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Hello, and welcome to Episode Forty-Three 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. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum.
We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News & Future Directions and then on New Findings.
This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014. To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud.
According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS.
Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.
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Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS.
Interviewer – Dan Keller
Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs?
Interviewee – May Han
So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics.
MSDF
What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well?
Dr. Han
Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication.
To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy.
MSDF
Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients?
Dr. Han
That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients.
MSDF
Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through?
Dr. Han
So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint.
MSDF
I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time?
Dr. Han
This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition.
MSDF
When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not?
Dr. Han
I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity.
Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding.
MSDF
You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present?
Dr. Han
Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know.
MSDF
Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need?
Dr. Han
The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life.
I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder.
MSDF
You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS?
Dr. Han
It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient.
So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment.
MSDF
Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added?
Dr. Han
I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system.
As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal.
MSDF
Good, thank you.
Dr. Han
Thank you.
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Thank you for listening to Episode Forty-Three 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. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is 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 editor@msdiscovery.org.
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[intro music]
Hello, and welcome to Episode Forty-Two 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. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer’s disease, in an animal model of MS.
Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.
According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic’s disease. The conclusion of the meta-analysis is that there’s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.
Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.
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Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.
Interviewer – Dan Keller
Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what’s commonly viewed as a destructive molecule. How did you come upon this?
Interviewee – Lawrence Steinman
We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis – EAE. And when she put in these long peptides from an infamous protein named amyloid beta – A-beta – she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they’ll have no effect and then we’ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, “Well, I gave the A-beta peptides and the animals are all better, they’re walking around.” And I first reacted, no, you must have confused the cages, let’s do it again. And when we did it again there was the same result, so then we were off to the races.
There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let’s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it’s doing. But, again, my bias, based on the dominant theory in Alzheimer’s disease is that amyloid was going to cause harm in MS as well as Alzheimer’s.
MSDF
In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?
Dr. Steinman
Actually, it does not get to the brain. We’ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we’re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they’re sort of tilting the balance to enhance spread if it’s going to occur, but we don’t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.
MSDF
So if you’re injecting them peripherally, do you think that there is some direct effect, or do you think they’re acting through lymphocytes or other circulating cells?
Dr. Steinman
Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they’re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they’re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.
So what they’re doing when we put them into the circulation is they’re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we’ve heard about in reference to Alzheimer’s, we’ve heard the most about apolipoprotein E. So these amyloid molecules, when they’re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.
There’s another set of mechanisms that we’re learning about that we’re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It’s doing another thing that we’re on the verge of publishing, but I’ll sort of give the headline without too many details; it’s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.
MSDF
And you have done adoptive transfer of some of these lymphocytes and find similar effects?
Dr. Steinman
Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what’s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 – Th1 – then the type 1 interferon is beneficial. So we’ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.
I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that’s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they’re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there’s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.
Now what does this all mean for the Alzheimer’s hypothesis? And we’re doing an audio interview, so I’m sort of smiling wryly. I don’t want to get into that because we haven’t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven’t done that. And we’ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we’ve studied, we see benefit.
MSDF
But as a further proof of concept of what you have found in the protective effect of amyloid, you’ve looked at amyloid precursor protein knockout mice. Is that right?
Dr. Steinman
Yes. Well, that’s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who’s actually one of the leaders in the field of Alzheimer’s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.
We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there’s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it’s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.
So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer’s, whether Alzheimer’s is an example of neuroinflammation, I leave it to people in that field because I really don’t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I’m talking about, not only from my own lab but from other investigators all over the world.
One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer’s, but I’m not going to be the one that takes on that massive scientific opinion, we’ll just have to see how it works out. I hope everyone’s been right over all these years because we certainly need some answers in that field. And if they are right, then we’ll have to integrate the kinds of things that we’re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer’s when it’s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer’s, then it will be easier to reconcile these different outcomes. But I think we’ll have to be patient; science doesn’t move as fast as some of us would like to have it move.
MSDF
What was the time course of seeing a result by injecting the amyloid in your EAE models?
