Conversations in Progressive Multiple Sclerosis
Video: Researchers Discover Potential Biomarker for Progressive MS, Neurodegeneration
Deficiency of N-acetylglucosamine and its isomers appears to correlate with multiple sclerosis, particularly progressive MS, and neurodegeneration, according to a new study published in JAMA Neurology.
Michael Demetriou, MD, PhD, professor of neurology and director of the National Multiple Sclerosis Society Designated Comprehensive Care Center at the University of California Irvine, spoke with MD /alert about this association and how it may lead to a new treatment option.
What was the idea behind this research?
It builds on several decades of research. So, the metabolite we’re talking about is something called N-acetylglucosamine, which is a sugar that is similar but, you know, not the same as glucosamine. So, it’s a dietary supplement that you can buy over the counter. And we had shown in the past that this sugar N-acetyl glucosamine can regulate protein glycosylation.
All our cells are decorated with a large amount of sugar that’s attached to proteins at the cell surface. And we have shown that this decoration can impact cell function and viability. And that’s so that if you’re deficient in some of this protein glycosylation, for example, it limits the ability, at least in mice, to promote, you know, myelin producing stem cells to differentiate into myelin cells and promote myelination.
So, the idea is that if you’re deficient in this, it blocks it. And so, we wanted a method to try to reverse that. Metabolically we realized that this sugar N acetyl glucosamine can increase these sugars at the cell surface and reverse this phenotype. We’ve previously shown that this sugar can promote myelination in animal models. Distinct from that, we’ve also shown that this sugar can also regulate inflammatory responses. And both of those things can lead to neurodegeneration in MS.
MS is really two components of the disease. So, there’s the inflammatory attack where the immune system attacks the myelin, and this leads to clinical symptoms. But also, there can be damage to the nerve cells, and the axons, which are the wires of the nerve cells as well. And we think that leads to so called neurodegernation, sort of the permanent disability.
One of the problems in MS is that you don’t re-myelinate after this inflammatory attack. As we had shown that sugar can affect both the inflammatory attack in a good way and promote remyelination in a good way, we wondered whether we could detect this in normal serum.
And it really isn’t established as a normal serum constituent and there’s a number of reasons for that. It’s very difficult to detect. And it has what we call isomers. So, there’s sugars that are very similar to it.
What we did in this study, we asked the question, can we detect the sugar N-acetyl glucosamine in the blood of humans. And we used a mass spec assay that, unfortunately can’t distinguish between N-acetyl glucosamine and its isomers. But what we found is that assay, you know, detecting GlcNAc plus its isomers, we found that was dramatically reduced in patients with this neurodegenerative prominent disease in MS.
How was the study conducted?
It was looking at two different cohorts of patients. One in Irvine where we looked at healthy controls and the two types of MS patients, the one we call relapsing/remitting MS and the other one we call progressive MS. We found that if we looked at this assay for this serum GlcNAc and its isomers, that it was a little bit down in the relapsing remitting MS patients compared to healthy controls. But it was dramatically reduced in the progressive group compared to both healthy controls and the relapsing remitting MS patients.
So that was one cohort. And we wanted to replicate that as well. And that’s where we turned to colleagues at the Charité–Universitätsmedizin in Berlin, Germany where they had a very well characterized clinical cohort of MS patients. And there we asked the same question: Is there a difference in the serum levels of this GlcNAc and its isomers. And again, we saw the same thing that it was dramatically reduced in the progressive MS patients. That cohort also then had a lot of what we call, you know, clinical measures of disability and imaging measures.
So, MRI and OCT, and these can be used to measure, sort of, the extent of neurodegeneration, or at least proxies for neurodegeneration. If we looked at the MS patients those with low serum and GlcNAc and its isomers, it was associated with more brain atrophy, shrinking of the brain on the MRI, more nerve damage when we looked in the retina of the eye, the nerve fiber layer of the eye, and more clinical disability. So, the patients were more disabled. The more disabled they were, the lower serum GlcNAc level was. One thing I should stress that you know, these are associations. It doesn’t directly test cause and effect.
Why is this more associated with progressive MS and not necessarily relapsing/remitting?
We need to work to understand this. But we think based on our animal data, as I was saying earlier, that we know the sugar can promote myelination and remyelination. And it can also inhibit inflammation. And those are two probably important factors in this neurodegeneration.
