Selecting Immunomodulating Therapy in Relapsing-Remitting Multiple Sclerosis

An expanding body of data continues to confirm that patients on long-term natalizumab therapy have an increasing risk of developing PML. However, to date there has been only one patient with PML diagnosed at month 12. Several cases have occurred in year 2, where the risk is still less than 1 in 3,000. Unfortunately, most of the PML cases have been concentrated in year 3, and, by my calculations, the risk of developing PML for patients being treated between 24 months and 36 months has risen to 1 in 800.

However, several factors need to be considered in selecting patients for alternative therapies. First, patients with aggressive disease prior to initiation with natalizumab who are now well controlled may still be appropriate for long-term therapy with natalizumab because of the high risk of increasing disabilities. Therefore, the 1 in 800 risk of developing PML, which is a treatable disease but likely to result in increased disabilities secondary to poorly controlled MS, is unlikely to result in death and may be an acceptable treatment option in such cases. Secondly, emerging evidence suggests that, at least for roughly half of the MS population, there may be a low risk of PML by assaying anti-JC virus antibodies in the blood. Preliminary studies suggest that individuals who do not carry anti-JC virus antibodies in their blood are not at risk for PML. This assay will, hopefully, be available in the very near future. Finally, there is no accepted strategy for withdrawing patients from natalizumab. This is an issue, particularly in view of three brief reports suggesting that there may be a rebound or burst of CNS inflammation in a portion of the patients who are withdrawn from natalizumab. Therefore, withdrawing patients from the drug may also carry a risk of exacerbation of their MS requiring treatment. Strategies to deal with this may include initiating a first-line therapy—probably glatiramer acetate—3 months prior to discontinuing natalizumab. This may be effective based on open-label experience with patients from the GLANCE study [Goodman AD et al. Neurology. 2009;72:806-812]. Alternatively, one could discontinue natalizumab and then perform MRIs at month 2 and month 4 in an attempt to detect subclinical disease before it gets out of control. Whatever schedule is chosen, it must be realized that we are in the early stages of using this drug, and we need to monitor for withdrawal effects when discontinuing this therapy until we have clear evidence that such rebound effects do not occur.

As for alternate dosing schedules, there is little evidence to guide us here. A brief “holiday” lasting perhaps between 3 months and 6 months might result in a clearing of the anti-JC virus in the CNS if it were subclinical, but we do not know how long the prodrome asymptomatic stage of the JC encephalitis is. If it is relatively brief, then these drug holidays will need to be done fairly frequently, probably leading to reactivation of the MS and loss of efficacy. Therefore, I would recommend that clinicians not undertake drug holidays outside of a formal clinical trial with the appropriate safety monitoring, including MRI, so that we do not inadvertently place our patients at greater risk of both reactivated disease and ineffective strategies for preventing PML. There are studies being developed to look at alternate dosing regimens in the second and third years of treatment with natalizumab that might allow immunosurveillance to recover for at least 1 week out of every 8. Again, this should be done as part of a research protocol, but there are possibilities that we can develop a dosing regimen that can maintain most of the treatment effectiveness and still minimize the risk of PML.

In summary, for our patients who are reaching year 3 and wish to discontinue natalizumab, I personally would recommend that they do combined therapy with glatiramer acetate for 3 months and then be monitored closely once they stop the natalizumab.

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Yes, for patients who have very active disease placing them at greater than average risk for long-term disability, initiating therapy with natalizumab as a first-line drug is reasonable. Its safety is probably similar to that of interferon for the first 2 years overall. Year 3 is when most of the risk of PML with natalizumab treatment seems to occur. In addition, as noted in the answer to Question 1 above, if it becomes possible to identify those patients at risk for developing PML based on presence of anti-JC virus antibody in their serum, then natalizumab may become a first-line therapy for a larger percentage of patients in early disease.

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There are a large number of therapies in trials for MS ranging from phase 1 through phase 4. Certainly, the medications listed above are near-term drugs. In addition, there is teriflunomide, a drug similar to azathioprine in mechanism of action, in late-phase trials. There are also several active anti-CD20 monoclonal antibody trials; of these agents, ocrelizumab is the most highly developed therapy. This group of therapies, I think, is particularly promising both as mono- and combination therapies. Laquinimod is in phase 3 trials, which will complete in approximately 18 months. This is an oral medication with an excellent safety profile. We are still waiting for clarification of its clinical efficacy, but it does not work through immunosuppression and, therefore, is of significant interest due to its unique mechanism of action. Similarly, oral fumarate, particularly BG00012, is in phase 3 trials. Again, this is an oral medication with a relatively good safety profile that does not work through immunosuppression as a primary mechanism of action. In early stage development are antibodies to other B cell factors, including anti-BAF therapies and abatacept. Finally, daclizumab is a drug used in other diseases—rheumatologic diseases in particular; it is of interest as a therapy for MS, both as monotherapy and as add-on therapy. There are a number of different S1P1 receptor super-agonists that are in development, but they are generally at phase 1 or early phase 2 stages. Finally, there is a monoclonal antibody referred to as anti-LINGO. In my view, this is one of the more impressive therapies in development for repair of the nervous system. It appears to block Lingo-NoGo signaling, thereby removing a block that inhibits remyelination in MS plaques. In addition, it activates neurite sprouting and may facilitate cortical remodeling. It is hoped that this therapy will make its way into human trials in the near future. There are a number of medications I have left out that are in early stage development. The National MS Society’s website has the most complete list of which I am aware [www.nationalmssociety.org].

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Two of the commonly used classes of medications suffer from the development of neutralizing antibodies. The first and oldest class is the interferons, consisting of interferon beta 1-a and interferon beta 1-b. The development of neutralizing antibodies over the first 2 years of treatment varies from approximately 25% to 30% for interferon beta 1-b to 5% to 25% for interferon beta 1-a. The titers of neutralizing antibodies vary from patient to patient, but the data are very clear that the development of neutralizing antibodies is associated with at least some loss of efficacy. When the titers are relatively high, most studies have demonstrated that the MRI disease activity and relapse pattern in patients is indistinguishable from patients in placebo groups. Therefore, in my opinion, neutralizing antibodies in interferons are a major problem. I would recommend that all patients be checked for neutralizing antibodies after their first year of treatment. If they are positive, I would recommend alternative therapies be considered. I am perfectly aware of the arguments that interferons may continue to have some benefit, albeit at a reduced level, in the presence of neutralizing antibodies. However, I would point out that their overall efficacy is already relatively modest, and there are alternative therapies with safety profiles similar to interferons.

Monoclonal antibody-based therapies are the second class of therapies that suffers from neutralizing antibodies. The only one currently approved for use by the FDA in MS is natalizumab. However, rituximab and other antibodies are coming in the near future. For these molecules, the development of neutralizing antibodies is common; however, the prevalence is low—usually around 5% to 6%. With these drugs, development of neutralizing antibodies not only poses the risk of loss of efficacy but also increases the risk of infusion reactions to the drug that can be associated with anaphylactic or hypersensitivity responses and thereby pose a risk to patients who try to remain on these therapies. Data suggest that, at least for rituximab, the risk of antibodies rises as one lowers the dose of rituximab. This may affect the minimum effective dose strategy that is currently being pursued with ocrelizumab. Therefore, in patients on natalizumab and the other emerging monoclonal antibodies who develop neutralizing antibodies, therapy should probably be discontinued and the patients moved on to alternatives.

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