Dr. Steinman
It’s very fast. When you inject the amyloid, it’s within 48 hours. If you stop giving the amyloid – we like to give it every day – if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It’s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that’s very interesting.
MSDF
The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?
Dr. Steinman
So far, we haven’t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you’ll allow for remyelination if there’s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.
MSDF
Are you planning any early human trials?
Dr. Steinman
Ha! I chuckle because this is a tough one to bring into the clinic. I’ve been funded by people who first scolded me for saying don’t take this too fast into the clinic, because I like to translate results. In this one, we’ll have to be more cautious than we might for other types of therapies.
MSDF
Is there anything important to add?
Dr. Steinman
I thought the questions were very comprehensive. And as you can see from where our matters stand now, there’s a lot of positive leads to pursue. And I think we’ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I’m working with, but we’ll get there. Thank you.
MSDF
Thank you.
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Thank you for listening to Episode Forty-two 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. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is 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 editor@msdiscovery.org.
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[intro music]
Host – Dan Keller
Hello, and welcome to Episode Forty-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 Diego Cadavid, who discusses trials of anti-LINGO-1 in MS. But first, a few updates on the latest developments at MSDF.
Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 3 new trials and 11 other pieces of information. The drugs with important additions are dalfampridine, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, naltrexone, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.
According to our curated list of the latest scientific articles related to MS, 54 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One is a meta-analysis of mortality studies showing that excess mortality in MS relative to the general population has not changed over the past 50 years. In the other Editor’s Pick, Jagannadha Avasarala points out that 20% of patients who present with a symptom consistent with a diagnosis of clinically isolated syndrome do not meet radiological criteria on brain MRIs. Dr. Avasarala has contributed an essay to MSDF in which he discusses the consequences of this finding. To see his essay, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.
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Now to the interview. Dr. Diego Cadavid works at Biogen Idec, a pharmaceutical company involved in MS therapeutics. Our executive editor, Bob Finn, caught up with him in Washington D.C. at the annual meeting of the American Academy of Neurology, where Dr. Cadavid presented results of a phase 2 trial of an anti-LINGO-1 antibody called BIIB033 in which the antibody appears to promote myelin repair in the human brain.
Interviewer – Robert Finn
Dr. Cadavid, welcome.
Interviewee – Diego Cadavid
Thank you, Bob, for having us.
MSDF
First, what is anti-LINGO-1, and what does it target?
Dr. Cadavid
Anti-LINGO-1 is an investigation and treatment for a myelin repair. It targets a protein called LINGO-1 expressed in the myelin forming cells that normally inhibits the production of myelin. By blocking LINGO-1, we believe healthy cells actually make myelin and at the same time help patients with demyelinating diseases like MS.
MSDF
Tell me more about LINGO-1. Why this target makes sense in multiple sclerosis.
Dr. Cadavid
Yeah, so LINGO-1 is an inhibitor of myelination. So MS is a demyelinating disease, and it's well established that the majority of patients once they lose myelin they actually are not capable of repairing it. And the question in the field has been why? It's becoming clear that it's not because of a lack of cells; the myelin forming cells are there, but they're not making myelin. So one of the leading hypothesis is that there is a blockade of the ability of these cells to make the myelin. Biogen – more than 10 years ago – was looking for a molecules that could mediate that inhibition, and that's when they found LINGO-1. And through a series of experiments in animal models and in vitro, they showed that when you block LINGO-1 these cells actually differentiate and make myelin. Here we are more than 10 years later reporting the first results of an efficacy trial of anti-LINGO in humans. That's the RENEW study in acute optic neuritis.
MSDF
So tell me about the use of optic neuritis sort of as a model of MS.
Dr. Cadavid
Yes, we chose acute optic neuritis as the first efficacy trial because, first of all, acute optic neuritis is how many of them, as patients, actually initially present. They're healthy, living in the community, and so then they lose vision in one eye due to acute optic neuritis. In fact, during their lifetime, most MS patients will develop acute optic neuritis, so it is very relevant to MS. But also because it's the one part of the brain that is readily accessible. Through the pupil, we can actually image the neurons of the optic nerve. And using electrophysiology and something called visual evoked potentials, we can very accurately measure the function of this neuronal pathway. So it is not only relevant to MS, we have really good tools to investigate not only the disease but what anti-LINGO-1 may be doing to help the patients.
