Four Experts, 4 Opinions in Treating MS?

Andrew N. Wilner, MD ; Mark S. Freedman, MD


May 16, 2012

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Editor's Note:

Since the filming of this conference video, the US Food and Drug Administration (FDA) completed its investigation into the death of a patient with multiple sclerosis (MS), which occurred shortly after taking the first dose of fingolimod (Gilenya, Novartis). Although the FDA did not conclude that the agent was related to the death, it did express concerns regarding the potential cardiovascular effects of fingolimod and offered first-dose monitoring guidance as well as recommendations on patients in whom the agent is contraindicated. For the full story, see Medscape's news coverage .

Andrew N. Wilner, MD: Hello. I'm Dr. Andrew Wilner. Welcome to the 64th Annual Meeting of the American Academy of Neurology in sunny New Orleans, Louisiana.

I'm here today with Dr. Mark Freedman, Professor of Neurology at the University of Ottawa in Ontario, Canada. Dr. Freedman is also Director of the Multiple Sclerosis Research Unit at The Ottawa Hospital. He is here today to help us understand some of the new developments in MS and the difficult decisions that we need to make as neurologists with our patients.

Mark, we talked earlier about the new developments in MS. There are many new drugs in the pipeline. Some, like Gilenya™, have recently been approved and there are already choices to make. Are there any official or formal guidelines?

Mark S. Freedman, MD: I hesitate to use the word "guideline" because that would suggest that we actually have evidence on how to use one medication over another. I think of them more as recommendations -- healthy recommendations from people in the know -- because our colleagues look to us for guidance, not necessarily guidelines. They look for advice on where this new oral drug should be placed vs the injectable. Should we take everybody off the current therapy if they are doing well? When would you consider them to not be doing well? If you have to switch from one medication to another, would you automatically go to the new one or would you do a lateral switch and try one of the other first-line drugs that we have had?

The story has become more complicated because now we have to put in all these new therapies and describe their levels. When do you go up or down, and what do you mean by "up"? Are some drugs better than others? We have had some studies that clearly show that some of the new medicines are superior through direct comparator studies. More studies like that are coming.

In Canada, because of a lot of the restrictions that we have on reimbursements for medications, rather than having the government dictate how we should use them with no knowledge, we came up with treatment optimization recommendations and published them. We are in the process of republishing a 2012 version of the recommendations and introducing some of the new therapies that we anticipate to be on the market: how one looks at these therapies relative to the old ones and, more importantly, how to judge response to therapy. How do you follow the patient, judge response, and then, if you have to switch, how do you switch? How do you make that decision? It will be coming out later this year.

Dr. Wilner: I have a few procedural questions. Are you seeing more patients in the MS center whose doctors in the provinces have said, "This is just too complicated -- go to the MS center"? Is that a phenomenon that is occurring as the landscape becomes more complicated?

Dr. Freedman: We would anticipate that, but our structure is very different from the United States' because 80% of the patients in Canada with MS are being treated in major MS centers.

Dr. Wilner: They're already there?

Dr. Freedman: Yes. In provinces like Ontario and Quebec, which are huge, community physicians treat the patients. When it gets a little more complicated, they will refer to the tertiary centers. In the United States, it's flip-flopped; I think only about 20% of patients are in tertiary centers and 80% are in the community, so if there is going to be a problem like that, you're going to see it in this country.

Dr. Wilner: That's what I'm wondering about. In terms of guidelines or recommendations, you are in close contact with all of the other thought-leaders. Would you say that there is a general consensus among most MS specialists -- 9 out of 10 -- who would say, "Do it this way," or is it still up for debate?

Dr. Freedman: I think that if you had 4 or 5 of us here, you would get 4 or 5 opinions, especially if we are looking at some of the newer therapies, because some of us are more familiar with them than others. If you have done trials and worked with a drug for a long time, you become rather comfortable with it. If you have never used a drug, either in a clinical trial or because it has not been available, then you question it. It has to do with experience. I think that the recommendations need to be aligned for each country because there are going to be nuances. Each country rates drugs differently, like the recent change in the way Gilenya has been labeled by the federal government. That is going to change the way people use the drugs.

Dr. Wilner: Let's talk about that. Gilenya is the first oral medication for MS. Fingolimod is the generic name. There was a recent safety issue that resulted in a relabeling with a black box warning. Can you tell us about that?

