Multiple Sclerosis Discovery -- Episode 1

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum Transcript of Episode 1 with Dr. Timothy Vollmer [intro music] Host – Dan Keller Hello, and welcome to Episode One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s Podcast features an interview with Dr. Timothy Vollmer, who discusses strategies for maximizing brain health in people with MS. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org. First, oral contraceptives. According to a retrospective study published in the journal Fertility and Sterility, women with relapsing remitting MS who used combined oral contraceptives tended to have less severe disease, and they were less likely to move on to secondary progressive MS. On the other hand, this study showed no association between oral contraceptives and annualized relapse rates or EDSS scores. An intriguing set of associations, but correlation does not imply causation. Next, the blood brain barrier. A study in PLOS ONE showed that when cultured blood-brain barrier cells are treated with serum from MS patients the cells decrease their production of tight junction molecules and increase their production of cell adhesion molecules that promote cell migration. Breakdown of the blood-brain barrier is an early feature of MS, and this allows activated leukocytes to migrate into the brain. Understanding this process is important in its own right, but the study also raises questions about the safety of blood donations from people with MS. Does this study suggest that people with MS should be barred from donating blood? Let us know your opinion in the comments. Finally, we hope you’ll check out our new data visualization section, which will allow you to see MS-related data in new ways. Our first visualization is a bubble chart presenting data from 106 MS clinical trials published between 1986 and April 2014 involving 44,606 patients. You can easily sort the data by compound, by trial phase, by dose, by year, by funding, or by population. Please let us know if you discover something unexpected or particularly striking in the data. [transition music] Now, onto the interview. Dr. Timothy Vollmer is a practicing neurologist specializing in MS. He’s also professor and director of clinical research at the University of Colorado Denver. Bob Finn, our executive editor, caught up with Dr. Vollmer at the annual meeting of the American Academy of Neurology in Denver. Interviewer – Bob Finn This is Bob Finn from the MS Discovery Forum. I'm here with Dr. Timothy Vollmer of the University of Colorado Denver Rocky Mountain MS Center, who among other things is interested in how to maximize lifelong brain health in people with MS. Dr. Vollmer, welcome. Interviewee – Timothy Vollmer Thank you. MSDF Why is now a good time to ask about maximizing brain health? Dr. Vollmer Well two reasons: one is because recent research has indicated that there are both medical ways and lifestyle ways to actually improve brain health, and the the data suggests that if we do that that's going to improve people's function later in life and allow them to be the grandparents that they want to be or other things that they want to do later in life. And the second reason is is that we now have nine FDA approved therapies to alter the course of MS by inhibiting the inflammation that causes the damage in the brain. And our challenge is figuring out how to use those most effectively. MSDF So how do you measure a concept as broad as brain health? Dr. Vollmer The easiest measure is actually the size of the brain. One of the unfortunate consequences of multiple sclerosis – as is true with hypertension, cardiovascular disease, strokes, dementia, and other things – is that neurons are dying. So MS is not just a disease of myelin; it's a disease of the entire brain, and it affects neurons and cells called astrocytes and cells called oligodendrocytes that make up the bulk of what the brain is. The result of of loss of these neurons is the brain has less and less flexibility in terms of shifting function around from areas that are not working well to areas that are working well. That ability to switch, or shift function around, is something that we do automatically throughout life. Every time we bump our head and get a little bit of bruising in the brain the brain can compensate by shifting function around. This is the same issue that the NFL is dealing with with its football players and mothers are worried about with their kids in contact sports. The problem of multiple sclerosis is that most of the disease activity is actually below the radar – it's not presenting as relapses – and you don't see it unless you're doing regular MRIs, or you're doing a a more modern MRI technique called a volumetric MRI where you can actually measure the three-dimensional volume of the brain. And we do that routinely in studies, and we know that in MS the brain is shrinking at a rate of about six times faster than the normal healthy controls. That's the fundamental problem in terms of maximizing lifelong activity is we're losing brain function too fast in the early phase of the disease. MSDF So how does this concept help guide treatment? Dr. Vollmer Well it turns out that there actually are three components to a treatment plan that wants to maximize brain health over a lifetime. The first one in multiple sclerosis is obviously to try to prevent further damage to the brain by using the immunological therapies that we have in the most effective way possible. And that's a a bit challenging, but the fact is we have a lot of opportunities now that we've never had before. And this is an issue for the medical field. The second aspect is it turns out that more