MSDF
But are there indications that anti-LINGO-1 has affects more centrally than the optic nerve?
Dr. Cadavid
So the optic nerve – we call it a nerve, but it is really not a nerve – it's a part of the brain. So anti-LINGO-1 is actually a central molecule. What we mean? It's really expressed only in neurons and in the myelin forming cells; it's not expressed outside of the central nervous system. So all the effects of anti-LINGO-1 are believed to occur centrally.
MSDF
Where is anti-LINGO-1 in the development process?
Dr. Cadavid
We are in the middle of drug development process, Bob, I assume you're asking me. We are in the middle of phase 2. We just finished the first of the two phase 2 trials called RENEW. These are results we are communicating at the academy this year. We believe the RENEW trial results showed efficacy on the primary endpoint: recovery of latency of the visually evoked potential. And we believe this is the first evidence that blocking LINGO-1, in fact, is leading to remyelination in the human brain, first episode of acute optic neuritis. So it's only approved for biology. At the same time, we are running a larger study in MS patients both relapsing-remitting and secondary-progressive. It is a longer trial, 22 months. That trial is fully enroll, ongoing, and we are looking forward to the results next year. The results of both trials will inform on the next steps.
MSDF
Is that a phase 2 trial, as well?
Dr. Cadavid
Correct. It's the MS trial; it's called SYNERGY, and it's a phase 2 trial. It is dose ranging. Unlike RENEW in which we only tested one dose, in the MS trial – SYNERGY – we are testing several doses.
MSDF
How is it administered?
Dr. Cadavid
It is a monoclonal antibody given every four weeks by an intravenous infusion.
MSDF
So you said that the results of this larger phase 2 trial will be available next year. Assuming that those results are favorable, what's the next step after that?
Dr. Cadavid
The final phase of drug development is what we call phase 3, which is when we actually run definite trials where the primary endpoint it's some meaningful clinical endpoint. For example, improvement in disability, slowing of disease worsening. So those phase 3 trials are usually longer and larger, and if the primary endpoints are met and the safety and tolerability is adequate, we file hoping for drug approval and to make this therapy available to patients.
MSDF
Four or five years?
Dr. Cadavid
Phase 3 trials are usually longer, and we don't know until we're there. But yeah, these are a longer part of the drug development process.
MSDF
Now assuming that the clinical trials do pan out – and maybe it's a little bit too early to ask this question, but I'm going to ask it anyway – how will anti-LINGO-1 be used? Is it going to be used early in the disease, late in the disease? The way other DMTs are used now continuously or to respond to a remission?
Dr. Cadavid
Ultimately, it will come from the results from the trials. But if you think about demyelination, it is a core component of MS. All forms of MS – from very early to very late – have a loss of myelin. So as long as there is ongoing or preexisting loss of myelin, we believe there is a potential for a remyelinating therapy like anti-LINGO to help the patients.
MSDF
Now you mentioned not only relapsing-remitting but secondary-progressive, and I'm sure you know there's a long history of things that have not worked well for progressive disease. Do you have a reason to believe that anti-LINGO-1 will be efficacious for progressive disease?
Dr. Cadavid
So, Bob, it is true that there really no effective therapies in SPMS right now. It is an area that we are focusing on anti-LINGO because we know there is extensive demyelination in secondary-progressive MS. Interestingly, there is a lot of cortical demyelination with relative preservation of axons and neurons. So we believe that if this drug is capable of repairing the myelin we could actually be able to help patients with SPMS. The phase 2 program includes patients with SPMS, so we obviously are looking forward to the results from the ongoing phase 2 trials to help us make decisions on next steps.
MSDF
Why not primary progressive?
Dr. Cadavid
Primary progressive MS is also under consideration. Right now we have to focus. Obviously what we learned from secondary-progressive MS will also inform us as to pursue primary progressive MS. We are aware there is a high unmet need, and we keep those patients at heart too.
