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Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

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Now displaying: November, 2014
Nov 24, 2014

[intro music]

 

Hello, and welcome to Episode Twenty-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. Paul Matthews about the Optimize project in the United Kingdom. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Some good news came from the pharmaceutical company Genzyme. On November 14th at 9 pm Eastern time, the FDA approved the drug alemtuzumab – trade name Lemtrada – for relapsing forms of MS. The FDA previously rejected the drug in 2013 due to concerns about study design and side effects. There is still some concern over safety, though, so the company is releasing it to only a limited number of patients. The prescription will also come with a host of other drugs to protect against harmful side effects. Researchers aren’t quite sure how the drug works, but it appears to target monocytes, T cells, and B cells.

 

Researchers announced a new mouse model for fatigue at the 2014 Society for Neuroscience meeting in Washington, D.C. The model works by enhancing expression of the pro-inflammatory cytokine, interleukin-1-beta. The model caused mice to reduce physical activity, without showing other signs of illness such as fever or anhedonia. Middle-aged and aged female mice were most affected by the treatment, whereas young mice showed no difference in signs of fatigue. The model gives credence to the idea that fatigue is not produced from dysfunction in the arousal system, but rather is a result of inflammation. The researchers said that they hoped the model will help illuminate the neurobiology of fatigue, the most common and debilitating symptom of MS.

 

If you would like to keep up with all things MSDF, please consider subscribing to our weekly newsletter. We keep our newsletter up-to-date with all of our news stories, blogs, and items from our professional and research resource sections. We’re also on Twitter; follow us at msdforum. And on Facebook, you can like us at facebook.com/ms discovery forum.

 

[transition music]

 

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. Last week he talked with MSDF about imaging in MS. This week we’re discussing his involvement in a UK-based project intended to optimize and personalize MS treatment.

 

Interviewer – Dan Keller

Welcome, Professor Matthews. You’re participating in the Optimize project in the UK. Can you tell me about that?

 

Interviewee – Paul Matthews

Well, thanks, Dan. Optimize has been an exciting journey and we’re still at the early stages, but let me tell you a little bit about it. Over three years ago, a number of us got together to discuss what the barriers to development of stratified or personalized medicine for multiple sclerosis was. We all recognized what the potential could be if we could really figure out how to target medicines to responders, we would have a way of most appropriately staging the introduction of different medicines across patient populations, not exposing people who didn’t need them to drugs of higher risk and insuring that those who did need them got them early. This is a particular problem in the United Kingdom where there is a much more formal process for progressing from first-line DMTs to more powerful agents. And, in fact, there’s also – dare I say it – I mean, a frank therapeutic nihilism and a surprisingly small number of MS patients receive treatment because of the perceived lack of benefit to many of these first-line therapies.

 

Now how to change this. I think what we realized is that we need to have much more granular data on the characteristics of patients being treated and how they fared after their treatment over the long-term. The data provided within the usual clinical context is not only limited, but it ends up being rather patchy over time. In order to enable that, we needed tools that would both collect data and incentivize collection of complete data of high quality. Now a note about this. We all know how to do this within the context of clinical trials, but it’s hugely expensive; it’s expensive because there are multiple people always involved to crosscheck that the data is completely acquired in each paper, and secondarily, there are audit procedures in place in retrospect to insure that this is being done. This really isn’t feasible in routine clinical practice.

 

A colleague of mine, Rory Collins, who has specialized in setting up very large-scale clinical trials in areas like China and India, has shown how very simple electronic tools can help both insure that data is acquired completely and that there is an electronic audit trail to follow-up on data that isn’t. What they showed is that by creating simple electronic questionnaires that wouldn’t let the questionnaire be closed unless data of an appropriate type was entered in the field, and then automatically interrogating the data for quality from center to center and following up where there were potential lapses, one could begin to incentivize acquisition of the right data and actually make it flow faster.

 

So how could we make this happen within the MS space in the UK? Well, what we realized is that the toolkits were all there. The EU IMI program already has funded my colleague, Yike Guo, who’s head of the Imperial College Data Science Institute, to create a tool built around a platform called eTRIKS. This is a data management environment that allows links to apps or iPads or any other peripheral electronic tool for very powerful distributed data capture. We then, in gathering together a number of stakeholder meetings which involved people with MS, the MS societies, a number of industry representatives, and what I’m really pleased to say is leads from fully 18 of the major MS centers across the United Kingdom pretty much ringing the country, together created the vision of building such an electronic tool, distributing the types of input devices across the different centers, and beginning to create a database that could be held centrally or in a distributed fashion using all the new tricks of modern IT.

 

The first thing is acquiring the data, the second is doing useful with it. The second thing that’s rather neat about the eTRIKS platform is that we have shown how it can be built to allow different levels of access, so that there can be access by high-level users who get to see the whole dataset, but also by specialized users who might want to see only a part of it – like a doctor interrogating it for his or her patient – or, importantly, a person with MS interrogating it to see how the data that they have entered stands relative to that that’s entered across the country by all patients; it allows people with MS to begin to gauge how they’re doing relative to others with their disease.