and more research – including that presented here at the American Academy of Neurology meeting – suggests that if you exercise and are intellectually and physically active that increases your brain reserve. It does that because as you fire neurons by doing something – learning a language, volunteering, going to church, reading, whatever – that causes the nerve cells to put out new branches called neurites. And those neurites randomly connect with other neurons in the vicinity. If you do something to activate that pathway, then you make it permanent. If you don't do something to activate that pathway, it breaks automatically within 24 to 48 hours. So you need to be active on a daily basis really to try to maximize those connections. And what you're doing you're just creating this three-dimensional network of connections between nerve cells that gives the brain the flexibility of shifting function around. And it was reported at this meeting – and it's been reported in the literature a number of times – that people who are intellectually active actually have less disability controlling for all other factors than people who are not intellectually active. And we now know that that's also true by being physically active. And again, this cuts across multiple diseases, but it's just as important in MS as it is in other ones. And then, the third factor is diet. The reason for that is not that there's a specific MS diet; there isn't. But we know that if you develop other dietary related diseases, that substantially increases your risk of disability from MS. So for example, just developing diabetes almost doubles your risk of being disabled from MS than just having MS alone. So just having high blood pressure, just being overweight or obese increases your risk of disability. So that means if we want to maximize lifelong outcomes then we prevent injury by using the drugs as effectively as we can; we get people to exercise and be intellectually active to create more connections with brain, create more cognitive and brain reserve; and we also help them develop a healthy lifestyle from a nutrition aspect, as well, to prevent them from developing other diseases that would compromise neurological health.  MSDF Well all of this sounds interesting, but it sounds completely obvious to me. What is controversial about this subject? Dr. Vollmer There are two things. One is that the medical profession is just now beginning to evolve in the direction of trying to think about global health and chronic diseases. Primary care physicians have been thinking about this for some time, in general, but in terms of applying it to chronic diseases this is a a relatively new concept, and how to do it is still a challenge. The second reason is that regulatory agencies, in other countries, and then in this country, health insurance organizations, prevent us from doing this. So for example, in early phase disease for patients who don't carry a virus called JC virus, a drug called natalizumab or a drug called fingolimod might be actually be the best drugs for them. But the insurance companies, even Medicare and Medicaid, make it very difficult for us to use them in the patients. They tend to approve the old drugs first because they perceive them as cheaper usually through sweetheart deals made by the private insurance companies or just because of concerns of cost on the part of Medicaid. And they prevent us from using more effective drugs earlier; they don't understand this concept of preserving brain volume and brain health in terms of trying to maximize lifelong outcomes. MSDF Is there any proof though that starting with fingolimod or natalizumab – starting with the "heavy hitters" – will prevent the the long, slow progression? Dr. Vollmer Yes and no. The problem is the gold standard would be a 50-year study looking at 10,000 people. That's never going to be done partly because the target is constantly moving as new therapies come into the marketplace, but also it's just not practical. However, having said that, published both in the peer reviewed literature and at the American Academy of Neurology meeting are a number of relatively large studies done at centers around the world – most not funded by drug companies – that have reported that patients on fingolimod or natalizumab are significantly better off after two years of treatment than patients using interferons or glatiramer acetate. And at this meeting, specifically they compared in an open-label way patients who were started on fingolimod versus patients started on interferons or GA or switched, and again they showed a 50% reduction in relapse rate. And in the literature for natalizumab, there have been reports since 2010 of the fact that if you're treating relapsing MS patients over two years period of time, on average, that group is improving in function. And that includes fatigue, cognition, mobility, employability. So with highly effective therapies, we do have evidence, substantial evidence, that slowing down brain volume is important, and that results in better function and often resolution of symptoms – patients actually get better on these highly effective therapies. And we've not seen that with interferons and glatiramer in most patients. MSDF As a physician, can you recommend strategies for making the argument to third party payers? Dr. Vollmer Yes. There is a lot of research data that proves that brain volume or gray matter volumes or the number of neurons that you have in your brain is the most powerful predictor of what's going to happen to you in terms of disability over your lifetime, and this is not an arguable point. However, regulators tend to look at relapse rate reduction and gadolinium-enhancing