Andrew N. Wilner, MD; Daniel Kantor, MD

Disclosures

November 17, 2010

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Editor's Note:

On September 22, 2010, the US Food and Drug Administration (FDA) announced the approval of fingolimod for the treatment of relapsing multiple sclerosis (MS). Fingolimod is the first oral MS medication approved in the United States, and at this year's 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in Gothenburg, Sweden (October 13-16, 2010), Dr. Andrew Wilner interviewed MS expert, Dr. Daniel Kantor, about how fingolimod -- along with other new and investigational therapies -- will likely affect MS care.

New MS Therapies: Introduction

Andrew A. Wilner, MD: I'm Dr. Andrew Wilner, and it's my pleasure today to speak with Dr. Daniel Kantor, Medical Director of Neurologique in Ponte Vedra Beach, Florida, and President of the Florida Society of Neurology. We're here today in Gothenburg, Sweden, at the ECTRIMS meeting, and we're going to talk about MS. What do you think are the most interesting presentations so far?

Daniel Kantor, MD: This is a really exciting time for MS. We started in 1993 with the first medication, and there's just been an explosion of medications since then -- and it is going to continue. We'll start with the new medicines that have been approved by the FDA. [In] the past couple of years, there was Tysabri® (natalizumab). Then, most recently, on September 21, we heard about the approval of what we called FTY720, or fingolimod, and which is now called Gilenya™. Then there was also a symptomatic -- or what I call, a neurofunctional enabler -- called dalfampridine, or Ampyra®.

We heard a lot about fingolimod at ECTRIMS 2010. We're also hearing more about how you write the medication, what kind of monitoring you need for the medication, and safety concerns you might have for it.

Then in terms of dalfampridine, we're hearing about what it might do besides just helping a patient's gait. It's FDA approved to help improve gait function -- to help improve the Timed 25-Foot Walk -- but it does much more. It's a potassium channel antagonist, meaning that it extends the action potential. If a patient has problems walking and has damaged nerves, it's going to make those nerves work better. Some of us use it off-label for other indications; we use it for spasticity because it will help with that as well. Some of us use it for fatigue and for other [types] of weakness.

I actually had a poster at the American Academy of Neurology called Intractable Eructation Responsive to Compounded 4-Aminopyridine. Eructation is belching or burping; a patient of mine had it for 2 years. She had to quit her job, not because she was in a wheelchair or because of cognitive problems, but because she was always belching. I gave her the medication for spasticity, and within 5 days her symptoms stopped. So there are amazing things that you can do when you enable those nerves to work better.

We also saw the approval of Tysabri, or natalizumab, and so there's been a lot of interest in [this agent]. Most people know that it was taken off the market and then put back because of the risk for PML (progressive multifocal leukoencephalopathy), which is really hard to say and to spell -- but which is a reactivation of the JC virus. The question is: How can we mitigate that risk?

There's a new ELISA [enzyme-linked immunosorbent assay] -- a new antibody test -- called the JCV, the JC virus antibody test. The idea is: Can we stratify what a patient's risk is of developing PML? For instance, if a patient is negative, they've never been exposed to the virus. How can a virus reactivate if a patient hasn't been exposed? There is likely a 3% false-negative rate, but overall, if we can identify a significant portion of patients with MS who have a very low to nonexistent risk of developing PML, that's most likely going to change how most physicians use natalizumab.

Putting Fingolimod Into Practice

Dr. Wilner: Let's go back to fingolimod; what's unique about this agent?

Dr. Kantor: Patients have been clamoring for a long time for one thing, and that is to get away from the injectables and to get to an oral medication. Fingolimod is a daily oral medication to disease-modify in MS. It's FDA approved for relapsing MS.

We often now see in FDA indications no mention of relapsing-remitting MS. [They will only refer to] "relapsing" forms of MS, leaving treatment open to interpretation. What do you do if somebody has secondary-progressive MS with relapses? You can go even further and ask: If a patient started with relapsing-remitting MS but now has secondary-progressive -- even without relapses -- does he/she still have a relapsing form of MS?