 

Now, I think the latter point is worth building on, because I think all of us have been hugely impressed by the power of sites like Patients Like Me to engage people with the disease in the dialog about their disease and make them full participants in capturing data information. With this kind of distributed data platform where doctors and people with MS can enter data whenever and wherever they are to a central database which can organize it and allow it then to be interrogated as needed, means that we can begin to think about asking patients to enter data on the fly from home. Why is this important? Well, this actually completely transforms the way in which we understand the disease, it really gives us a much deeper sense of the patient experience. Rather than sampling a patient once every month or once every six months, we can actually capture how they’re doing through a day. And if we add to this some extra sensor technologies – say, for example, about movement – we can literally do this from moment to moment.

 

So the vision thus is that if we can use these modern IT tools to capture data from distributed sources – from doctors using iPads, from patients using apps, from sensors that people with MS wear – we can capture data in a central resource that can be distributed to those for the purposes that they need it in near real-time, and in turn provide a common environment for its analysis. I think it’s exciting. Now we’re at the early stages, the basic tools have been designed, we’re starting to build the sensor technology. And our genuine hope is with the completion of the first set of agreements with one of the companies who’s been the first to really take a plunge with us, we’re going to be able to create a beta form of the tool in 6-9 months.

 

Now before closing, I do want to add one thing. This is an exciting vision but the notion of building a database is hardly a new one and many people have had it. There is something that’s special about this vision and it’s the thing that I’m most proud of that’s come together from all of these stakeholders. It’s the vision of creating a database that will be an open database; open to all researchers once it’s built, not held privately by those who built it. And I think this is what could become a game-changer. Moreover, we see that the tools that we’re building in order to create this – the IT tools, the distributed apps, and so on – are tools that the community should own and should be able to improve on. So our intention is fully, as this program develops, to release a software for open-access use as well as the data. Our hope is that even if this doesn’t provide the solution of the future, it will begin to incentivize this kind of practice where we all share this important data to work together to find solutions to this disease.

 

MSDF

Besides collecting MS-specific data, will it also look at general health and comorbidities to see how that affects outcomes?

 

Dr. Matthews

No. That’s a really good question. Like so many doctors now, we’re very much focused on the progressive forms of the disease. Our belief is that comorbidities make major contributions to this, and that by influencing these comorbidities we may have the biggest short-term impact on our patients’ lives. So one of the advantages of a big data capture tool is that we can capture data on all of the other disorders that afflict people with MS, as well, and begin with, again, greater granularity because of contributions from people with as well as their doctors to look at this in ways that wonderful databases like NARCOMS haven’t been able to do. This is an important task for the future and one that we really want to grasp. We’re hoping with further funding to be able to link this to bioresources, as well, and the ability to access a patient’s fluid samples for Omics analyses certainly can add greatly to this.

 

MSDF

Very good, I appreciate it.

 

Dr. Matthews

You’re welcome, Dan, it’s been good speaking to you.

 

[transition music]

 

Thank you for listening to Episode Twenty-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.

 

 [outro music]

 

Nov 17, 2014

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Twenty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Paul Matthews about imaging in multiple sclerosis. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We recently reported on a draft of a review released by the Agency for Healthcare and Research Quality about discontinuing disease-modifying therapies in patients with MS. Though the report’s main conclusion was that little evidence is available to assess the risks and benefits of discontinuing therapies, several MS groups came together to criticize the report during the open comment period. Groups like the National MS Society and Medical Partners 4 MS raised concerns that the review was not conducted properly and that insurance providers may use it as justification to reduce coverage of DMTs for MS. The AHRQ told Multiple Sclerosis Discovery Forum that they would consider the comments carefully and make any necessary revisions.

 

MSDF’s parent organization, the Accelerated Cure Project, is launching a new research resource called iConquer MS. Hollie Schmidt, Vice President of Scientific Operations at the Accelerated Cure Project, recently wrote a blog post explaining that the new initiative aims to take data and biosamples from 20,000 people with MS and make them open-access to researchers. We want your input about what you may want to do with such a resource. If you’re interested, go to the blogs section of MS Discovery Forum under the “News and Future Directions” tab and click on the blog post titled, “Invitation to Share Your Thoughts on a New MS Research Resource.”

 

Our list of meetings and events is ever-growing. We’ve posted multiple meetings of all shapes and sizes sprinkled throughout 2015 and even into 2016. And if you know of a meeting that’s not yet listed, please do submit what information you have. We’ll take care of the rest. Just go to “Meetings and Events” under the “Professional Resources” tab on our website and click on the “submit new item” button to tell us about your event. We’re even willing to list local departmental seminars and journal clubs.

 

[transition music]

 

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. He met with MSDF to talk shop about imaging in MS.

 

Interviewer – Dan Keller

Welcome, Professor Matthews. What do you see now as new modalities or new ways of doing imaging, and what’s coming along?

