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Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

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Now displaying: October, 2014
Oct 27, 2014

[intro music]

 

Hello, and welcome to Episode Eighteen 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. Samuel Ludwin about new approaches to remyelinating therapies. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.

 

Speaking of remyelination, we recently published an article in our animal model section about zebrafish and their use in studying MS. Though a fish might not jump to mind as an adequate model for modeling the complexities of a disease like MS, zebrafish are actually very useful for studying myelination. Researchers can engineer the fish to be transparent while also fluorescently tagging myelin, oligodendrocytes, and more. If you’re curious to learn more, go to the “Animal Models” section under “Research Resources” and click on “Zebrafish.”

 

Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”

 

[transition music]

 

Now to the interview. Dr. Samuel Ludwin is a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. He met with MSDF to talk about the latest in remyelination therapies.

 

Interviewer—Dan Keller

In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it?

 

Interviewee—Samuel Ludwin

Remyelination is a very interesting process. We know that it occurs in animals. We can well demonstrate its temporal progression. We can demonstrate the conditions under which it occurs. Demonstrating this in the human is very much more complicated because we are always taking snapshots in time in looking at human specimens and we can never be sure whether we are looking at a remyelination of a previously completely demyelinated process or not. So we draw all of our analogies about human remyelination, which we believe is present in multiple sclerosis and other diseases, but we draw these analogies from what we have shown in experimental animals where we have been able to control the process.

 

In animals, first of all, it is very feasible for a variety of reasons. The first is that – many mammalian, especially rodent brains, and marmoset brains which we generally work on – are considered in a way functionally immature which tends to suggest that their brains are much more capable of plasticity and therefore much more able to be repaired. The same process probably does occur in humans but as I said is probably a little bit less certain. We have done a lot of work in multiple sclerosis in demonstrating that the hallmark of remyelination which is a reconstituted sheath, although with different physical characteristics to the original myelin. We can find these sheaths in the human tissue in areas that we think are remyelinating. This brings up the promise that a certain amount of natural remyelination occurs in response to demyelination in disease. There is always the hope that one can use some of the same factors that we have discovered in rodents and other experimental animals to enhance this remyelination and make for a much wider area of functional…both enhancement of function and also protection of the underlying axons.

 

So remyelination is one of the hopes and maybe promises in multiple sclerosis research. Proving it is a little bit more difficult. We have many possible mechanisms for enhancing remyelination. Some of them are considered to be cell-based. By that we mean what is preventing remyelination often is the destruction of the oligodendrocyte and its precursor cells which can develop into myelinating oligodendrocyte. A lack of these cells will obviously result in a deficient remyelination. Secondly, there may be blocks from either the axon which gives the message and the signal for remyelination. Thirdly, there may be physical barriers such as the reaction from other cells in response to the inflammatory insult that are hindering access by these oligodendrocytes to the axon in order to make myelin.

 

There are many possible reasons that we don't have adequate remyelination. For each of these, there are at least some punitive answers as to how we may enhance. There is a lot of interest in cell transplantation, especially with mesenchymal stem cells at the moment; which have been shown not only to have immunological benefits of antiinflammatory qualities but also to be able to then differentiate into these oligodendrocyte precursors which will then differentiate into myelinating oligodendrocytes. These may enable the brain to reconstitute its quotient of myelinating cells.

 

There are lots of attempts underway to try and prevent any of the physical barriers of access of these cells to the axon such as from the astrocytic gliosis, but there are also many drugs which have the possibility of enhancing human remyelination. Many of these have been shown to work very well in animal models. We have whole classes of drugs that enhance remyelination. There are steroidal compounds that have been shown to enhance myelination and there have been many that have been shown to either block some of the cytokines that may be hindering or interfering with the progression of oligodendrocyte maturation. Drugs that will block some of these cytokines will allow this maturation of proliferation of these cells to continue, and therefore lead to maturation. It is true to say that apart from some of the mesenchymal stem cells which have some hope; it has been very difficult to measure remyelination in response to these therapeutic attempts at the moment in humans. Certainly in rodents we have been able to do it and there are certain clinical trials going on based on some of these animal experiments. There is a trial which the NIH is doing in conjunction with the Myelin Repair Foundation over a compound 008 which has been shown to be very beneficial in certain demyelinating models and enhancing remyelination. There are certain growth factors that have been given in animals such as hepatic growth factor that have been shown to enhance the number of oligodendrocyte precursors and their development into oligodendrocytes. These all give promise for what is possible in humans but have not yet been taken to that level yet.

