MS Learn Online Feature Presentation Understanding MS Research Robert Lisak, MD. Tom>> And I'm Tom Kimball. Welcome to MS Learn Online.

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1 Tracey>> Hi I'm Tracey Kimball MS Learn Online Feature Presentation Understanding MS Research Robert Lisak, MD Tom>> And I'm Tom Kimball. Welcome to MS Learn Online. Tracey>> There's so much to learn when you live with MS. I know I want to learn as much as I can about the disease, treatments, management strategies and so on. But I also want to know what the future holds. And the key to the future lies in the research that's being done today. Tom>>...Yes, but sometimes understanding what the research means without a PhD can be a bit challenging. In this installment, Our medical correspondent Rick Somers spoke with Dr. Robert Lisak a neurologist with Wayne State University in Detroit, Michigan Tracey >> Rick asked Dr. Lisak about the progress that's being made in MS research. >>Robert Lisak: Well, I think it's a very exciting time for MS research, because we're making a lot of progress. We're dealing with a very complex disease and with a very complex system, the nervous system, and the other systems involved, such as the immune system. And we need to be optimistic. We also need to be realistic, and we need to be thorough in our research. Page 1

2 I think the areas of tremendous progress, one is genetics. We're at the stage where we have the technology to look at minor changes in multiple different genes, because the hereditary factor in MS, while strong, is not a classic single gene, like Huntington's, Duchenne muscular dystrophy, or sickle cell anemia, or something like that. We're making incredible progress with molecular biology using new, modern techniques to look at brain tissue and spinal cord tissue, animal models, tissue culture models, to try to get an idea of how the lesions evolve and how we can try to interfere with that. I think the research in MRI is spectacular. I mean, MRI, when it first came out was a wonderful diagnostic tool for MS and still is, but it's given us tremendous insights into the evolution of the disease, how early it starts, even before the symptoms are present. And with the newer technology, we're being able to see and predict things downstream to distinguish different things going on in lesions that we were not able to distinguish with the older techniques of just simply is there a lesion, and then is it likely to be MS or not? I think we're seeing a lot of very interesting things with clinical trials. For those of us who date back far enough to remember when there were no real clinical trials with MS, we have a huge number of clinical trials going on. Some NIH funded, some pharmaceutical company funded, some other independent foundation funded. And these not only are giving great promise to new ways of treating MS, but we learn about it. Even a trial that unfortunately turns out to perhaps be negative, we're learning from that. We like the trials not to be negative, but a negative trial that we learn something from is not really a negative trial in totality. It's at least positive from learning something about the evolution and pathogenesis of multiple sclerosis. Page 2

3 >>Rick Somers: I want to come back and talk to you about clinical trials, which we'll do in a couple of minutes. First, I wanted to ask you, from a person of your perspective looking at all the information that is now accessible to John Q. Public sitting at home on his computer, or getting, for instance, this webcast, which you could have never fathomed when you were in medical school all those years ago. I guess the question is, with all this information out there, does that concern you? Does that please you? Are there practical ways that you think that the information should be guarded or disseminated? >>Robert Lisak: Well, you can't be displeased by dissemination of knowledge and by availability of facts and knowledge. The problem with what's available with modern websites and blogs, and so forth, is that there's very poor to absent filtering. That is, people can pretty much say whatever they want to say. And while I'm an absolutist, pretty close to it, on the First Amendment, there is a limit. And when you're dealing with science, there is a need for some kind of focus and for some sort of making sure that what people hear is correct or as best we know. Not saying this because this is through the National MS Society, but the National MS Society, I find, to be an excellent source for the patients. They have Web pages, they have updates, they have material that's published that is available through the local chapters, the educational programs for the local chapters. The material is available in physicians offices. And there are other reputable ways of looking things up through NIH, and things like that. And those, I think, are balanced. I know that the NMSS spends a lot of time and has a lot of people involved in reviewing different material that goes out about progress, research or treatment, making sure it's balanced, making sure that people don't make it optimism from hearing something in an animal model but not running out and trying it themselves without any reason to believe that it really would work in patients. Page 3