 

Interviewee - Paul Matthews

Thanks, Dan. Imaging continues to reinvent itself in areas particularly like MS. Magnetic resonance is becoming more and more powerful with use of particularly multiband techniques, allowing multiple coils to be used to accelerate the imaging process, and because of that being able to collect much more data to enhance particularly diffusion images. So, for example, within the Human Connectome Project, development of new multiband techniques has accelerated imaging to the point where very high resolution diffusion tensor images can be acquired in spaces of 15-20 minutes. The implications of this for MS are that we can begin to develop powerful approaches to expression of the diffusion tensor information in terms of diffusion parallel to the fibers, perpendicular to the fibers, and free diffusion that is anisotropic. This means that potentially we’re going to be able to separate out free-water contributions from those contributions arising from myelin and axonal loss, providing a very powerful complement to magnetization transfer images.

 

A second area of major development in magnetic resonance is the increased use of ultra-high field systems at 7T, and potentially higher, for applications in MS. The first advantage this has brought is for increased spatial resolution that can be used to begin to image cortical lesions with a really impressively enhanced sensitivity. The second area has been new kinds of contrast. The high magnetic fields allow new susceptibility-weighted contrast to be generated which provides a powerful way of visualizing vessels. It’s very clearly defining the vessels at the center of most of the inflammatory lesions, helping a little bit with differential diagnosis, but even more importantly helping us understand what the microvascular architecture is in and around lesions.

 

A second potential advantage of the ultra-high field is simply increasing the sensitivity of MR for applications in magnetic resonance spectroscopy. We’ve known for a long time that signals from myo-inositol can help us understand glial components of inflammatory lesions, but there’s increasing interest in applying this kind of tool to measurements of glutathione, to provide indices related to reactive oxygen species generation, and potentially also to measuring excitotoxic neurotransmitters such as glutamate.

 

In a completely different space, positron emission tomography (PET) has begun to play a renewed kind of role in MS. I’ve always been a little bit disappointed that more wasn’t done with it over the last decade or so since pioneering studies that demonstrated that assessments of energy metabolism based on simply the fluorodeoxyglucose signal not only discriminated people with MS from healthy volunteers, but, more importantly, began to show discrimination between different stages of the disease and a relationship to cognitive impairment, with potentially reversible components with treatment. Now, that still is an area of potential work.

 

But more recently focus has shifted particularly to use of ligands that bind to the 18 kilodalton translocator protein which provides a marker of microglial inflammation in the brain. While it’s not entirely specific and with the caveat that we have little understanding of the relationship between the TSPO expression and the microglial phenotype, it clearly is highlighting some very interesting things. First, we found that the TSPO binding by ligands is increased multifocally in brains of people with MS; it’s increased multifocally in the white matter and in the grey matter. Moreover, increases in binding in both regions are related to degrees of disability; patients with higher disability show increased binding particularly in the cortex.

 

There’s emerging evidence, driven first by elegant preclinical studies done by the Finnish group and some human studies yet to be fully reported, that there are also strong treatment effects with powerful amino modulators. So because this provided us a window that is clearly giving us information distinct from that provided by T2 hyperintense lesions on MRI or by gadolinium enhancement on MRI, it promises a powerful adjunct.

 

And, finally, just to kind of round that idea out, it’s clear that it will be the combination of MR and PET that’s powerful rather than PET replacing MR in some way in our diagnostic or monitoring armamentarium for treatment. One manufacturer has already started supplying commercially integrated MRI-PET systems. Another manufacturer is expected to do so very soon, and potentially a third. This may become a platform for brain imaging that is very powerful for disorders like MS that have multifocal manifestations where the registration – the precise registration – between the MRI and the PET becomes important. Moreover, the potential to use dynamic MRI acquisitions where we’re just imaging very, very rapidly throughout the entire PET scanning period to follow the position of the head within the PET scanner may allow a new kind of precision of special resolution in the PET scan that allows MS studies where we rely on this very much to be done with far greater precision than it’s been possible in the past. So with these developments in MR, with the new radioligands in PET, and with this new technology for integrated MRI-PET, I think the brain imaging is off in incredibly new spaces.

 

Now I can’t close the discussion of imaging without at least making a mention of the revolution in applications of optical coherence tomography that have been conducted over the last five years in particular for MS. This is really exciting, too. It’s an inexpensive examination that can be performed very rapidly in any clinic that provides very high-resolution measures of optic nerve fiber layers, of multifocal edematous regions within the nerve fiber layer, all of which can provide measures to stage MS and its associated neurodegeneration, and potentially to usefully monitor it in assessing the progress of patients on treatments. It’s an exciting time for imaging.

 

Interviewer - MSDF

Now just to clarify, this is optical coherence tomography of the retina and its surrounding structures.

 

Interviewee - Dr. Matthews

Yeah, Dan, thanks for clarifying that. Absolutely. So it’s an eye examination, but it’s an adjunct because the retina is just an extension of what we study in the brain.

 

Interviewer - MSDF

Either using metabolic markers or following metabolism with PET or something else, or using other ligands and markers, can you discern or image where remyelination is occurring?

