Answer: This is a very timely question, given the new options that are now available for patients with MS. (Table 1)
We have a number of trials that have compared the auto-injectable medications head-to-head.1-6 One study compared thrice weekly interferon beta-1A with glatiramer acetate (REGARD), and another study compared every other day interferon beta 1B with glatiramer acetate (BEYOND). Both of those studies showed no substantial differences in efficacy between these agents. We’re expecting results of an ongoing trial that is comparing once weekly interferon beta 1A to glatiramer acetate versus the combination of the two drugs (COMBIRx).7 Two earlier studies compared interferon beta 1B to once weekly interferon beta 1A (INCOMIN), and thrice weekly interferon beta 1A to once weekly interferon beta 1A (EVIDENCE). So we will have all the possible comparisons for the front-line therapies, and I suspect that the results are going to be more or less as expected. Differences, if any, between these medications are relatively small.
In terms of a front-line treatment for patients who can tolerate injections, these are the medications of choice in MS. They have been around for the longest period of time. We have the greatest patient-years exposure to these medications. We know that they are generally very safe and well tolerated. Given the comparable efficacy between these medications, we have to make decisions on an individual basis with respect to the associated side effects. That's a matter of talking with each patient to determine what he or she can tolerate with respect to the regimens and adverse events associated with each of these drugs. For example, glatiramer acetate injections are administered every day into the skin, and there can be skin site reactions associated with that. Interferon beta 1A can be injected in the skin or into muscle, depending on the formulation. The regimens vary as well, with every other day, three times weekly, or even once weekly injections. However, interferon therapy is associated with flu-like symptoms. Patients may also experience liver function abnormalities, alterations in blood cell counts, as well thyroid function abnormalities and depression. As a result, patients who are taking interferon therapy require more monitoring than those taking glatiramer acetate.
For patients who are simply unwilling to accept the use of auto-injectables, fingolimod is a good alternative. Fingolimod, which has been available for about 1 year, is the first oral agent for MS. There are now three randomized controlled trials that all showed, more or less, significant reductions in relapses and MRI metrics of disease activity. Two out of the three trials showed a significant impact on disability.8-10 Fingolimod has all of the successful endpoints that we look for, but there are some safety issues with this medication. Use of fingolimod has been associated with the potential for bradyarrhythmias, particularly after the first dose. In addition there could be some hepatotoxicities. In the course of one clinical trial, there was a death due to an opportunistic infection from varicella zoster in a patient who had not previously been exposed to the virus. So we know that the drug can have an immune suppressing effect in certain patients and in particular circumstances can be associated with life-threatening opportunistic infections.
In January 2012 the European Medicine Agency announced an investigation of fingolimod after reports of 11 deaths associated with its use.11 While the review is ongoing, the Agency’s Committee for Medicinal Products for Human Use (CHMP) is advising doctors to perform an electrocardiogram (ECG) before treatment with fingolimod and then continuously for the first 6 hours after the first dose, with measurement of blood pressure and heart rate every hour. After 6 hours, any patients with clinically important heart-related effects, such as bradycardia or atrioventricular block, should continue to be managed and monitored until their condition has improved. What recommendations, if any, the United States Food and Drug Administration (US FDA) will make following completion of the safety review remains to be determined.
This raises the question about how to best use this medication: should it be used as a front-line therapy or should it be used as a second-line therapy in patients who have had ongoing disease activity despite treatment with medications with a better safety profile? In general I would say that fingolimod is used primarily as second-line treatment in MS in patients either who can no longer tolerate interferon or glatiramer acetate or who have had ongoing disease activity.
For second-line or third-line therapy we have natalizumab.12 This drug is associated with the severe brain infection, progressive multifocal leukoencephalopathy (PML), in patients who have tested positive for exposure to the JC virus (named after the patient from whom the virus was first isolated, John Cunningham). As of January 2012, the Stratify JCV Antibody ELISA test became available to test patients before initiating therapy with natalizumab, or to ensure the safety of those patients already taking it.13
As the treatment options for MS increase, the question of when to switch therapy become highly relevant. Certainly it's a lot easier to make a decision to switch patients if they have clinically active disease, and have experienced relapses or have experienced increasing neurologic impairment. Under those circumstances I think that most neurologists would favor switching a patient from a front-line to a second-line therapy. The controversial question is what to do with a patient who is clinically stable but has radiographically active MS, with evidence of new lesions on MRI or contrast-enhancing lesions.
Studies have shown that patients who have evidence of active disease as measured by MRI after 6-12 months of front-line therapy with interferon or glatiramer acetate are at higher risk for greater degree of disability. One study followed 450 patients with MS who were treated with interferon beta with an average follow-up time of 4.8 years.14,15 Patients who experienced new MRI lesions on T2 weighted imaging or contrast-enhancing lesions one year after they had started interferon were much more likely to become poor responders to treatment and have greater disability and worse outcomes several years after treatment. Given these findings, it might make sense to re-image patients after about 6-12 months of initiation of therapy. If there are new lesions on the MRI study or a contrast-enhancing lesion, we might want to consider switching therapy even if the patient has been clinically stable.
Most recently, a study presented at the 2011 Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis Amsterdam, showed that MRI scans taken one year after starting disease-modifying therapy in patients with relapsing-remitting multiple sclerosis (n=396) were strongly predictive of outcomes after 5 years.16 The nonresponder rate at 5 years was nearly twice as high among patients in a retrospective study whose 1-year MRI scans showed more than two gadolinium-enhancing T1 lesions (32% versus 18%, P=.009). Among the patients with 1-year MRI scans, the number of active lesions was a powerful predictor of long-term response.