MSDF
Just in terms of procedurally a technique why are you focusing on secondary-progressive before primary progressive?
Dr. Cadavid
So there are some practical reasons. One of them is that SPMS is viewed as closer to relapsing-remitting MS relative to primary progressive MS. So in the phase 2 trial, we have to try to keep some focus on the population. If we spread too much, it may become more difficult to actually interpret the data. There is a strategic reason as SPMS is closer to RRMS than PPMS is.
MSDF
Well, Dr. Cadavid, I've come to the end of my prepared questions. Is there anything I haven't asked that I should have asked or anything you'd like to add?
Dr. Cadavid
I like to finish by saying that the results of the RENEW trial it's really the first time we have seen evidence from the human brain that it appears possible to repair the myelin. This is a very important step in the field. There is a lot of work to do. But it is encouraging news, and we are happy to share this with the community. And Biogen is very committed to MS and to help patients who are living with this chronic disabling condition. So we welcome the news, and we also are ready to embrace the following stages of drug development, which are obviously very challenging.
MSDF
Well Dr. Cadavid, thank you very much.
Dr. Cadavid
Thank you, Bob, was a pleasure.
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MSDF
Thank you for listening to Episode Forty-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. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is 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 editor@msdiscovery.org.
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Host – Dan Keller
Hello, and welcome to Episode Forty 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 Raj Kapoor who discusses a clinical trial of the epilepsy drug, phenytoin, for MS. But first, a few updates on the latest developments at MSDF.
We posted an essay by Dr. Katie Lidster of the National Centre for the Replacement, Refinement, & Reduction of Animals in Research, a U.K.-based scientific organization. In her essay, she points out that Dr. Kapoor’s phenytoin study was made possible by the prior development of a refined mouse model of MS that is more humane than experimental autoimmune encephalomyelitis, which results in paralysis. To find Dr. Lidster’s article, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.
Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of April, we added 9 new trials, we updated information on 28 trials, and we've added 42 other pieces of information. The drugs with important additions and changes are alemtuzumab; BAF312; BIIB033, which is also called anti-LINGO-1; daclizumab; dalfampridine; dimethyl fumarate; fingolimod; glatiramer acetate; interferon beta-1a; interferon beta-1b; laquinimod; mitoxantrone; natalizumab; phenytoin; rituximab; RPC1063; and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.
According to our curated list of the latest scientific articles related to MS, 42 such articles were published last week. We selected two of them as Editors’ Picks. One is a review of the role of microRNA in MS. The other is an analysis of the cost of MS drugs in the U.S. This study reports several startling facts. For example, first-generation MS drugs, which cost $8000 to $11,000 annually when they were first released, now cost $60,000 a year. And disease-modifying therapies cost two to three times more in the in the US than in comparable countries. This study ties in nicely with our interview with Dr. Kapoor. Phenytoin has been off patent for many years and is dirt cheap. Good news for MS patients? Maybe not. Paradoxically, phenytoin’s low cost may mean that it will never be fully developed for use in MS. To see our curated list of recently published papers, go to msdiscovery.org and click on Papers.
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Now to the interview. Dr. Raj Kapoor is a neurologist at the National Hospital for Neurology and Neurosurgery in London, England.
Interviewer – Robert Finn
Hello, this is Bob Finn. I'm at the American Academy of Neurology meeting Washington, D.C., and I'm talking with Dr. Ray Kapoor, who's presenting a very interesting study on a trial of phenytoin – also called Dilantin – in optic neuritis. Dr. Kapoor, welcome. So my first question is why phenytoin and why optic neuritis?