 

Interviewee - Dr. Matthews

So, of course, the world of PET is a big one because what we can observe changes with the type of radiotracer that we use. Recently, Yanming Wang, who I had the privilege of collaborating with at Case Western, published, I think, a really groundbreaking paper. Although it was a preclinical study, I think it shows the way we could be moving in this space. Using a novel radiotracer that he developed called MeDAS – MeDAS for short – this carbon positron-emitting isotope-incorporated tracer allows specific myelin proteins to be imaged, and thus provides a marker of myelin integrity in life. Yanming has shown how it can selectively image myelin, it can image both established myelin and new myelin being formed, and he demonstrated in a proof of concept study in rodents that the dynamics of demyelination and remyelination following therapeutic intervention can be followed, and moreover, that the therapeutic effect can be quantified relative to an untreated control group.

 

Really exciting and a potentially important adjunct to MTR or diffusion measurements in human studies. The trick of moving a tracer from preclinical studies into humans is not without some need for care, but because only microdoses of these tracers are used for the human imaging experiment, Yanming, myself, and colleagues believe we can make this transition rapidly. We’re watching closely to see what happens next.

 

Interviewer - MSDF

Pretty good. I appreciate it.

 

Interviewee - Dr. Matthews

Thanks, Dan.

 

[transition music]

 

Thank you for listening to Episode Twenty-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.

 

 [outro music]

Nov 10, 2014

[intro music]

 

Hello, and welcome to Episode Twenty 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. Jeffery Cohen about two clinical trials. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org. Genome-wide association studies are raising more questions than they answer for multiple sclerosis, according to new research. As the number of risky genetic variants grew, researchers began to wonder if many of those variants would be found in the murky waters of “noncoding DNA,” which comprises about 98% of the human genome. Those fears were confirmed in a study published last month in the journal Nature. According to the report, almost 90% of the risk variants fell within the noncoding region and 60% were found in areas known as enhancers or switches. These areas manage gene activity, though researchers are far from fully understanding how they work. While genome-wide association studies have been helpful to researchers, this study highlights that they are just a first step towards a better understanding of MS and the human genome.

 

The International Progressive MS Alliance recently released a call for applications for their second round of grants. To go along with this announcement, Professor Alan Thompson, the head of the Alliance’s scientific steering committee, penned a post for our blog. In his post, he emphasizes the urgent need for more research into progressive MS. He notes that over one million people worldwide live with progressive MS, yet no specific treatments exist for this condition. You can read Professor Thompson’s post in the blog section of the News and Future directions tab at msdiscovery.org. To get more information about the grants from the Alliance, visit our “Funding Opportunities” section under the “Professional Resources” tab on our website.

 

In addition to the latest funding opportunity from the Progressive MS Alliance, we also recently posted a long list of funding opportunities from the National MS Society.

 

[transition music]

 

Now to the interview. Dr. Jeffrey Cohen is a neurologist and director of the Mellen Center for multiple sclerosis at the Cleveland Clinic. He spoke with MSDF about two clinical trials, one examining the clinical use of stem cells, the other about a generic version of glatiramer acetate, Copaxone.

 

Interviewer – Dan Keller

First of all, what was the aim of the clinical stem cell trial and what phase was it done in?

 

Interviewee – Jeffrey Cohen

So we now have 11 medications approved to treat multiple sclerosis. They are all effective in the early, relapsing remitting stage of the disease, but there is a major unmet need for treatments that repair damage and might be effective in progressive MS. Our main goal was to explore cell-based therapies to treat multiple sclerosis, specifically to test the feasibility and safety of administering so-called mesenchymal stem cells. This was a Phase I study of mesenchymal stem cells. These are stem cells that are present in many tissues of the body. We isolated them from bone marrow which is probably the version that is the best studied previously. We grew them in the laboratory to increase their numbers, and then readministered them intravenously. We were focusing primarily on safety, as I said. We had fairly intense monitoring for any complications. Thankfully, we saw none. We also looked in a very preliminary way for benefit using clinical measures, a variety of imaging approaches and immunologic measures.

 

MSDF

What is the hypothesis here that they are doing? Do they actually get into the brain? You are infusing them IV. There is a blood-brain barrier, these are pretty big objects.

 

Dr. Cohen

There are actually a large number of studies in the laboratory and in animals that suggest that these cells have a number of properties that we think would be of use in a disease like multiple sclerosis. First of all, they seem to modulate the immune response. They dampen down inflammation. But more importantly, they appear to be able to produce a wide range of soluble factors, growth factors and other substances that we think promote repair. We think of them as the delivery system for growth factors that promote repair. We don't think that they themselves develop into brain tissue but will become neuro-cells, but rather that they create a milieu that is conducive for the natural intrinsic repair processes to remyelinate or restore neurologic function. The other property that is potentially very advantageous is that they appear to be attracted to areas of tissue damage or inflammation. They appear to have the ability to migrate within tissues, and in fact to migrate from either the cerebral spinal fluid into the brain or from the blood into the nervous system. So we think we can take advantage of that by administering them intravenously.