So patients have these naked axons. And when they don’t have myelin they’re more susceptible to damage, subsequent damage. And so we think the potential reason for this is that if you have low serum GlcNAc levels you have reduced your ability to remyelinate and therefore you have these axons that are more susceptible to damage and over time accumulate damage. Whereas if you had high levels that would promote, you know remyelination, and protect the axons and prevent this sort of neurodegeneration and disability. So that’s all theory based on animal data. You know, we need more studies in humans to investigate that and confirm.
Could this help develop new treatments for MS or better guide what’s available to the right patients?
I think both. And I think we want to pursue both. So, you know, we’re trying to develop a more clinically useful assay so that physicians could react to that in terms of maybe changing their current availability of treatments. And in parallel, we’re also pursuing whether we can use N-acetyl glucosamine as a therapy in MS. So, we’re in the midst of completing a phase 1 clinical trial of N-acetyl glucosamine in MS patients, so I can’t talk about any results about that yet because we’re not done. But, you know, that is sort of a parallel track approach, doing both.
What is the future of this research?
Phase 1 studies are usually, you know, for safety. And, in our case, we’re also looking at dose, you know, what dose of this N-acetyl glucosamine is required to affect the, glycosylation on the surface of the cell. So we think we’re going to get an answer for that at the end of this analysis of the phase 1. And we hope to publish that in the next six months hopefully. And then the next steps would be what we call a phase 2 clinical trial.
A complicating factor in all this is that as a dietary supplement, you know, there’s no interest, shall we say, from pharma to develop this as a drug because the patent protection is limited. So, we’re trying to do this through, you know, NIH funding and/or philanthropy. Our phase 1 study was, you know, funded by the NIH.
Any views expressed above are the author's own and do not necessarily reflect the views of MD /alert. This transcript was digitally generated and edited for clarity.
Video: BTK Inhibitor Tolebrutinib Proves Safe, Effective for Multiple Sclerosis
Tolebrutinib, a central nervous system–penetrant Bruton’s tyrosine kinase (BTK) inhibitor, was found to be safe and effective for multiple sclerosis with highly active disease, according to a phase 2b trial of 130 participants presented at the American Academy of Neurology Virtual Annual Meeting.
Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia in Vancouver, discussed the results of the randomized, placebo-controlled trial.
What were the findings of your study?
0:26- The new class of drugs emerging for multiple sclerosis or relapsing forms of MS are the Bruton tyrosine kinase inhibitors or BTK inhibitors. And these are a class of oral medications that were used in cancer treatment, blood cancer treatments that affect B cell or modulate B cell function.
And so we're leveraging really off of the ocrelizumab and rituximab story that is a highly effective treatment for MS to see if using a different type of a drug going after the same target is as effective and the phase two trial in overall showed that at well tolerated oral dose of 60 MG was very effective preventing new MRI lesions, which is our primary outcome in phase 2 trials that helps us find the dose that we need.
This subgroup analysis was looking at patients who met an accepted definition of highly active disease going into the trial, and those are the patients that are at highest risk for future disability. And so they're important interest to know if if the drug is broad spectrum to impact on them as well as the average MS patient. And, it was really nice to see, of course, is that group was well represented in the population of close to 50% of the overall population had those features of highly active disease, which was an enhancing MRI lesion at baseline, a relapse in the past year or two relapses in the past two years. And that group did very well on treatment. The 60 mg dose was just as effective, in other words, highly effective at preventing numerations as it was in the overall part relationship. So that I think that’s very encouraging.
The other neat thing too is that effectiveness is seen within three months of starting treatment, which is very encouraging. That’s what we want out of our treatments that to be quickly effective.
What role can tolebrutinib play in patient care?
2:59- It's a really crowded field right now with multiple medications ranging from injectables into the skin, infusions or pills. And so you know, I was wondering what is like what is the role of a yet another medication for relapsing forms of MS. Where the room is for relapsing MS or medications that are well tolerated and easy to take and this medication really fits that bill.
None of our patients dropped out of the trial because of side effects from the medication, which is really encouraging, and we didn't see any infections though, it’s a short period of time, right, and it’s highly effective, which is also attractive.