 

MSDF

It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work?

 

Dr. Ludwin

What is very interesting is that there is a whole gamut of drugs that are being investigated ab intio arising out of experiments that have been shown to have an influence on the inflammatory aspect of autoimmune disease. Many of the cytokines induced by the autoimmune diseases have multiple effects on the oligodendrocyte proliferation, maturation and then access to the axon. So drugs that will inhibit this cascade of cytokines in autoimmunity will also remove some of these inhibitors and allow for enhanced proliferation and maturation and therefore enhanced remyelination. In addition, there are a whole emerging group of drugs that have been found to coincidentally have an affect experimentally on remyelination and many of these drugs have been in the pharmacopeia for other diseases and these are side effects or side discoveries. Some of them have not been used for their initial purpose for a long time and this includes a drug that is currently under clinical trials with the NIH and the Myelin Repair Foundation called MRF-008, the details of which are not public, either in mechanism or in the structure of the drug. There are also classes of drugs such as estrogen and progesterone based drugs which have been introduced because of observable influences of normal estrogen progesterone function on oligodendrocytes and Schwann cells in the periphery in culture and they relate also to hormonal variations in multiple sclerosis and are a natural outcome of some of these observations.

 

MSDF

It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that.

 

Dr. Ludwin

Oh absolutely. I mean when we look at general repair foundations, we are looking at two of them. First of all, there is the whole question of neuroprotection and second of all there is the whole question of regrowth and these in form, are we looking at regrowth of axons, sprouting of axons in multiple sclerosis. There is a large amount of axonal damage which needs to be investigated for protection and such strategies will be very useful in axonal damage and in the hope of producing axonal regeneration.

 

MSDF

Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories?

 

Dr. Ludwin

Some of them may do both but in general the neuroprotective drugs are generally a different class or different kind of drugs. There is a great need to introduce them into stroke, into trauma, the neuroprotective drugs and people are looking at the same strategies that are being used for ischemia and anoxia which are the results of strokes but may also very possibly play a role in the lesions in multiple sclerosis to protect the axons. Some of these are excitotoxic protection agents which the axon is particularly susceptible to both in ischemia and in multiple sclerosis.

 

MSDF

You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate?

 

Dr. Ludwin

No, that is a very good question. In fact, neurotransmitter excitotoxicity has been demonstrated very well in multiple sclerosis, especially in the acute lesions where perhaps most of the axonal injury takes place. We always used to think that it was all a progressive lesion but a huge amount takes place early on in and much of this is in excitotoxic damage. I might add also that in many respects the oligodendrocyte has got many of the same neurotransmitter capacities as does the axon and neuron and the oligodendrocyte itself is susceptible to excitotoxic damage as well. Excitotoxicity is a very important target for neuroprotection and protection of the oligodendrocyte as well.

 

MSDF

On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add?

 

Dr. Ludwin

I think that covers it in general. Of course, what we really are looking for is what the triggers to the acute process are. What we are doing, the autoimmune aspect, is the largest looming figure in the one that is proven most and almost certainly represents the major way that tissue is damaged. But what provokes the autoimmune attack may give us the answer to at least preventing or slowing down the AMS process. The therapy is at the moment largely based around dampening of the autoimmune attack and preventing subsequent damage. Although I should point out that it is not only the loss of myelin that leads to excitotoxic damage in the axon but the inflammatory infiltrate that kills oligodendrocytes and myelin has the same mechanisms that kill the axon as well. We are not just trying to protect, we are trying to prevent the axon from being damaged in the first place, early.

 

MSDF

Very good, I appreciate it.

 

[transition music]

 

Thank you for listening to Episode Eighteen 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.

 

 [outro music]

 

 

Oct 20, 2014

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Seventeen 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. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at msdiscovery.org.

 

In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process.

 

The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model.

 

We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at msdiscovery.org and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.”

 

[transition music]

 

Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders.

 

Interviewer – Dan Keller

In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS?

 

Interviewee – Hans Lassmann

That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process. 

 

MSDF

So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways?

 

Dr. Lassmann

Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury. 

 

MSDF

What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do?