Interviewee – Raj Kapoor
So phenytoin we use because it works as a sodium channel blocker, and this is based on years of experience and validation in animal models over the years about how neuroprotection could be achieved in MS. And it turns out that sodium channels are quite important for neurodegeneration in the setting of inflammation. And work in London that we've done, work in Yale has validated animal models that say that if you block sodium channels you can achieve neuroprotection. So why phenytoin? Well that comes down to why optic neuritis? We wanted to test sodium channel blockade in a relapse. And optic neuritis has a lot of advantages because you can study the visual system in so many ways. So why phenytoin? Because we think there's a window of opportunity, and a relapse degeneration occurs pretty rapidly. You need to treat quickly to switch off the mechanisms of neurodegeneration. And phenytoin has the advantage that we can load it very quickly and achieve therapeutic levels. So we have here a model of neuroinflammation and neurodegeneration, which we can study using multiple techniques. And we have a drug that we can load and inhibit those mechanisms quickly.
MSDF
I find it fascinating that optic neuritis, which is one of the many symptoms of multiple sclerosis, can be used as a model for multiple sclerosis itself.
Dr. Kapoor
The important thing there is it's part of the model. And the key is that we have – in MS – two processes going on. We have inflammation flaring up and leading to relapses like optic neuritis; and then, there is perhaps an allied or even a second process going on, which is the slow grumbling degeneration that leads to progression of disability. Now, we've studied both, but what we're focusing on in this study is that acute process that leads to relapses, you know, attacks which occur from time to time. I mean they're quite important in themselves because they don't always recover. We know that with every attack – even if there's apparent recovery – there is underlying damage to the nervous system. So to protect the nerves in any case is self-serving; it's a good idea. But what we are hoping is that this may even be a key to preventing progression, and that would really be a worthwhile target.
MSDF
So you say you chose phenytoin because of its effects as a sodium blocker. What's the connection between sodium and neurodegeneration?
Dr. Kapoor
What we found many years ago was that in areas of inflammation there can be nerve damage. And the inflammation drives nerve damage through a number of pathways, but one of them is that it actually indirect leads to sodium accumulation inside the nerve fiber, the axons. This has been well worked out in ischemia, as well. So sodium enters axons; it can't leave through the normal sodium pump because they're metabolically inhibited by the inflammation itself. And the sodium exchanges with calcium. So there's a sodium/calcium exchange in the membrane of nerve cells, and if you load them with sodium then sodium has to get out and gets out by driving the influx of calcium, and that's dangerous; that kills axons. So the whole process can be inhibited by inhibiting sodium entry. Now there's another thing that's very important, which is in acute inflammation one of the things that drives it is microglia, activated microglia release chemicals such as nitric oxide, which in themselves drive the whole inflammatory damaging cascade. But it turns out – and this is work from Yale – that actually the microglia themselves have sodium channels, and that their functioning can be inhibited by inhibiting those same channel. So what phenytoin is doing is it's actually inhibiting not only the cascade that damages the axons but is actually inhibiting the cells which are driving the inflammation and causing the damage in the first place.
MSDF
Now, is there any indication that phenytoin may be working in this way more centrally than the optic nerve?
Dr. Kapoor
It's very unlikely because the mechanism that we've testes is really something well characterized as inflammation within the optic nerve. And we are measuring the damage and the effects of treatment by actually imaging the retina looking at retrograde degeneration from the optic nerve lesion. So I think it's very unlikely given the timescale – you know, we're treating within a couple of weeks of onset, we're having a readout within six months – that it's doing anything other than what we're asking of it, which is a readout of what's going on in the optic nerve and retina.
MSDF
If I understand you correctly, even if this is working exactly the way you want it to be, it's not going to be doing anything for people with central damage. Is that correct?
Dr. Kapoor
Well I think the thing to understand here is it may do in MS where damage is happening everywhere. This is really a proof of concept. We've tried our very best to isolate the damaging process and to work out whether the theory works. So yes, there may be more general implications, and we think there probably are. But it's important to note that really what we're doing here is choosing a very clearly defined model to test the hypothesis.
MSDF
Now one of the advantages of phenytoin is that it's generic; it's dirt cheap. But is that a liability, as well?
Dr. Kapoor
Yeah, this is a very important point. So we're talking here about this whole issue of repurposing drugs. And we think that there may be many different drugs on the shelf which may have a role in treating diseases like MS. Now for us that was an advantage. This is an investigator led study, and it was funded by charitable means from the National MS Society and UK MS Society. So that's an advantage because the drug is really cheap. But of course, in terms of development, the commercial reality is that there's very little money in this. And so to take this further, it makes it harder not to have a drug that makes money.