 

MSDF

Did you do dose-ranging here?

 

Dr. Cohen: We did not. One of the things we learned from this study is that there are a lot of unknowns about cell-based therapies. What the appropriate dose is? Whether multiple doses are needed? What is the best route of administration? Whether there are nuances as to how you grow the cells in culture? What characteristics you want to augment? Dose-ranging in particular is something that has been very difficult to do in the field, particularly for some of these cells that are grown in culture; you usually have the dose that you have. That has been an issue that we have struggled with as have others in the field.

 

MSDF

How long did you follow these patients and what did you find?

 

Dr. Cohen

We followed them for two months prior to infusion. That is the time during which their cells were being cultured, and then for six months after infusion. So very reassuringly there were no serious or severe adverse events. In fact, there were very little, if any, side effects. Patients were not immunosuppressed. They had no premedication. The only side effect was that the culture media contains a chemical called DSMO. Some patients got a garlic taste in their mouth. If they don't like Italian food, they didn't like that. We also looked in a preliminary way for evidence of benefit with the caveat that this study was not really designed to look for benefit. We used this as an opportunity to explore a variety of measures that might show tissue repair. We saw enticing improvement in some measures in some patients, but for patients as a group, there was no clear-cut evidence of benefit. We have to be very careful how we interpret these results.

 

MSDF

Could you follow them in any way? Were they tagged or any other way that you know where they went?

 

Dr. Cohen

No. That is another aspect of the cell therapy field that is getting a lot of attention. At the moment it is largely a black box. After we administer the cells, knowing whether they survive and where they go and how long they live there. That is another line of research besides pursuing further clinical trials of these cells is also to develop methods to track them within the body. There are some promising approaches that we are in the process of developing.

 

MSDF

Now I take it these were not modified in any way, they were just cultured to multiply them?

 

Dr. Cohen

There were some growth factors in the culture media, but they were from the regulatory point of view, not very manipulated. That is the terminology that is used. That is another area of debate is some of the specifics of the culture approach, whether we should add other factors that might change the properties of the cells. Whether it is okay for them to be frozen, which we do largely for convenience because then we can schedule the infusion. Or whether they should be taken fresh from the culture and administered. There are arguments for both approaches.

 

MSDF

Many cells seem to hone right back to where they came from. Do these just go back to the bone marrow do you think, or do you think they actually went somewhere because that area needed repair?

 

Dr. Cohen

There have been a few studies in some other conditions where these cells have been given. One of the interesting properties is that you can administer these cells from another person and they are not rejected. They become, I wouldn't say the standard, but a very common treatment for what is called graft-versus-host disease, which is a very severe complication of allogeneic bone marrow transplant where the transplanted immune system attacks the recipient's body. That is where the immunomodulatory effects of mesenchymal stem cells were first observed. There are, unfortunately, have been a couple of instances where MSCs that were from another person of a different gender, were administered to someone with graft-versus-host disease who unfortunately, subsequently died of GVH. In those cases, these cells were found in a range of tissues including bone marrow. Probably a more important obstacle is for after intravenous administration is the lung because that is where the blood goes from the veins. These cells probably collect in the lung initially and then percolate out into the tissues.

 

MSDF

Do you have any concerns, any caveats about potential harms, limitations, from using this? Is it feasible on a large scale?

 

Dr. Cohen

We took a very conservative approach with the idea that there are so many unknowns of cell-based therapies, including precedence in multiple sclerosis where therapies had a different effect than we anticipated. We thought it was appropriate to take a very careful systematic approach starting with a small safety study and then building from there. At least within the limitations of our study, meaning that it was relatively short, and relatively small, we saw no indications of any complications. Some of the hypothetical concerns would be cancer. Stem cells share some properties that are similar to cancer cells, or ectopic tissue formation. Stem cells have the natural ability to develop into almost any kind of tissue. At least, presumably they could go to one tissue and develop into another type of cell, so bone within the heart or something like that. We really saw no indication of that. There are really no examples of that in the literature, but because of those sorts of concerns, we took a very careful approach. We feel comfortable now moving on to a bigger program. 

 

MSDF

You had discussed some of the problems that arose using allogeneic cells. Just to clarify, this was using autologous cells?

 

Dr. Cohen

Correct. These were cells from the patient themselves. There is still some debate in the field, which approach is better. Whether to take cells from the person themselves or whether to take cells from someone who does not have the disease that you are treating. That again is an issue that has not been settled. I think some of the cell tracking we were talking about earlier may help with that. Rather than answering all of these questions one trial at a time, we may be able to adjudicate some of these questions by seeing whether cells traffic more effectively.

 

MSDF

Let’s shift to your other trial, the GATE trial using generic Copaxone. Is that available now and what was the point of the trial?