 

Dr. Lassmann

I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset. 

 

MSDF

How does the glia enter into this, both as a target and maybe as a mediator or effector?

 

Dr. Lassmann

Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica. 

 

MSDF

Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release?

 

Dr. Lassmann

No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death.

 

MSDF

Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences?

 

Dr. Lassmann

Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases. 

 

MSDF

Is that a failure of phagosomes? Is there a defect at that level?

 

Dr. Lassmann

No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore. 

 

MSDF

What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing? 

 

Dr. Lassmann

We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things. 

 

MSDF

In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress?

 

Dr. Lassmann

We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination. 

 

MSDF

Is there a role for glutathione here?

 

Dr. Lassmann

Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one. 

 

MSDF

It’s a player in the injury or in limiting injury?

 

Dr. Lassmann

That is not entirely clear yet.

 

MSDF

What have we missed or you think is important to discuss or add?

 

Dr. Lassmann

There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly. 

 

MSDF

It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain?

 

Dr. Lassmann

Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active.

 

MSDF

Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas?

 

Dr. Lassmann

I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy.

 

[transition music]

 

Thank you for listening to Episode Seventeen 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.

 

[outro music] 

 

Oct 14, 2014

[intro music]

 

Hello, and welcome to Episode Sixteen 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. Revere “Rip” Kinkel about how to improve patient outreach. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

First, researchers are questioning if cognitive MS is a distinct entity. For some patients with MS, cognitive symptoms dominate over all other symptoms. Some of the symptoms could even be described as dementia. Researchers examined a small sample of this distinct subset of patients in a recent study in Clinical Neurology and Neurosurgery and found that many had severe brain atrophy and a high lesion load. While the results suggest that cognitive MS may be a distinct disease entity, the researchers are cautious not to draw any conclusions due to the small sample size and the weight of the term “dementia”.

 

An experimental oral agent for the treatment of relapse-remitting MS looks promising as it progresses through clinical trials. The drug, currently called RPC1063, was shown to be both safe and effective in a sample of about 200 patients. It may even be safer than fingolimod, which is currently the only oral drug FDA approved for the treatment of MS.

 

For women with multiple sclerosis, pregnancy is especially tricky. In a previous news synthesis, science writer and immunologist, Griselda Zuccarino-Catania, looked at many challenges for women with MS who are trying to get pregnant. But postpartum can be a tumultuous time for MS patients as well, since the risk for relapse increases after delivery. In this part of her series on pregnancy and MS, Zuccarino-Catania explores the current research on postpartum relapse risks, breast feeding, and disease-modifying therapies.

 

[transition music]

 

Now to the interview. Dr. Revere—or “Rip”—Kinkel is the director of the multiple sclerosis program at the University of California, San Diego. He is also the chief medical officer for an initiative managed by the Accelerated Cure Project, our parent organization, to establish an MS patient-powered research network. He sat down with me at the joint ACTRIMS-ECTRIMS meeting in Boston earlier this year to discuss how to improve patient outreach.

 

Interviewer – Dan Keller

Welcome, Dr. Kinkel. You are now interested in new models of care. What do these entail, and why do we need them?

 

Interviewee – Revere Kinkel

Well the traditional model is, of course, the patients coming into a clinic setting at a variable interval and having a diminishing amount of time to spend with a physician or any other kind of provider that they are seeing. Going forward in the future with fewer neurologists, fewer MS specialists available, we need to find ways to reach larger populations of patients. Whether that be through Internet portals, whether that be through outreach, through community clinics where we travel or whether it be through telemedicine or a combination of those things. So we are particularly interested in developing tools and models that allow us to reach patients in this way.

 

MSDF

What are some of the ways that you reach them: go out in the community or how do you specifically reach people who would not typically be contacted?

 

Dr. Kinkel

Currently we are doing a number of things. The first thing we have done is we have developed a virtual MS center online called HealthCareJourney.com which allows patients anywhere to sign up, ask questions relevant to their disease and the problems that they have and get answers. Both the questions and the answers are posted online for the entire community to see. We are also trying to find ways, particularly in California; this is true around the entire country, but particularly in California, to outreach to communities. What we have noticed with the transition with the Affordable Care Act is that a significant number of patients have been switched over to Medicaid programs. In our case we call it Medi-Cal in California. Many of these patients have been away from doctors for many years, off drugs for many years. They are not aware of services that are available to them. Many of them don't speak English as a primary language. We recognize the need to go out to the communities, have community outreach programs to reach these individuals, to do mini consults, tell them what kind of services are available, try to connect them to those services and then get them to come to our centers periodically and work with their local physicians.