MSDF
So what's the solution to that problem?
Dr. Kapoor
We don't know. I mean there are lots of ways that we're taking this forward. I mean you may know that there is a thing called the Progressive MS Alliance, which is an international body of MS societies, which is trying to work its way through questions exactly like this establishing industry relations. And it may be that they're a scope for industry to step in. And governments step in sometimes. I mean in the U.K. we have a trial running at the moment which is using funds from government to do a moderately sized Phase 2/Phase 3 trial of neuroprotection. So I think, actually, this all depends on the results. If the results are good, then we hope that either through industry or through government or, indeed, through charitable means there may be a way through. Just to get back to your question, I think that, you know, repurposing is a problem because clearly the commercial angle is far less prominent.
MSDF
Is one possible solution to find a drug that's still under patent?
Dr. Kapoor
Indeed, that would be a remarkable thing to do. But of course, a trial in the beginning would then need commercial collaboration. But certainly that's an angle.
MSDF
So assuming that your research is confirmed and extended and phenytoin proves to be truly neuroprotective, when in the course of MS is it likely to be useful?
Dr. Kapoor
So by definition, phenytoin is going to be useful for relapses. The idea that relapses sometimes leave damage and that a drug like phenytoin or phenytoin itself prevents some of that damage speaks for itself. The real question, though, comes down to whether progressive MS is also driven by similar mechanisms. We did a trial of lamotrigine, which is another sodium channel blocking anticonvulsant, and published the results about five years ago now. And that trial was reportedly negative for its primary outcome, which was brain atrophy; could we reduce the rate of loss of brain volume. I suppose what we've done is to go back to that trial and look at positive signals there because after all the question is do sodium channel blockers prevent progressive MS or prevent progression? And in fact, it turns out that there was some remarkable positive signals in that trial. So I have the knowledge that phenytoin should be useful for relapsing MS. But I also have a hunch that it may be useful for progressive MS, as well.
MSDF
Now there's a flipside to the fact that phenytoin is so easily available, and that is that physicians listening to this podcast or to other news reports may consider prescribing it off-label. How would you counsel somebody considering that?
Dr. Kapoor
I think it's difficult for somebody to use phenytoin in that way because the way the trial was designed was to treat people in a very narrow window after the onset of a relapse. Now people may say well, you know, the next time I see a patient who has a relapse, you know, can't walk or the vision is affected I will immediately prescribe phenytoin. The difficulty I have there is that this remains a very attractive study but hasn't proved the point. And phenytoin is not without its side effects. You know, I'm always somebody who's evidence led, and so I would counsel against using drugs without even further evidence. This is one Phase 2 study after all. I think the temptation will be there nevertheless.
MSDF
And if a physician falls to that temptation, what should he or she look for?
Dr. Kapoor
Well again, this is the point. We have shown a concept works. You know, we have shown that phenytoin, by a number of measures, prevents nerve damage. I think the difficulty – and I need to be very clear about this – is that with acute optic neuritis where vision generally recovers we didn't see better recovery with phenytoin. So again, perhaps another answer is that if I treat somebody with a relapse with phenytoin I'm not really sure that I may be protecting nerves, but am I producing a better outcome? So that may be another reason to say let's wait for a better drug or a better trial.
MSDF
That's a very good point. So is there anything I haven't asked that I should have asked, or anything you'd like to add?
Dr. Kapoor
No, I think that really the way I want to convey the result is that it's a robust result. I mean what I'll be presenting is that on a number of measures the drug worked. I think it worked with a modest amount of success. I see this is opening a door. I don't see this as the final answer to a problem. You know, if you think about it, we've been looking for a long time for a neuroprotective drug in MS and a strategy. And I think this is opening a door, which I think needs to be opened a lot wider.
MSDF
Dr. Kapoor, thank you very much.
Dr. Kapoor
Thank you.
[transition music]
MSDF
Thank you for listening to Episode Forty 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. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is 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 editor@msdiscovery.org.
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