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Health See other Health Articles Title: Promising New Approach in MS Therapy Editor's Note: While on-site at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Dr. Andrew Wilner spoke with Dr. Mark Freedman about exciting new developments in sphingosine-1-phosphate (S1P) receptor agonists for the treatment of multiple sclerosis, as well as the safety issues with these drugs. Andrew N. Wilner, MD: Welcome to Medscape. I am Dr. Andrew Wilner and I am here with Dr. Mark Freedman in Lyon, France, at the annual ECTRIMS meeting. Dr. Freedman is Professor of Neurology at the University of Ottawa and is an expert in multiple sclerosis. At this ECTRIMS meeting there were 7000 attendees and more than 1000 posters. What were the most impressive findings reported at this meeting? Mark S. Freedman, MD: It is incredible how much has advanced in just a single year, and we are not just talking about the results of clinic trials, although it has been an exceptional year. We also heard some good basic science. We are learning much about the disease and gaining some clues about how to treat it. The big news has been about the new oral treatments. The second oral agent has now been approved in the United States and we are hoping that it will be approved elsewhere in the world. There is a lot of interest in the development of several other molecules. We are looking at drugs such as the S1P receptor agonists, which seem to be multiplying. Fingolimod, which was approved in 2010, is the first oral agent, and now we have another, teriflunomide. Dr. Wilner: Tell me more about the S1P receptor agonist. Dr. Freedman: Fingolimod was the first, and it has been licensed in the United States now for the last several years. The second phase 3 study, which we have never seen before, FREEDOMS II, was presented this week.[1] Those data reaffirm the effect of fingolimod on reducing relapse on MRI but unfortunately did not hit the endpoint of reducing disease progression. Effects on brain atrophy on MRI were reaffirmed as well. This drug seems to protect the brain from wastage. We have extension data and pooled data now from the 2 studies. S1P receptor agonists are a whole new kettle of fish when it comes to talking about therapies for multiple sclerosis. They have a potential for a dual punch that none of the drugs have had to date. They have the effect in the periphery of trapping activated lymphocytes in lymph nodes and preventing them from gaining access to the vasculature and possibly penetrating the brain. But on top of that, these drugs have been shown to penetrate the blood-brain barrier and act within the brain. We have not proven that effect in humans yet, unless you buy the atrophy data as perhaps a suggestion of that effect. We are trying to latch on to that as a potential effect, but certainly in animal models these agents go into the brain, act on the same receptors that are on the lymphocytes, internalize the receptor, and trap it in the lymph node in the brain cells, such as the oligodendrocytes that make myelin. They stimulate these cells to become quite active in extending processes, which is exactly what we want in multiple sclerosis. We want these cells to reach out and remyelinate, if possible, some of the damage. If that pans out, we will have drugs with dual roles. Other people are trying to make similar molecules to be more specific for the receptors in the brain and lymphocytes and away from some of the other body organs where they have had some problems, such as the heart. Dr. Wilner: Because there are S1P receptors in the heart, and it looks like they are the ones responsible for the bradycardia. Dr. Freedman: Absolutely. You stimulate these receptors, they internalize immediately, and until the heart can adjust, you get a first-dose phenomenon where the heart rate drops precipitously, or you set up arrhythmia such as heart block. We discovered the hard way that once the drug was released into the general community; several patients who received it might not have been the ideal patients. First-dose monitoring is now specified by the authorities -- exactly how to monitor the patients after the first dose. We have heard about some of the new competitor molecules, such as ponesimod, which is a little bit more specific to the S1P receptor, with less effect on the S1P receptors on heart muscle. That is much better tolerated because it can be titrated; it is possible to ease people onto the drug to prevent the first-dose bradycardia problem. Other issues came up with these drugs in phase 2, but they are still phase 2 studies. Even siponimod is a better-tolerated drug from a cardiac standpoint, hopefully without sacrificing efficacy. We are looking at 5-6 different S1P receptor agonists all entering phase 3 studies in the next few years. It should be an interesting time. Dr. Wilner: I am going to have to come back to you soon and ask how we choose between this agent and that agent. Post Comment Private Reply Ignore Thread
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