 

MSDF

Do they typically respond well to this, or are they at all wary of what you are doing?

 

Dr. Kinkel

Well we haven't started doing it on a large scale basis. This is actually in the planning stages for next year. Interestingly we have kind of noticed this over time with drug company sponsored programs. So many of us will do these education programs for patients where we will go out and meet with a large group and we are always intrigued by the interactions we have one-on-one with the patients afterwards. That is when we really find out the issues they have and they start to hear about the things that are available for them and their eyebrows go up, they are interested, and you hear from them again because you can help them. That kind of setting has shown us that this kind of reaching out to communities helps. What I am talking about is going a step further; which is reaching out through community health centers, through other advocacy groups to find even less advantaged patients that might not have been even going to these kinds of programs and helping them, but also, including them in the process. Right now we have an understanding of MS that is based on a population that primarily goes to tertiary care centers, which is highly over-represented by Caucasian well-educated upper middle class individuals. We have far less of a knowledge of the needs and requirements of the less fortunate.

 

MSDF

Have you heard it all or can you discern anything from reaching out to these people and what they tell you that is either surprising or new?

 

Dr. Kinkel

I am totally amazed at kind of the lack of information they have. Just from basic MS-101. So you have to start there. Many of these individuals have kind of higher needs. When you have the needs of just putting food on the table and paying the rent and trying to make sure their children are safe, MS takes a back seat. Often in many of these families you see the effects of MS on the children, much as we see in all populations, but it is particularly acute on those individuals with less resources available to them. So there is a greater community need for support for these individuals both in terms of real services as well as in terms of education.

 

MSDF

What are you getting out of PCORI? First of all can you define what it is, and what sort of resources they can provide you?

 

Dr. Kinkel

PCORI stands for the Patient Centered Outcomes Research Institute, and the Accelerated Cure Project has a grant to develop a 20,000 patient centered research network. I am the chief medical officer for the PCORI Initiative. This will allow us to reach a large population of patients, but the challenge, much as I said a second ago, is reaching those individuals that might not even use the Internet or the web that often. So we need to find ways to not only include the traditional MS patients we see in many of the tertiary centers but also to reach out to these communities. What we intend to do with this reaching out is to get patients involved in the PCORI Initiative as one of the main things that we do when we reach out to the community. That will allow them a forum for describing their experience and potentially getting further resources available to them. 

 

MSDF

If they are not presenting to healthcare facilities, how do you reach them? Do you go to schools and get parents of kids or churches, or where do you get the word out?

 

Dr. Kinkel

One of the advantages that we have now when the law of the land is that everybody has healthcare insurance; is that we can actually track people. It is interesting. What happens in many communities is the physicians don't accept Medicaid for instance, some don't even accept Medicare. But what they do is they will accept this when patients are acutely admitted. The scenario that we hear over and over again is these patients go to a healthcare facility when there is some kind of an acute decline in function. They get taken care of. They have a diagnosis code of 340 for MS attached to them, but then they are discharged with no followup plans. They are actually not seen again until there is another acute decline in function. Well, we can identify them as soon as they are identified as a number 340. Once that is done, then we can reach them for these community outreach initiatives.

 

MSDF

Is this purely for diagnosis and treatment or can you do this for research? Do you get information from this?

 

Dr. Kinkel

What we do is we outreach to patients and provide education. We do not initiate a patient physician relationship without their approval. So you reach out to those individuals. There is no problem with that. They have to make the step of following through and initiating that kind of an interaction. They also have to make the step of deciding that they are willing to participate in something like the PCORI Initiative. All we can try to do is be as persuasive as we can and educate them about the benefits to both them as well as the greater society. 

 

MSDF

Do you find that there are people who don't even recognize a symptom? They just think their arm is numb because it must have been something they did at work and pass it off?

 

Dr. Kinkel

Oh yeah. It is an interesting phenomenon especially when things have been going on for a long time. If an individual is born blind, they don't see being blind a problem. If for the greater part of their life they have noticed that they have numbness in their feet, sometimes they don't mention it, because they don't consider it a problem. We always find that when we are seeing patients for the first time, they will describe these vague neurological symptoms that go back for many years. 

