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.

Back to top

Answer: Long-term safety is one the things we are asked about most often by our patients in clinic. We have three different new compounds in MS, and each one has different safety risks for patients. Since these are all new drugs, we don't have long-term safety data.

With respect to fingolimod, there is a strong interest to identify long-term safety outcomes with this drug. A 5-year phase 2 study extension showed that patients with relapsing MS treated with fingolimod maintained low disease activity with a safety profile consistent with that seen in other fingolimod clinical trials. Of the original 281 patients at the start of the phase 2 study, approximately 50% completed 5 years of treatment.¹⁷ However, safety concerns related to fingolimod have come to light, and the US FDA has implemented a risk evaluation and mitigation strategy (REMS) for fingolimod. This package insert recommends that healthcare providers must closely monitor patients to avoid bradyarrhythmia and atrioventricular block, which have been known to occur with the first dose. In addition, there is a risk of infections, macular edema, respiratory effects, hepatic effects and fetal risk.¹⁸

With respect to the other oral disease-modifying therapies, there are a couple of agents that we anticipate that will be approved soon. One is dimethyl fumarate, which is also known as BG12. This medication has been shown to be highly efficacious in two large randomized controlled studies showing a significant reduction in relapses as well as MRI metrics of disease activity. In one study, BG12 showed an impact on disability changes as well.^19,20 BG12 is an oral medication taken twice daily, and we expect based on a prior experience with a similar European drug used in psoriasis (Fumaderm® dimethylfumarate and monoethylfumarate salts) that it will to be quite safe and well tolerated.

Teriflunomide is the third oral agent in development that was also submitted to the FDA for consideration after two successful phase 3 studies showed efficacy.^21,22 There is a 5000-patient registry and several phase IV postmarketing studies going on with this medication to evaluate its safety and efficacy, as well as impact on quality of life and other important patient-reported outcomes. While results from those studies are promising, the very notion of “long-term” means that we need time to gather information and make observations. We’ll have to be patient to accumulate these data, and then analyze this data in a meaningful way.

We're now in an era where the standards for conducting patient registries and performing long-term follow-up studies have been raised significantly. The idea of doing a 5000-patient registry didn't exist back in the early and mid-1990s, when the front-line therapies were first introduced. They wound up being very safe to take long-term, but the newer medications I think are going to have much more intense scrutiny, and we probably are going to understand their full spectrum of side effects in a much more comprehensive way than we ever did with the interferons and glatiramer acetate. So I think it's going to be a very interesting time as we see these various medications launch, and directives from the regulatory agencies requiring that, not only do we have to demonstrate safety and efficacy in a phase 3 study, but we also have to conduct patient registries and a risk assessment of these medications on a very large-scale basis. As an MS clinician, I would say that the goals of making these medications as safe as possible and as efficacious as possible for our patients are being met by the partnerships that have evolved out of the industry and the regulatory agencies.

Natalizumab is a good example of this. This is an extremely efficacious drug encumbered by significant safety concerns. There is approximately a 1 in 500 risk to patients treated with natalizumab for development of PML.²³ All of the patients for whom serum samples were available before the onset of PML-related symptoms tested positive for the JC virus, and this is about 75 out of 75 patients. As of December 31^st, 2011 there are 207 cases of PML worldwide associated with natalizumab. We also know duration of exposure is important: prior treatment with an immunosuppressant, testing positive for the JC virus, and being on the drug for more than 2 years all increase the overall risk of developing PML to about 1 in 90. That group of patients is at highest risk for PML, and, in my opinion, probably should not be treated with this medication.

Now that the JC virus serological assay has become commercially available, any patient who's considering going on natalizumab or patients who are currently on natalizumab can be tested. If they test positive, then a discussion has to occur with the patient to reevaluate the ongoing risks of treatment versus discontinuing therapy. If the patient hasn't started, we need to make a decision as to whether they should start natalizumab at all. I think what we're probably going to see the incidence of natalizumab-associated PML decrease in the years to come. As more patients are tested for the JC virus, those who are positive will either not go on natalizumab, or might go on natalizumab for only a year or two before switching to an alternate therapy.

As that occurs, we'll have more and more patients who are on natalizumab and who test JC virus seronegative. As long as they continue to retest seronegative periodically, then they can continue treatment with natalizumab with minimal risk of developing PML. This raises the question: how often should you retest patients? Right now, we are retesting patients once a year, but it might be that we may need to test patients more often. Perhaps we'll be testing patients every 6 months as some neurologists have suggested.

Back to top

Answer: Pain is one of the most difficult aspects of multiple sclerosis to treat. There aren't many studies that have been done specifically on MS-related pain. Typically what we do in clinical practice is use a number of therapies, such as antiepileptic medications that have provided pain relief in other disease states, off-label. So if an agent works in diabetic neuropathy, trigeminal neuralgia, or zoster-associated pain from shingles, it might work in MS-related pain. However, these agents often have unwelcome side effects, such as sedation or weight gain.

We have seen a couple of studies that have focused on MS-related pain.²⁴ One study involved 239 patients with MS and central neuropathic pain who were randomized to receive placebo (n=121) or duloxetine (n=118). After 6 weeks, patients rated their pain. Interestingly, both groups experienced an improvement in their pain scores over the 6-week period, but there was a 30% greater improvement, which was statistically significant, in the duloxetine-treated patients. That was encouraging. There were some adverse events associated with duloxetine and discontinuation due to those adverse events was more common in the duloxetine-treated group (13%) versus the placebo-treated group (4%).

There is also a study with a relatively new medication that has received US FDA approval for treatment of pseudobulbar affect (PBA) in patients with multiple sclerosis and ALS.²⁵ A combination of dextromethorphan and quinidine, this medication is now being investigated in MS-related central pain in the context of the phase 3 trials that resulted in US FDA approval for treatment in PBA. Patients in those trials were also assessed for pain scores, and the patients who are on active treatment had lower pain scores than the patients who were on placebo. There is now a dosage finding phase 2 study with this medication exploring several different doses of the drug in MS-related pain.²⁶ Hopefully we will have results of that study sometime next year. This study has a slightly longer follow-up period, 4 months, so it will be very interesting to see these results.

I'm glad that we are starting to think outside the box with respect to some of these medications, using medications that are either already FDA approved, or modifications in terms of dosage for medications that are already FDA approved for which we have some safety information available. Treatment of pain is the neurologic syndrome that has the greatest and most pressing need in society, and so we really have a long way to go in terms of developing better pain medications.

Back to top