 

Dr. Cohen

The purpose of this trial was potentially to have a generic version of one of the established multiple sclerosis drugs come available. The incentive would be that presumably because of the lower development costs, that the generic version would save money for payers and for patients. The trial we just completed was of a generic version of glatiramer acetate, Copaxone, one of the initial drugs approved to treat MS, a drug that we have a great deal of experience with. It has established efficacy and a known good safety profile. This study tested a generic version of that with the intent of showing that it had equivalent efficacy, in this case, as tested by MRI and had equivalent safety and tolerability.

 

MSDF

These were all patients with relapsing, remitting MS? You had, what, about 735?

 

Dr. Cohen

Correct. This was in a patient population with relapsing, remitting MS; the population for which Copaxone is approved.

 

MSDF

What were the interventions, the test group?

 

Dr. Cohen

There were three groups in this trial. One group was treated with generic glatiramer acetate. One group was treated with the brand Copaxone and then there was also a small placebo group to demonstrate what is called study assay sensitivity. The purpose of which was to show for the trial overall that the generic glatiramer acetate is equivalent to the brand-name, the reference drug as it is called, but also that within this trial with this population, that both drugs were effective.

 

MSDF

Where was this done, and is that ethical?

 

Dr. Cohen

One of the things we have encountered increasingly in developing multiple sclerosis drugs is that there are ethical and practical issues to including placebo groups. At this point it has become extremely difficult to include a placebo group in a large Phase III study that goes on for several years. In this case, this was a short trial, with the advantage of using MRI as the endpoint. It was conducted to some extent in North America, but primarily in Eastern Europe and other  countries where unfortunately, multiple sclerosis treatments are not as available. 

 

MSDF

What did you find?

 

Dr. Cohen

The study was successful. It showed equivalent efficacy as measured by gadolinium-enhanced MRI, and also showed equivalent safety and tolerability as measured by adverse events and injection site tolerability.

 

MSDF

What would this mean for patients if someone brought out a generic?

 

Dr. Cohen

The hope would be, is that if this drug is approved, that it would be less expensive. Multiple sclerosis is an expensive disease to care for and a great part of that cost is medication costs. So the hope would be that this would be less expensive. The other caveat is that complicated molecules such as Copaxone are difficult to replicate. In addition to very extensive chemical and biophysical analyses, that is why a trial was conducted, because of the feeling that it would only be with clinical data that we could…we assure ourselves that this was in fact similar to Copaxone.

 

MSDF

I would take it, that this would only apply to the generic you tested. I mean generics have a certain tolerance level margin compared to the approved brand, so not all generics are the same.

 

Dr. Cohen

That is correct. It is actually quite tricky to develop a generic of a complicated molecule, either a complex mixture such as glatiramer acetate or a so-called biological like a monoclonal antibody. Each one has to be tested one at a time.

 

MSDF

Anything important that we have missed, or to add?

 

Dr. Cohen

This trial was designed with the assistance of, and discussions with EMA, the European Regulatory Agency. It has been somewhat more difficult in the United States. The FDA is still somewhat unclear on their policies and the procedures for testing complex generics and biosimilars. The status of this trial in the United States is still somewhat uncertain.

 

MSDF

Very good. Thank you.

 

Dr. Cohen

Thank you.

 

[transition music]

 

Thank you for listening to Episode Twenty 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]

 

 

Nov 3, 2014

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Nineteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features the second half of an interview with Dr. Samuel Ludwin. This time Dr. Ludwin and I discuss the implications of treating multiple sclerosis subtypes. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

This week we reported some good news: a large case-controlled study showed that there is no causal link between vaccines and multiple sclerosis. However, the study came with the caveat that there is some increased risk for developing MS in younger patients who receive vaccines. This increased risk is likely due to the vaccines triggering a pre-existing asymptomatic condition, the researchers said. The study, which was published in the journal JAMA Neurology, was most concerned with the role that vaccines for hepatitis B and human papillomavirus play in the long-term risk for developing MS.

 

We also reported on a new iPad app that will allow clinicians and MS patients to track their disease course. The app, called Bioscreen, is currently in beta-testing at the University of California, San Francisco. The developers, including Pierre-Antoine Gourraud who is on MSDF’s scientific advisory board, assert that Bioscreen has the potential to be a powerful tool for researchers, clinicians, and patients. At the core of the app is a dataset of around 600 patients who have been participating in a data collection survey for the past 10 years. Physicians can compare their patient’s disease course with other confirmed MS cases and use that information to influence their recommendations. The researchers also believe that patients’ ability to visualize their own disease in this way will improve adherence to medical recommendations and ultimately strengthen the bond between patient and physician.

 

Every week we publish at least one “Research Roundup” where we curate stories from around the web related to multiple sclerosis. Recently we published roundups about advances in spinal cord injury treatment, the recipe for selling the perfect bogus drug, and the report of a rare brain infection in a patient taking dimethyl fumarate, trade name Tecfidera. To view Research Roundups, go to the “News Briefs” section of the “News and Future Directions” tab at msdiscovery.org. Look for the blue Research Roundup logo and stay up-to-date with all the latest MS news.

 

[transition music]

 

Now to the interview with Dr. Samuel Ludwin, a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. Last week we aired an interview with Dr. Ludwin in which he discussed remyelination therapies. This week he speaks with MSDF about MS subtypes.