 

MSDF

Tell me about the OPT-UP project?

 

Dr. Kinkel

So the OPT-UP project is just a part of the normal evolution of the Accelerated Cure Project. The Accelerated Cure Project was developed to have a repository of well characterized patients with their biological samples for researchers around the country. We recognize that there were issues with the repository. We didn't have good longitudinal samples; we couldn't guarantee that we had samples on patients before and after they went on drugs so we could look at biological responses. So the OPT-UP study was to address that as well as the need to begin to create an environment where we were combining clinical and research activities to get more patients involved in research activities. By that I mean we know very little about long-term outcomes in MS. Part of this is because there is no coordinated manner to collect data longitudinally that is agreed upon between all of the clinicians that are caring for these patients. So we wanted to kind of operationalize that process so that we could follow these long-term outcomes and collect them. By doing so, we can answer a lot of questions that we have. For instance, in the near term with the OPT-UP study, since the only requirement for the study is that a person be initiating a drug, whether it be for the first time or for the tenth time, they are just initiating drug. One of the things that we will learn is; what are the reasons why people start drugs, what are the reasons why they stop drugs, what are the reasons why doctors are putting them on this drug or that drug. We know very little about that. What we really do know still is that a tremendous number of patients at least 50% discontinue a drug within two years of starting it. If we don't first know exactly why this behavior exists, it is hard to keep patients on therapies for a longer period of time, and to see which therapies are going to be most beneficial. 

 

MSDF

Will this go on indefinitely?

 

Dr. Kinkel

It is a long-term study. The duration of a study is always dependent upon a number of factors; funding, interest, but yes we are building in a number of mechanisms that allow us to follow patients for a very long time in the study. Probably the key to this is a dedicated nurse research coordinator at each site that will be responsible for entering and following patients over a period of time. And when sites exceed a certain number of patients then they hire another one, because what we have discovered in the past from the many research studies that we do is there are competing interests. Whenever we try to continue to follow people for a long time, other interests win out. There is no one there to kind of encourage the patient to continue their participation. The studies that have been more successful – a long-term study like the Nurses' Health Study – they are able to do that primarily because they put the resources into ensuring that, that experience is meaningful for the patients and that they will want to continue to contribute that data.

 

MSDF

Will this initiative also collect general health data knowing about comorbidities and be able to correlate those with the course of the disease?

 

Dr. Kinkel

Yes absolutely. It is one of the main things that we want to do. In fact, one of the reasons why pretty much the only inclusion criteria is, that a person be starting a drug. Most Phase III studies exclude people when they have other health conditions. This is why there is so little external validity to these studies. The way we gain that validity is to encourage those patients who do not normally contribute to clinical research to participate in the study, either because they don’t want to, they can't get to the site, or because they are excluded by the exclusion criteria.

 

MSDF

On these topics, is there anything important to add?

 

Dr. Kinkel

I think the most important thing to add is that we are entering into an era…we are already in an era in which technology is rapidly transforming how we reach patients, and we need to kind of embrace it. I see that many of my colleagues are reluctant to. I see it in their unwillingness to embrace electronic medical records for instance. They see it as a burden. 

And it is true; there is some burdensome aspects to it. I believe, however, in a world in which they have less time to spend individually with their patients in a clinic setting, in that kind of a world, they need to find other mechanisms to reach and meet those needs of their patients. One of the ways to do that is through these kinds of technologies. Using the website. I encourage them to send their patients to the healthcarejourney.com website for instance to get general information about MS so that they can reduce the burden on their own centers and their own staff with patients calling in with questions every other second.

 

MSDF

Very good. I appreciate it.

 

Dr. Kinkel

Thank you.

 

[transition music]

 

Thank you for listening to Episode Sixteen 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.

 

 [outro music]

 

 

Oct 6, 2014

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Fifteen 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 Professor Ludwig Kappos about a recent head-to-head clinical trial of the experimental drug, daclizumab, versus interferon. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We recently released a news synthesis by science writer, Carol Morton, that goes along with this podcast. The article is all about daclizumab, its history, and the recent results of the phase 3 clinical trial. The results of the clinical trial show that the drug is better than interferon at reducing disease activity in patients with relapsing-remitting multiple sclerosis. Surprisingly, recent research suggests that daclizumab works by natural killer cells to target autologous T cells. It may also work in two more unusual ways—go to our website to read the whole story.