Dr. Freedman: Yes. In the United States it was given a first-line label, but not in the rest of the world. In Canada we drifted between the European Medicines Agency and the FDA, and the wording was, "Fingolimod is generally not used as a first-line drug." They haven't changed the wording, but the reality is that it is not being reimbursed as a first-line therapy. That will guide how it is going to be used.

In the United States, I don't think that they are going to change it so that you can't use it as first-line therapy, but the FDA is certainly questioning the safety of picking it over the incumbents, such as long-term injectables, that have given us 20 years of data.

Dr. Wilner: There were safety issues. Patients are supposed to be monitored because there is a first-dose bradycardia, but what happened that changed things?

Dr. Freedman: It goes beyond bradycardia. It's a given that you are going to get bradycardia. The problem is that there has been a death within 24 hours of having received fingolimod. The exact cause of death is unknown. It's very suspect that it is cardiac related. Exactly why that is is not clear, but there are arrhythmias that can be set up by fingolimod in the first 6 months or so.

During this meeting, you are going to hear about a study that was done specifically to look at the types of arrhythmias that occur. It is clear that these are arrhythmias that are more common. There is a dose effect with the arrhythmias. The European Medicines Agency has suggested that there is going to be more prolonged monitoring necessary, and the FDA has mirrored that for patients who have had problems or who fall into a certain risk category with regard to their heart.

As neurologists, we're suddenly going to have to go back, take a proper cardiac history, and ask questions about things that we don't normally ask, in anticipation that the patient might need to be watched with more vigilance after being given fingolimod. That has changed the landscape for sure.

Dr. Wilner: For the average MS patient, who is a 30-year-old woman and is perfectly healthy, nothing is really going to change.

Dr. Freedman: Not a problem.

Dr. Wilner: But if the patient is a 60-year-old woman with a history of hypertension, is taking several medications, and maybe has had angina, that is a red flag; she might not be the best patient for fingolimod.

Dr. Freedman: I would agree, except that it's unlikely that 60-year-old patients are going to be started on these disease-modifying drugs. The concern is the younger, so-called healthy individual who may have a strong cardiac history, may have had some early angina, or may have had some cardiomyopathy. There may be some issues. A little flag should go up even on the first cardiogram, and you may want to get an opinion from a cardiology colleague to decide whether fingolimod is appropriate. I know that there is an attempt to try to get cardiologists together to understand more about fingolimod. We have safety issues with another drug that is on the market, which is natalizumab.

Dr. Wilner: I wanted to ask you about that. What happens with natalizumab, and what is the big thing that doctors have to worry about?

Dr. Freedman: You have to worry about progressive multifocal leukoencephalopathy (PML). PML has never been seen in MS. Now the number-one cause seems to be natalizumab-induced PML, which is clearly dependent on the duration of therapy.

Dr. Wilner: Duration of therapy. More than 2 years on the drug.

Dr. Freedman: Correct. The other element that is still a hypothesis, but seems to make sense, is whether you have been exposed to the JC virus. The way you find out whether you have been exposed is to do an antibody test to the JC virus. If the test is positive, then clearly the virus is onboard. Being JC virus antibody-negative, however, does not confer that you are okay for life, because the conversion rate can be 3%-4% per year.

Dr. Wilner: Per year. But for that day, you're safe?

Dr. Freedman: We have already had a case with a patient who was JC virus-negative but developed PML. The patient converted within 6 months of developing PML. It is going to require ongoing vigilance and, in some cases, imaging tests every 6 months, especially if the antibody test is positive. It is very difficult to detect because the lesions of PML on MRI look exactly like MS lesions. There are some ways of detecting PML, but you have to have a very high index of suspicion.

Dr. Wilner: It's a good argument for close follow-up of patients who are taking natalizumab.

Dr. Freedman: Especially if they are antibody-positive.

Dr. Wilner: Is the test available?

Dr. Freedman: Yes. In most countries that are using natalizumab, either the company sponsors the test or the test is commercially available to anyone who needs it.

Dr. Wilner: It's really a requirement now if you are taking natalizumab.

Dr. Freedman: Absolutely. Why wouldn't you test?

Dr. Wilner: Mark, thank you for these insights. We're running out of time. There is a lot more that we could discuss about MS and the new developments. I would like to thank you for coming today.

Dr. Freedman: My pleasure.

Dr. Wilner: This is Dr. Andrew Wilner. Thank you for watching the highlights on MS from the 64th Annual Meeting of the American Academy of Neurology in New Orleans, Louisiana.


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