4 So, I think knowledge is good. I think in science, where it's hard for the people without a lot of scientific or medical background, I think somebody needs to be responsible for trying to balance and filter it, and make it yet widely available, and I think the MS Society has done a very good job of that. >>Rick Somers: What is it they say, that knowledge can be a dangerous thing if it's in the wrong hands? >>Robert Lisak: It can be. It can be. The idea is to not prohibit the dissemination of knowledge, but if you can't keep it out of the wrong hands, which you can't under these circumstances, is to make sure that the right hands give the best of how to interpret that new information and that knowledge. Again, a reputable group like the National MS Society, some of the other partners in the MS coalition, like the Consortium and several others, have no axe to grind and can give a balanced view. >>Rick Somers: Let's get back, because I did want to ask you about clinical trials. When I was diagnosed back in the mid 1990s, which all of a sudden is now turn of the century, I was invited by my MS doctor to participate as a newly diagnosed patient in a trial, and I didn't know exactly what that meant. Talk me through, first of all, how people get involved in trials other than being invited. And then once they do, moving forward, just give me kind of a snapshot. >>Robert Lisak: Well, clinical trials are, as you probably know, as you're involved with this, are divided into different types. There are local clinical trials that are just out of one or two institutions, and there are others that lead to larger trials. So, we have, as you know, Phase I trials. Phase I trials are mainly safety and dose finding. Phase II is proof of concept. They are usually relatively brief, they have much larger number of patients. And they often use a surrogate endpoint to try to get a relatively quick idea of whether this is a Page 4

5 promising drug or a promising line of clinical trial research, or whether it's likely to be a dead-end and not worth wasting both patient, physician time, pharma time, NIH, MS Society time on it. And those are the so-called Phase II. And we use MRI a lot in those, especially for relapsing-remitting MS. The Phase III are what we call the pivotal trials, and those have to have a clinical outcome as their main outcome, at least in the United States, for the FDA to license a drug, if it's new. And to allow the company to promote the drug, if it's already on the market for some other disease. And those trials require large numbers, because MS is quite a variable disease, especially relapsing-remitting MS early on. So, you have these types of trials which are important, and they have primary outcomes, which is usually clinical. And then secondary outcomes, such as MRI and sometimes laboratory studies, and so forth. >>Rick Somers: Tell me about the terms double-blind and placebo, which are terms that people will encounter. >>Robert Lisak: So, double-blind means that the patient does not know what therapy they're on, nor do the investing physicians. So, if you take a standard pivotal trial, the patient doesn't know if they're getting a dummy injection or a live drug, or a dummy pill or a live pill, potentially live pill, meaning the drug under test. And the physicians involved, and we usually have what we call a treating physician and an examining physician, they don't know either. So, the computer knows, which allows us, in case of any problems, if necessary, to break the code and take the patient out of the trial, if there is a safety issue. But this allows as objective as one can get in doing a clinical trial in a variable disease. So, that's what double-blinded means. There are Page 5

6 single blind, where the patient knows but the physician doesn't. Those are sometimes done. Then you have the other type of question about placebo. So, placebo means that a group of the patients, sometimes half, sometimes a third, depends on what's being studied, are getting an inert substance. That is, if it's an injection it's frequently the carrier that the active drug, or the presumed active drug, is dissolved in. If it's a pill, it's often the same material that is used to help make up the pill of the drug being tested to try to allow for variation in the disease where patients may not have relapses or may not progress if they're on placebo. And we need to know if the drug is better than nothing, or placebo, which is usually better than nothing as well. And when you look at people who have not bee in trials. >>Rick Somers: These are highly monitored through every step of the way. >>Robert Lisak: These are monitored every step. FDA is involved, the funding agency, if it's an NIH trial is heavily involved. Every institution that participates has to have their own institutional review board review these and make sure that they feel they're ethical and safe. And any significant side effects, whether the patient may be on placebo or not, get reported back to the central coordinating center, and get reported to the local IRB board. And if it's a significant one, even if it comes from another center, our center would know about it, because it would then be sent through the centralized coordinating center, so that these are safe, as safe as can be. Now, there are no guarantees and no one should think that these are not potentially a problem. The Phase I and Phase II studies should hopefully pick up significant safety side effects, but since they tend to be shorter studies, sometimes they don't. And I think that patients Page 6