 

Antibodies to myelin oligodendrocyte glycoprotein—also known as MOG—may play a role in a subset of patients with neuromyelitis optica spectrum disorders according to several labs in Europe and Asia. At the ACTRIMS-ECTRIMS meeting in September, several of these labs presented data that showed patients who test positive for the MOG antibody had a very different clinical phenotype from the majority of NMOSD patients who have an antibody to a different protein, called aquaporin-4. The findings could mean that anti-MOG-positive patients represent a distinct disease subgroup.

 

Recently we’ve added quite a few items to our meetings and events page. From webinars to large annual meetings, there’s an event for everyone’s schedule in the remaining months of 2014 and well into the summer of 2015. Go to msdiscovery.org and click on the “professional resources” tab. From there, click on “meetings and events” to view all the items. And if you have a meeting you’d like us to list, please send the information to editor at msdiscovery.org. Hardly any meeting is too small. We’re even willing to list local departmental seminars.

 

[transition music]

 

Now to the interview. Professor Ludwig Kappos is the chair of neurology at the Neuroscience Network at the University of Basel in Switzerland. He met with me at the 2014 international ACTRIMS-ECTRIMS meeting in Boston to discuss the findings of the phase 3 DECIDE trial of daclizumab versus interferon. Daclizumab is a monoclonal antibody against the alpha subunit of the interleukin-2 receptor. 

 

Interviewer – Dan Keller

Welcome, Professor Kappos. Let's talk about the study you're presenting here at ACTRIMS on daclizumab. What was the aim of the study?

 

Interviewee – Ludwig Kappos

The aim of the study was to position this compound in relation to an established treatment with interferon and to see if these positive effects that had been observed in studies where it was used as an add-on to interferon or as compared to placebo if these also stand in comparison with interferon. 

 

MSDF

How did you go about it: methods, interventions, patient population?

 

Dr. Kappos

It was double-dummy controlled, parallel group study lasting a minimum of two years per patient in a population of active relapsing-remitting multiple sclerosis. And patients were randomized equally either to daclizumab once per month subcutaneous or to interferon beta-1a once a week intramuscularly and received dummy injections in order to keep the blind. 

 

MSDF

How did you decide on a once monthly dose for the daclizumab?

 

Dr. Kappos

That was the result of previous studies where it had been shown that this once monthly dose is sufficient to achieve the effects that we expected to see. 

 

MSDF

Because it's a monoclonal it has a long pharmacokinetic profile. Is that right?

 

Dr. Kappos

This is something that is shared also with other monoclonals. The advantage here is that you can apply it subcutaneously; they don't intravenous infusions like, for example, with natalizumab.

 

MSDF

What did you find?

 

Dr. Kappos

The primary outcome was reduction in relapse rate, and as compared to interferon beta-1a, it do add to a reduction that was close to 50%. 

 

MSDF

What about a proportion of patients experiencing relapse?

 

Dr. Kappos

Again, there was a significant reduction, and the curves separated already after the first half year. So the effect was relatively early. 

 

MSDF

And what about some of the imaging? What did you find on MRI and how about patient disability?

 

Dr. Kappos

Yeah again, as compared to interferon, it had a much more pronounced reduction of inflammatory activity, as depicted by T2 lesions or gadolinium-enhancing lesions in the scans during the study. And it also had an affect on T1 hypointense lesions that were reduced as compared to interferon. And interestingly enough, although it had a more pronounced antiinflammatory activity also in early and over the whole duration of the study, positive affect on brain volume loss. 

 

MSDF

It appears that in both groups about 30% of the people discontinued. Were there any differences in reasons or couldn't you discern that?

 

Dr. Kappos

Overall there was a similar incidence of adverse events, but there were somewhat more serious adverse events and adverse events as a reason for discontinuation. This was mainly related to cutaneous side effects; so rashes itching that in some cases needed discontinuation, in others could be treated sufficiently with ongoing medication or resume medication with steroids.

 

MSDF

This was not just local infusion reactions but more generalized skin reaction?

