, another first-line treatment for multiple sclerosis, is available as a subcutaneous injection given once/day. Its mechanism of action in multiple sclerosis is not fully elucidated but is thought to be related to alteration of T-cell activation and differentiation.[4] Adverse effects of glatiramer acetate include injection-site reactions such as indurations and masses, as well as depression.[6] This drug is an appropriate choice for patients who are unable to tolerate flu-like symptoms or have coexisting depressive disorder.

Natalizumab

Natalizumab is a humanized monoclonal antibody that antagonizes α4-integrin of the adhesion molecule very late activating antigen (VLA)-4 on leukocytes. Inhibition of VLA-4 is responsible for blockade of T cells across the blood-brain barrier.[4,7] Natalizumab is very effective at decreasing relapse rates and slowing disease progression. A phase II study showed a 50% reduction in relapses and a 92% reduction in gadolinium-enhancing lesions on MR images compared with placebo. Additional trials have confirmed these results, showing a 42% reduction in sustained disability and a 68% reduction in relapses. Compared with once-weekly intramuscular interferon β-1a, natalizumab reduced relapses by 56% and decreased gadolinium-enhancing lesions by 87%.[8]

However, natalizumab carries with it the risk of progressive multifocal leukoencephalopathy (PML), which is a serious and potentially fatal opportunistic infection caused by the JC polyomavirus.[4,8] It is proposed that PML occurs as a result of a weakened immune system, incapable of normal leukocyte trafficking.[8] This virus causes a demyelinating condition similar to multiple sclerosis, but the myelin cannot regenerate as in multiple sclerosis. As of January 2010, 31 cases of PML have been reported, with four cases resulting in death. The risk of developing PML is reported to increase with the number of infusions received.[9] A restricted access program has been developed for the drug called the Tysabri Outreach: Unified Commitment to Health (TOUCH) Prescribing Program (Biogen Indec, Cambridge, MA; and Elan Pharmaceuticals, Dublin, Ireland), the goal of which is to monitor for PML. Patients, prescribers, and infusion centers must be enrolled in the TOUCH Prescribing Program before natalizumab infusions can be given.[7]

More common adverse reactions include infusion and hypersensitivity reactions, infections including those of the respiratory and urinary tracts, depression, headache, fatigue, diarrhea, cholelithiasis, and arthralgia.[8] Despite its efficacy, because of the occurrence of PML, natalizumab is considered a second-line treatment for patients who are nonresponsive or intolerant to first-line therapies.

Mitoxantrone

Mitoxantrone is an immunosuppressive agent chemically related to the antineoplastic agents doxorubicin and daunorubicin. It works by intercalating with DNA strands causing breaks, as well as inhibiting DNA repair through topoisomerase II.[4,10] It affects rapidly dividing cells and therefore has secondary effects on the immune system, including antigen presentation, proinflammatory cytokine expression, and decreased leukocyte migration.[4] Mitoxantrone is not a firstline agent because of its cardiotoxicity at cumulative doses above 100 mg/m2. Therefore, there is a limit on lifetime cumulative exposure to this agent. It also causes severe bone marrow suppression, necessitating that hemoglobin levels, white blood cell counts, and platelet counts be monitored before each infusion. Women who are of childbearing potential must also have a negative pregnancy test before each infusion may be administered.[10] To our knowledge, there are no data on efficacy, either clinically or on MR images, compared with interferon β or glatiramer acetate. Mitoxantrone is recommended to be used as a second-line treatment in patients with very active relapsing disease who have failed other therapies.[4,10]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....