 

Interviewer – Dan Keller

Welcome, Dr. Ludwin. Let’s talk about some of the subgroups of multiple sclerosis, as has been proposed by Professor Hans Lassmann, and you wrote an editorial some time ago about it. First of all, can you tell me what subgroups he identified and what progress there has been made since then?

 

Interviewee – Samuel Ludwin

This is a very groundbreaking paper, very controversial, and over the years many people who have followed this particular pattern, others who’ve not been able to reproduce it and believe that the conclusions are not valid. However, what Claudia Lucchinetti and Hans Lassmann showed in a mammoth first-time examination of very acute lesions; they had access to a particularly unique group of specimens that are from both the Mayo Clinic and other areas, where very early lesions were examined. And in looking at this, they looked at patterns of tissue breakdown and the mechanisms of tissue breakdown, and essentially came up with four different categories. The two most important ones are very important to discuss because in the one, the features were very, very consistent with the kind of immune injury that one finds in experimental allergic encephalomyelitis where we know the damage has been caused by the injection of the antigen with a subsequent immune reaction to that antigen. And the other main group was one where there appeared to be a primary damage of some sort to the oligodendrocyte and then a subsequent immune reaction.

 

Now this is important for a couple of reasons, and the first is that there is a big debate going on in the multiple sclerosis literature or research as to whether the disease starts from the outside peripheral activation of immune cells and then homes in on the brain because they are cross-antigens or cross-antibodies or cross-cells, or whether the process actually starts with damage to something in the brain which subsequently sets off the – and this is called the “inside-out” or “outside-in” controversy at the same time. What this might mean, according to the way they have done the study – which was a very good one – was they suggested that there might be multiple mechanisms towards the end result of damage to oligodendrocytes and myelin, and subsequently the physical appearance of multiple sclerosis lesions.

 

Other people have challenged this and suggested that maybe it is a question of timing, and the mechanism is the same in all patients, but we’re looking at a different kind of progression and timing. And that controversy is still being discussed, as is the inside-out, outside-in phenomenon. But when you look at some of the things that might be causing these inside-out or their type 3 pattern where the primary damage could be in the oligodendrocyte, there are many reasons that the mechanism could be due to either stroke-like causes such as a lack of oxygen or blood flow that damages the oligodendrocyte, possibly certain infections that may target the oligodendrocyte. And we know that there are many mouse models where you can target oligodendrocytes with certain viruses. And those overlap very significantly with mechanisms of tissue damage in other diseases.

 

So it is a very important paper because it has set people thinking about multiple mechanisms. The fallout from this is that, in fact, when you have different mechanisms of causing disease, there are potentially different ways of treating it. And if you have a primary immune-based phenomenon from the outside, antiinflammatories as are given on disease-modifying therapies are perhaps the way to go, whereas if you’ve got something that is damaging it from the inside and some other cause, we need to elucidate what that cause is and go straight for that particular cause. In addition, what we are trying to find out is whether we can predict what sort of pattern has caused the disease, either with imaging or with biomarkers, and be able to do this without biopsies and other things so that patients can be treated accordingly. It’s an advance on perhaps what we might call personalized medicine in multiple sclerosis. 

 

MSDF

Are there imaging or clinical correlates of these different types of processes? You’re not going to do a biopsy on most people.

 

Dr. Ludwin

No, there isn’t. But in fact, there are some therapeutic differences. For instance, in the type 2 pattern, which is the autoimmune pattern or the outside-in pattern, these patients respond very well to plasmapheresis where one is removing the offending gammaglobulin. And patients with the type 3, which is the main oligodendrocyte-based pattern of the disease, they don’t respond to that well. And that’s perhaps the best clinical differentiation that we know at the moment that helps us. A lot of the data is not clear. They based a lot of the data on the fact that they felt that every patient had a uniform pattern in the lesions. Other people have questioned this and found that there might be a multitude of different kind of patterns in the same patient, and therefore it supported modifications of the same inherent cause.

 

MSDF

Does the efficacy of plasmapheresis correlate with the presence of oligoclonal bands in the CSF, or that’s not a correlation?

 

Dr. Ludwin

There doesn’t seem to be a correlation, leastwise I know. Certainly plasmapheresis where we know that there is antibody, such as in neuromyelitis optica is more effective as a treatment early for diseases where we know that there is circulating antibody, but patients will have oligoclonal banding, I think, in both patterns.

 

MSDF

You’d alluded to damage to the oligodendrocyte in one of these forms as the primary dysfunction or lesion. Does that imply that something is being exposed, an antigen that might be reacted to, or how is that leading to damage?

 

Dr. Ludwin

Absolutely, that if you get damage to a tissue, various proteins are being broken down and antigenic epitopes are being exposed, which then are transported back to the peripheral lymphoid tissue for reactions to take place. I mean, there are counter-arguments to this. One can ask why, with a lot of trauma injury, a lot of stroke injury which is far more common than MS, why you don’t get a secondary immune response to that, even though we know many people with the genetic makeup makes them susceptible to MS or exist in the normal population, and almost certainly some of them have strokes. So there are questions on both sides and arguments. And we know from other experiments that you can induce circulating antigens with tissue destruction of any cause, and potentially these are circulating to be able to produce reactive antibodies in the periphery.