Dr. Wilner: So most patients with MS will be eligible to take this new pill -- so would qualify -- based on their type of MS?

Dr. Kantor: Right. Thus, 85% of patients with MS start out as relapsing-remitting -- that's an overwhelming majority. The question is how we decide, as physicians, who we want to put on it. We have to look at side-effect profiles. We have to look at how you're doing on the current therapy.

A lot of physicians would argue: If a patient is stable on current therapy, switching might not make a difference. Why should we go ahead? Is it really worth it given the risk-benefit ration? We've been lucky in that we've had drugs that are effective but also safe. No one dies from them; no one develops cancer from them; and no one gets terrible infections from them.

As we [move toward] immunosuppressants and away from immunomodulators, we are going to see side effects, specifically opportunistic and other sorts of infections. Often we see herpes infections. [An increased risk for] malignancy is also possible. The FDA actually reported that pooled data for fingolimod showed that there isn't an increased risk for malignancy, although they do mention that there was some lymphoma. Overall, they think that it's pretty safe in terms of malignancy.

Fingolimod Side Effects: What to Watch Out for

Dr. Wilner: If patients decide to take fingolimod, they'll need to be carefully followed up by their neurologist in regular visits and regular surveillance for these problems, right?

Dr. Kantor: Right, especially at the beginning -- especially the first 3-4 months, and even the first day. We have to do a 6-hour monitoring because 6 hours is the maximum drop in heart rate. There have, unfortunately, been people with AV [atrioventricular] block, but very few with symptomatic AV block. In most people, their heart rate is going to go down. You just don't want that to happen while they're at Starbucks or at home, so we watch them in the office. We don't even need ECGs for everyone. Does that mean a lot of us won't do it? No, I think a lot of us will do ECGs. If we're going to have patients sitting in the office, we might as well go ahead and do this as well.

We're still thinking about how to [properly monitor] patients. We know there is a small, but potential risk for macular edema. In the package insert, it talks about sending them for an ophthalmologic evaluation, although it doesn't specify an ophthalmologist. Obviously, a lot of neurologists are neuro-ophthalmologists and feel comfortable, even if they're not neuro-ophthalmologists, assessing for macular edema. However, after 3-4 months, if it hasn't happened, it's probably not going to happen.

Reduction of pulmonary function tests [is also a potential issue]. It looks like that's probably not that meaningful, but it's something we have to look out for. Of course, we have to consider laboratory monitoring, and the one drug that I think shouldn't be [heavily] used anymore is ketoconazole because so many drugs interact with it.

Other New Prospects in MS Therapy

Dr. Wilner: We have 2 new drugs that are very exciting: fingolimod and then dalfampridine, which is for any type of MS and is used to treat the disability, the walking. I understand that there are many new drugs in development?

Dr. Kantor: Absolutely. There's a new drug that's close to being approved with the FDA. It's been approved already in Russia and in Australia, and it's called cladribine. Cladribine has been around for a long time, but it was administered parenterally for cancer. Now there is a pill formulation. What makes it special is that it's not a daily pill. We're talking about taking it between 8 and 20 times a year, which is amazing.

The question is whether it's going to be approved and when it's going to be approved in the United States. Unfortunately, we just heard a few weeks ago that it was not accepted by the EMA [European Medicines Agency], so [the company] is resubmitting. They're trying to figure out exactly what data the EMA is looking for. They're going to come back pretty fast, hopefully, and say: This is why this drug should be approved.

Dr. Wilner: It's potentially very potent, but potentially very toxic, correct?

Dr. Kantor: We have to be careful with the biggest risk, which is lymphopenia. This is due to the fact that cladribine is a deoxyadenosine analog, meaning that it is going to preferentially ablate lymphocytes. Of course, you're going to have low lymphocyte counts, but the question is: What is that going to do? How much infection are we going to see? Is there risk for malignancy or not? It's unclear. We have to see more patients in order to answer these questions.