7 being in a clinical trial requires dedication by the patient. It's a major commitment. >>Rick Somers: So, Dr. Lisak, what are some of the trends that we are seeing in MS research? >>Robert Lisak: Well, there are several trends. So, one trend is combination trials. So, taking from the cancer people, the colleges, they try drugs in combination. In fact, there is a very large NIHsponsored clinical trial comparing one form of interferon with glatiramer acetate, with the combination. And the question is, is the combination that much better than either drug by themselves? There is no placebo in that group. And you need a very large number of patients, because everybody's going to do better than you would think untreated, because they're all on at least one active drug. So, that's one example. A second phase you're going to see is oral agents, because obviously, from the point of view of the patients, weekly, daily, three times a week injections, even intravenous once a month or so is not something people like to do. And it does tie up time and so forth. So, obviously oral agents are another trend. We're seeing a lot of so-called monoclonal antibodies, that is, humanized or partially humanized monoclonal antibodies merged with mouse specificity against particular candidate molecules that may be important in the pathogenesis of MS. So, we're seeing those. In fact, one of them is currently available, and that's olizumab. There are several others that are in Phase II and early Phase III studies. So, we're seeing that. And then there's a whole question of things called small molecules. So, they can be either oral or injectables. And the idea behind those is that they would not only be able to affect the presumed immune pathogenesis in the peripheral immune system, but by being small and presumably soluble in lipids and fats, would be able to get into Page 7

8 the brain and might potentially be able to work directly on the inflammation and the damage going on in the brain and help with regeneration. But right now all we have is indirect evidence in animal models for a few of the immunomodulating agents. And the knowledge that one of the agents that has been successful in a Phase II and now is being randomized into Phase III, a drug called fingolimod. That we do know can get into the brain, and that may be for good or for bad, we don't know yet. So, I think those are the major trends. But there is always somebody who has another idea. The MS Society publishes, I believe it's once a year or maybe every two years, a book of the clinical trials that they know about. That is, those that either pharma or the investigators, or the NIH, or the NMSS, if they're a sponsor of one of the trials, will publish this to let it be known. And the other thing is that the American Academy of Neurology's official journal, Neurology, does now have a section which investigators, not just in MS, but in other neurologic diseases, can essentially have announcements that we are doing a trial in drug X in MS, or drug Y in ALS, or drug Z in Parkinson's disease, and we are looking for volunteers for the study. Please call the study coordinator at So, those are the trends I think we're seeing. But I think all bets are - - I mean, all possibilities are out there. >>Rick Somers: How about beyond our borders? >>Robert Lisak: Well, I think what we're seeing is not only trials done separately in Europe and in Latin America and in Asia, and in Australia and New Zealand, but we're seeing some of these studies Page 8

9 that are actually multi-country, not just multi-center. So, in order to do -- >>Rick Somers: Pooling resources. >>Robert Lisak: And the patients are the resources as well. Because there are a large number of patients, especially in the United States, but also in Canada and Western Europe and Israel, Australia and New Zealand, the countries that have reasonably modern economies. And there are a paucity of patients available for some of these studies, especially for early disease, moderately early disease. And so a lot of these trials are not only multi-center but multicountry. Now, it used to be U.S. and Canada, and then the EU in some other European countries. But now several of the studies that we've been involved in recently are multi-center, and the clinical coordinating center may be in the U.S., and the MRI coordinating center may be in Italy, or vice-versa. Or both centers may be in the U.S. and both centers may be in Italy, but all the participating centers are all over the world. So, we're seeing that in a lot of diseases, in MS, which is not a rare but not a common disease. I mean, you could do a study of hypertension probably at the Detroit Medical Center, where I am, and get a huge number of people, since people have estimated 20% of the U.S. population is hypertensive or pre-hypertensive. Fortunately, MS is not that common, but it's common enough that we need -- and important enough disease -- that we need to make more progress on it. And so we do need to pool. Because, again, it's not rare, but not common. And it's quite unpredictable. >>Rick Somers: It's in that gray zone, yes. Page 9

10 >>Robert Lisak: And so the combination of relatively small numbers, although not small, and a problem of variability in the disease in individual patients, where they can't even act as their own control from two years ago, make it very difficult to do it with small numbers. Large numbers, multiple centers. The study that I mentioned from the NIH comparing interferon with glatiramer acetate and the combination is about, I think, 75 or 80 centers in the U.S. and Canada, with a need for probably close to 1,000 patients in order to find out if the combination is better than either drug by themselves. Tracey>> There's a lot happening in MS research now and it's so exciting. Tom>>And I appreciate getting an explanation about research that even I can understand, AND getting an idea of where to go for accurate information Tracey>> Thanks to Dr. Lisak for helping us understand the world of MS research. Tom>> And thank you for joining us on MS Learn Online. Page 10