 

MSDF

I think Lassmann showed that even in healthy people you can find CNS antigens in the cervical draining lymph nodes, which raises the same question you just brought up; why do some people have a reaction and some not?

 

Dr. Ludwin

Absolutely, and there are now all sorts of theories coming out of the genetics that there are multiple genes, each having a small effect, but in totality may be adding up to a genetic defect that will allow some of these circulating cells to suddenly start having an effect.

 

MSDF

Now it seems, in terms of thinking of personalized medicine, so much of it is empiric – what works works, and you try something else if it doesn’t. Is there a possibility of any harm from these treatments to people for whom it doesn’t work? Do you have to be very concerned about also first not do harm, especially considering you can’t tell the difference among these types from the start?

 

Dr. Ludwin

Yeah, I think that it’s too early to apply personalized medicine to patients in this particular area in the different types. If you’re looking at personalized medicine that, you know, we treat patients as individuals, or we should, because a lot of the therapy is based on empiric choice and anecdotal experience sometimes with the clinician, and there’s no absolute algorithm that everybody uses to treat a patient. So in that sense, we already do practice it. But you’re quite right, a lot of that is anecdotal or empirical rather than mechanistic.

 

The do no harm is a very interesting point also, because you mustn’t forget that basically multiple sclerosis is an inflammatory disease, and very frequently we tend to look at inflammation as being something that’s bad. But the reason the body mounts an inflammatory infiltrate is usually to cure something or to clean up something that is attacking it from the outside. So in any kind of these interferences, we have to choose a very find balance between stopping an inflammatory infiltrate or reaction that may be doing a lot of good for the patient, while preventing it from its worst excesses.

 

And here, empiricism comes in quite well at the moment; we know which of these drugs that we give are more likely to give side effects, we know more about side effects than we do about potential for not allowing growth. We will stop a particular cytokine or block a particular protein in its action, but I think we should always be aware that the protein, if it’s a normal one and not abnormal protein, may be there for a reason and the patients will do worse if they don’t have this mess cleaned up, so to speak.

 

MSDF

We’re also finding today that we’re almost living in a proinflammatory environment; it has repercussions in heart disease, dental disease, MS, fat is proinflammatory. So do all these things add to the risk in MS if there’s other inflammatory processes going on?

 

Dr. Ludwin

Well, it’s not only the inflammatory processes that’s going on, it’s the things that are causing them. As you’re right, we are now discovering that things like salt, fast foods, the changes in the microbiota all tend to make us more proinflammatory. And certainly in experimental animals and now some human studies, it has been shown that experimental immune disease is worsened by a high salt intake which leads to increased salt in the tissues, as well as being prevented by some of these diseases. If you change the gut microbiota in many of these diseases from normal commensals into something that may be pathogenic, you will set off inflammatory autoimmune disease. It’s been shown very beautifully in ulcerative colitis and Crohn’s disease, and the same thing is now being looked at very strongly in multiple sclerosis, so certainly a proinflammatory environment.

 

On the other hand, it should be remembered that there’s certain kind of infections that produce a reaction that may very well be protective, and there’s some evidence that some of the parasites produce a factor and we believe it could be related to a particular type of protective T-cell that will then allow for patients to become resistant to multiple sclerosis. And there’s some very good data from South America that populations who’ve been exposed to parasites and have them are actually more resistant to multiple sclerosis, because the parasite has induced a protective antiinflammatory molecule in the cell as well. So it’s a very complex balance and we’re gradually discovering more and more about where this balance lies.

 

MSDF

Might the prevalence of parasites account, at least in part, for the geographic distribution of MS?

 

Dr. Ludwin

Well, parasites are just one part of it. There is a very strong feeling, and it comes back to also the gut microbiota – but it’s more than just gut microbiota; it’s environment microbiota – that this has a major role. And for many years, it wasn’t just parasites. People in the Third World had a much lower incidence of multiple sclerosis, and this could have been also from genetic reasons or from susceptibility. But it was not just for multiple sclerosis. All autoimmune disease was much lower in frequency in these populations, and the theory was that most of the people who grew up in developing countries were exposed to large numbers of bacteria and they developed robust immune systems, normal-functioning immune systems that could help them deal with it. And the theory is that in developed countries, the over-usage of antibiotics has aborted normal immune responses, and so in response to that autoantibodies are created and we are suffering the consequence of living too clean a life. And so I think if you look at that argument, it’s not just multiple sclerosis, it really has been mooted for the inflammatory bowel disease, juvenile diabetes, rheumatoid arthritis, and other immune diseases as well.

 

MSDF

Thank you, this has been very good.

 

Dr. Ludwin

Pleasure.

 

[transition music]

 

Thank you for listening to Episode Nineteen 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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