 

Dr. Kappos

They were independent of the injection site; so they did not occur at the site of injection but in other parts of the body.

 

MSDF

Is there an explanation in terms of IL-2 for that, or was it just sort of idiopathic?

 

Dr. Kappos

Of course, you would expect that this regulation of the immune system has this effect perhaps in the interaction of innate and adaptive immune system, but it's not yet clear what it means. The fact is that we didn't see other autoimmune diseases of relevance, only of increased incidence, and therefore it must be something unique to the skin. And fortunately, it's usually quite well manageable. 

 

MSDF

Is there a role for biomarkers? Can you discern anything here where it would indicate that you should use one drug versus another? Does daclizumab have anything unique about it that you can follow? 

 

Dr. Kappos

In the previous studies, we had had the observation that a certain subpopulation of immune cells – the so called CD56bright natural killer cells – are increased after initiation of treatment in those patients who seem to respond better to the drug. In this study, this response was seen in nearly all patients, and therefore it doesn't seem to differentiate good responders from perhaps not optimal responders. We have not finished the evaluation, and there were a series of biomarkers that had been evaluated during this trial. So I hope that we still will be able to find something.

 

MSDF

In the oncology arena, sometimes adverse effects actually correlate with good efficacy. Did you see anything like that here?

 

Dr. Kappos

No, there was no increased efficacy in those with cutaneous reactions, and otherwise the drug did not create problems. So you would not expect on a regular basis to experience adverse events. It's a different case than, for example, as compared to interferons where you have a very high frequency of flu-like symptoms. This is not the case here. So usually you would not realize, except for the injection that happens, that you take the drug. 

 

MSDF

Would there be any use to having a combination arm in a trial like this – interferon plus daclizumab?

 

Dr. Kappos

The first studies had been as an add-on to interferon and have shown an effect as compared to interferon without this add-on, without daclizumab. At the moment, yes, it would be something that could be followed, but I don't really see what the ideal combination would be and then not really the necessity for this drug in contrast to other drugs that have similar or lower grades of efficacy.

 

MSDF

I know it wasn't included in this trial, but can you compare the efficacy of daclizumab with anything currently available that people use?

 

Dr. Kappos

I think it's very difficult to tell because it's always a problem to compare across studies because of different methodology; even the selection criteria formally are very similar may result in different populations of patients. So I would say from the grade of efficacy that was achieved it is certainly at least at the level of fingolimod or dimethyl fumarate. How it relates to natalizumab; if it could be used in patients who stopped natalizumab? These are questions that will have to be explored in the future.

 

MSDF

Will you follow these patients further to see if there are any late effects either positive or negative?

 

Dr. Kappos

Yes, most of them are in the extension studies and had the option to continue with open-label daclizumab. I think it's approximately 80% or more of the patients who decided to continue in this followup, and we will have a long-term followup for another four or five years.

 

MSDF

From all of what you've said, what you make of this in terms of clinical significance, in terms of the future of this compound?

 

Dr. Kappos

Well I think that it deserves to be approved and also to be one of the available options that we will have in the treatment of relapsing multiple sclerosis. If it has also an effect on progressive disease is something that my personally would be interested to know more about.

 

MSDF 

Is there anything important to add that we haven't discussed?

 

Dr. Kappos

The data now are consistent with a good data that were derived from the placebo controlled SELECT trial. And we have to take into account that they are against one established drug with approved efficacy. So it's more than that, and that's, of course, encouraging. 

 

MSDF

I suppose anything that gets you away from the side effects of interferon are a good thing.

 

Dr. Kappos

Yes, anyway, of course, most other drugs that get you away from the side effects of interferons. But it seems, except for these cutaneous, manageable side effects, it seems also to be well tolerated. So a drug that could be used with a low threshold. 

 

MSDF

Is there tachyphylaxis? Does that side effect go away, or you just have to keep treating it the cutaneous?

 

Dr. Kappos

It was different. It seems to be the case that if we had treated initially with steroids and then do not wait too long then it recovers, and then you can also resume treatment, or you can continue treatment. But there are the cases where we didn't continue treatment and then it result, but we didn't start again.

 

MSDF

Very good. I appreciate it, thank you.

 

Dr. Kappos

Thank you.

 

[transition music]

 

MSDF

Thank you for listening to Episode Fifteen 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.

 

[outro music]

 

 

 

 

 

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