MRI lesion reduction, which are not very good at predicting long-term outcomes. So we need to reeducate health insurers and third-party payers that if you really want to optimize patients' lifelong health you need to make the investment upfront in highly effective therapies to prevent them from developing more disability. We know there are a number of studies reporting that total healthcare costs are less if you're using highly effective therapy like natalizumab or fingolimod over time than they are with interferon and and glatiramer acetate. So this has been published in many different ways; there's more than a dozen papers in the literature on this. The problem is is that any one study is relatively small, and it's easy to criticize it. But the field needs to step back and look at the overall literature. And the overall literature is consistent; we consistently demonstrate that if there's an effect the effect is in favor of using more effective therapies as early as possible in the disease course.  MSDF Aside from brain volumetrics, what are what are some other good ways of measuring brain health? Dr. Vollmer Well you can look at the number of what are called T2 lesions that are developing on the MRI; so your neurologist can look at that, and they can compare you to other patients of a similar age and try to determine are you on the good end of the spectrum or or the more worse end of the spectrum. You can look at what's called T1 black holes; it's a typical MRI measure that's always done. But T1 black holes are more correlated with worse long-term outcomes, and so if you have more T1 black holes you really should be thinking about being on a more effective therapy. And certainly, if somebody is on a therapy and they continue to have any evidence of disease activity – which means a relapse, a change in the MRI or progressive disability – they should probably be thinking about being on a more effective therapy, and they should be discussing that with their physician.  MSDF I'm a little surprised that you didn't mention any cognitive measures. Dr. Vollmer It’s only because I assume automatically that they're very important, and, in fact, most of the data on brain reserve is focused on cognitive function. However, I would argue that the same principles apply for mobility, for sensation, for vision, for creativity. And so, MS is a disease of the central nervous system, so it attacks the very core of what it is to be human. We tend to focus on the bipedal nature of human behavior, but that's not the most important thing. The most important thing is maintaining your interaction with your family, with your friends, with your profession, being able to progress and learn, etc. We can deal with mobility issues, but we don't have a way to recover cognitive function yet. MSDF Are you yourself conducting any studies in this area? Dr. Vollmer Yes. We have a number of studies; we actually have 28 clinical studies going on in MS. But two of the ones that I think are very relevant to this particular issue is we have been funded to be able to look at the changes on MRI in patients that have been on either fingolimod or natalizumab for two years or longer. And we're comparing them to age matched healthy controls. And what we're asking is is the rate of brain volume change, which all of us suffer, but is the rate of that change in those patients now similar to what it is in healthy controls versus patients who have MS? And as I said, we know that the percent change in brain volume for healthy people is about 0.1% per year; in MS it averages about 0.6% per year. So we're we're doing this study now to see the patients who are doing well – they're coming into the clinic, they're saying I'm feeling good, I feel like I'm as good or better than I was last year – is their brain now normalized in terms of its very modest loss of brain volume over time as a result of normal aging?  MSDF And you said there was a second one that that is particularly relevant. Dr. Vollmer The second one is is to take and ask patients, it's called patient reported outcomes – where we actually ask the patient about how they're doing in cognition, how they're doing with energy, how they're doing with mobility, how they're doing with sexual function, you know, the things that are important to us – and we're asking how that is changing over time on these therapies, and we're trying to correlate that back with what's happening to their brain MRI in terms of brain volume.  MSDF Dr. Vollmer, I've come to the end of my prepared questions. Is there anything else you'd like to add or any questions I didn't ask that I should have asked? Dr. Vollmer Two things. As I said, one is it's very important for patients and the healthcare profession to really begin to understand that MS is a disease of the entire central nervous system, and its impact on neurons is actually the most important aspect of this of this disease. The second one is that healthcare providers working with MS patients and MS patients and families need to advocate to the healthcare system to allow healthcare providers to use the most effective therapy that works best for that patient based on individual assessments of safety and efficacy.  MSDF Well thank you very much. Dr. Vollmer Thank you. Appreciate the interest.  [transition music] Host – Dan Keller Well that’s it for Episode One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum—MSDF--the premier source of independent news and information on MS research, Robert Finn, executive editor. MSDF is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is the Vice President of Scientific Operations.  MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].  [outro music]