14 Therapies and New Decisions in Multiple Sclerosis

Lily Jung Henson, MD


January 28, 2016

Considerations in Progressive and Relapsing Disease

The past two decades have been a boon for people living with multiple sclerosis (MS), as we went from having no treatments to now having 14 disease-modifying therapies commercially available via injectable, intravenous, and oral routes. In earlier years, neurologists would argue about the difference in efficacy between the available interferons of varying doses, injection frequencies, and routes, compared with the other injectable therapy, glatiramer. Now we must differentiate between the various available therapies, their efficacy vs their possible risks and side effects, and the comorbidities and history of prior therapy use that may complicate our choice of eventual treatment. The plethora of information on the Internet, some based on science and others based on wishful thinking, has added another layer of difficulty to the counseling of patients choosing a therapy for MS.

Of the 14 therapies currently available for MS, only one is approved for the treatment of progressive MS: mitoxantrone. However, its known association with leukemia and cardiotoxicity has limited its use by the neurology community. The lack of other effective therapies for progressive disease has left a large gap for this segment of MS patients. Some neurologists choose to use the existing therapies for relapsing disease for their patients with progressive disease, either extrapolating from the available findings for relapsing disease or preferring not to restrict their patients from accessing therapies purely on the basis of lack of data. Neurologists who are more concrete in their interpretation of the pivotal trials choose not to offer therapies to their progressive patients.

For relapsing disease, some neurologists choose to differentiate on the basis of aggressiveness of disease activity. The path for those with aggressive disease (multiple gadolinium-enhancing lesions and/or spinal cord disease) may start with the use of natalizumab or alemtuzumab, taking into consideration the patient's John Cunningham (JC) virus status as well as the neurologist's own comfort level using therapies for which the stakes are higher. For patients with less disease activity, a neurologist who is more cost-conscious or prefers a longer history of known drug safety may choose to go with the injectables (interferons or glatiramer), whereas one who practices in an area where the insurers may be less restrictive with oral therapies may be more likely to offer such treatments to their patients. Neurologists frequently make their recommendation after factoring in the perceived risks with the three available oral therapies, including what they see as the more onerous cardiac monitoring associated with fingolimod, the risk for progressive multifocal leukoencephalopathy (PML) with fingolimod and dimethylfumarate, and the black box label warning of possible birth defects associated with teriflunomide.

The use of natalizumab, a highly effective therapy for MS, has been limited by its association with PML. As PML is caused by the JC virus, some physicians restrict the use of this drug only to patients who have undergone testing to demonstrate a lack of prior exposure based on their JC virus status. Others will automatically stop the use of natalizumab after 2 years of therapy because of the higher risk for PML in that population, even if patients are clearly responding to natalizumab and are willing to accept the risk for PML. The concern over PML risk has also led to a greater resistance by some neurologists to using fingolimod, as well as dimethylfumarate. With natalizumab, the risk for PML was noted to be significantly greater with prior exposure to immunosuppressants. The unknown effects of the newer disease-modifying therapies on the immune system, and the compounded effect of prior disease-modifying therapy use, further complicate neurologists' ability to clarify risks vs benefits when advising their patients about choice of therapies.

A recent Medscape survey showed that 93% of neurologists routinely test their MS patients for prior JC virus exposure. The majority of these tests were done when considering the use of natalizumab (87%), fingolimod (56%), and dimethylfumarate (49%). Of neurologists surveyed, 41% were convinced that there is a definite PML signal associated with fingolimod therapy, and 60% indicated that they are likely to decrease their prescription of it. Additionally, 37% of neurologists have described a change in their perception of the risk-benefit profile of dimethylfumarate.