Then we shift to all the other drugs that are being investigated. We've seen [a huge] increase in MS research. Now you open up The Green Journal and sometimes most of it is about MS. It's an amazing time to be an MS specialist, and also for the MS community and patients.

There are a lot of other drugs. Some of them are going to be oral, like teriflunomide, laquinimod, and BG-12. Then you have other ones that are going to be intravenous, like monoclonal antibodies. First, they were developing rituximab. Now it's actually a fully humanized monoclonal antibody called ocrelizumab that depletes B cells. We're learning more and more that B cells and not just T cells are important in MS -- that itself is a paradigm shift for us. We also have agents, like daclizumab.

Medications, such as pegylated interferon beta-1a, [are also being investigated]. This agent is being studied as a subcutaneous injection taken either once a month or once every 2 weeks. If we have an interferon that patients can take once a month -- even though it's an injection -- there are going to be a lot of people wanting to be on that medication; this is going to be very important.

When to Begin Treatment

Dr. Wilner: Over the years, in terms of a treatment approach, it's my sense that doctors are treating earlier and earlier.

Dr. Kantor: Absolutely.

Dr. Wilner: Why is it important? Why not just wait for their second or third episode and then treat when patients have problems?

Dr. Kantor: [Let's look at] the original 3 interferons plus glatiramer acetate or Copaxone®: Studies were done with intramuscular interferon beta-1a. A trial called CHAMPS[1] [The Controlled High Risk Avonex Multiple Sclerosis Study] was conducted showing that when a patient has a first event of MS -- clinically isolated syndrome -- suggestive of demyelinating disease, [that patient] does better if treated vs being administered a placebo, so it looks like it's probably better to treat early than to treat later. Patients are going to have a better and more robust response. We don't have to wait for these patients to get sicker and sicker, and we should probably intervene earlier.

Then there was ETOMS[2] [Early Treatment of Multiple Sclerosis] -- which involved half the dose of interferon beta given nowadays -- and BENEFIT[3] [Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment] as well as, most recently, the PRECISE[4] trial with Copaxone. Thus, for all of those medicines, it really worked. It was a little different for subcutaneous interferon beta-1a because it wasn't the currently approved dose, but [all of these trials showed benefit]. Some of the [investigational therapies -- such as cladribine -- are being looked at in] clinically isolated syndrome, too.

Dr. Wilner: The argument against early treatment is that there are many people with benign MS in whom, if you treat them early, you're just exposing them to a medication that they don't need and that may have toxicity. Why not just wait? What sense do you make out of that?

Dr. Kantor: Benign MS -- I'm going to use quotations -- benign MS is a retrospective diagnosis. You can't look at someone yet and say that you are going to have benign MS. We're all looking for personalized medicine and biomarkers, so there's been more investigation -- especially at ECTRIMS -- into benign MS.

It looks like benign MS isn't necessarily so benign, and there are different ways of defining it. Is it that you have a low disability score, even 15 years [down the line]? Is it that you have an even lower score, but 10 years after [symptom development]? The problem is that our disability scores look at things preferentially, like walking and motor function. They're not looking as much at cognitive impairment, or at depression, and at other symptoms of MS. That makes it difficult to know if somebody is really benign or not. There have been other studies that looked at this, and in fact, some patients with "benign MS" developed secondary progressive MS. That doesn't sound so benign to me.

Dr. Wilner: It sounds like early treatment is the way to go, and I hate to interrupt you, but it looks like we've used up our time. You've been a wealth of information.

Dr. Kantor: Thank you so much.

Dr. Wilner: I've learned a lot from our 15 minutes together, and I hope that we have a chance to do this again. Thank you very much, Dr. Kantor.

Dr. Kantor: Thank you.

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