Multiple Sclerosis - Episode 6
Fred Lublin, MD, explains that up until about 5 years ago, disease-modifying therapies (DMTs) for multiple sclerosis (MS) were all needle injectables. Now, there are 3 oral DMTs for approved relapsing forms of MS, each with a different mechanism of action: fingolimod, teriflunomide, and dimethylfumurate.
Patricia K. Coyle, MD, states that fingolimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator. Fingolimod is a pro-drug that needs to be phosphorylated, after which it will bind to the S1P receptor. Coyle explains the agent’s mechanism of action in relapsing MS. She discusses the key pre-administration testing and routine monitoring that is required for a patient on fingolimod. For example, at first dose, 6 hours of observation with an electrocardiogram (EKG) at the beginning and the end, and hourly pulse and heart rate are necessary. Coyle says that once a patient has been placed successfully on once-daily fingolimod, it seems to be tolerated extremely well. She explains the other tests that should be conducted, including blood tests, eye tests, and EKGs to monitor for important side effects. In addition, if a patient does not have antibodies to varicella zoster or a history of discrete infection, the live varicella zoster vaccine should be administer prior to starting fingolimod.
Coyle describes the second FDA-approved once-daily oral agent, teriflunomide. Approved in Fall 2012, teriflunomide has the active ingredient of another oral agent, leflunomide, which has been used for rheumatoid arthritis since 1998. She explains that teriflunomide is a mitochondrial enzyme inhibitor, dihydroorotate reductase inhibitor, and targets rapidly dividing lymphocytes, T cells, and B cells. Teriflunomide has shown to have benefit in relapsing forms of MS and also in a first-attack clinically isolated syndrome trial.
Coyle stresses that teriflunomide has a pregnancy category X rating, and so is not be used in a patient who is pregnant or wanting to get pregnant. At the same time, it is the only DMT that can wash out completely within a couple of days. Hair thinning can occur in the first 6 days, but seems to be temporary. In addition, it is important to test patients for tuberculosis, and treat as necessary. Finally, she advises that if there is any comorbid rheumatologic condition, teriflunomide might be very appealing.
Dimethyl fumarate, approved by the FDA in March 2013,is the newest oral agent for MS.A twice-daily capsule, Coyle explains that while its mechanism of action is not clear, it appears to have a number of immunomodulatory properties and possibly neuroprotective or antioxidant actions as well. It has been successfullyintegrated into the armamentarium of MS therapies, in part because minimal pre-initiation testing is necessary—the FDA requiresonly a complete blood count with differential.
Dimethyl fumarate can affect liver enzymes in a small minority of patients, and Coyle advises monitoring these throughout treatment. She explains that 2 other major side effects seen when starting dimethyl fumarate include gastrointestinal toxicity and flushing. She comments that though at times severe, these side effects usually dissipate within a month after initiation therapy, and she provides strategies for mitigating these problems. A minority, maybe 2% to 4%, will develop a marked lymphopenia from this agent. She does describe a case where a patient developed progressive multifocal leukoencephalopathy, which is usually associated only with the use of natalizumab.
Lublin explains that the because of physicians’ lack of experience with the new drug, many patients will opt to remain on the injectables, which offer known efficacy and safety.