The other nice thing with this is it doesn’t cause depletion of lymphocytes. And that’s been an issue with some medications when you're trying to transition to a different medication, Often you're having to wash out the medication waiting months for the lymphocytes to come back before you can start yet another medication. With this drug which modulates cell function as opposed to destroys cells, it really gives that nice advantage of being able to stage therapy, which I think is advantageous. And then the final is the possibility that this drug may fit a missing piece of the treatment of MS and that's targeting the mechanisms of progressive MS. And all MS patients at risk of progression, and the mechanisms that drive progression aren't well known.
But one of the thoughts is that it’s cells in the brain, such as microglia, that are abnormally active and that are driving this smoldering inflammation in the brain. And most of the treatments that we use for MS don’t get into the brain. They work on the immune system, in the bloodstream, to prevent cells from getting to the brain. But once those cells are trapped in the brain, it would be interesting to see if a drug like tolebrutinib of that can cross well into the brain, will it affect those immune cells and shut off the mechanisms of progression. And that really would become the need in the field.
With an abundance of options, how do you approach treating your patients with MS?
5:22- The nice thing with MS is it’s not a rush decision like starting an antibiotic. There’s usually, for most cases, a time to lay out some options, take some cooling off time to consider those options, and come back and have a discussion. My own approach is I like to explain my philosophy to patients.
My personal goal is to really shut the disease down as soon as possible after diagnosis. And so that's using higher efficacy treatments up front. And then I always like to give them three options to consider taking. We have 12, 14, 15 drugs out there. Let's narrow it down to three after having had a discussion about what are your personal goals. What is your risk tolerance? And then reassuring them that whatever they choose today, they’re not locked to. We’re going to find the drug that has minimal to no side effects, good safety, and it fits your profile. And if your profile changes, let’s change with it and just really control this disease.
My feeling now in the field, I’ve been doing this for 20 years, starting off with the old interferons and whatnot, which were very very very modestly effective to now, having highly effective treatments. My patients, I want them to leave with a sense of hope and confidence that with the range of treatments we have now. We can find the right fit. We may have to play around a little bit. But we can find the right fit for their profile and their needs and their goals.
Where does your research go from here?
8:30- This medication tolebrutinib and some other BTK inhibitors are going into phase 3 clinical trials that are already underway, and so there will be the the trials in relapsing forms of MS. And it's the phase three that will give us the real sense of how effective it is and as well as longer safety information and tolerability information. One would predict that the data is going to end up playing out quite nicely because the phase 2 data was so promising and consistent across two different drugs.
But for me, one of the exciting areas is the trials in progressive MS. And that’s always a big gamble in this field to see if a drug that will work in progressive MS and that’s what I’m really hoping to see. In parallel to that, we've did some additional data collection in the phase 2 trial that's still underway looking at measures that could reflect impact on progressive mechanism. In the blood, looking at serum neurofilament's as a biomarker of degeneration as well as looking at different MRI measures such as MTR and brain atrophy from the long term follow up the phase 2 trial. So before the phase 3 progressive studies finish we hope to have some preliminary, some thoughts on how the stroke might affect the mechanisms of progression, but what we truly need, of course is the results of the phase 3 trial of impact on clinical outcomes, which is the most important thing to our community patients.
Disclosures: The study was supported by Sanofi Genzyme. Traboulsee reports receiving honoraria as a member of the scientific steering committee member for the phase 3 progressive MS trials of tolebrutinib, as well as past grant support honoraria for consulting and speaker’s bureau from Sanofi Genzyme.
Any views expressed above are the author's own and do not necessarily reflect the views of MD /alert. This transcript was digitally generated and edited for clarity.
Video: Guide to Starting, Sequencing Treatment for Progressive MS
With several new approvals for patients with multiple sclerosis in the past few years, clinicians are faced with making decisions about which therapy is best for their patient.
Jennifer Orthmann-Murphy, MD, PhD, Assistant Professor of Neurology at the University of Pennsylvania, discusses how she initiates and sequences patient treatment and the role diet and exercise play in the larger treatment picture.
Can you discuss the current treatment options for progressive MS?
I think it's important to start with the idea of even understanding what progressive MS is. So, secondary progressive MS is the way we think about is sort of something that develops overtime, typically in someone who's had the more common form of relapsing remitting MS, where unrelated to any particular relapse or new symptom you have gradual worsening of other symptoms you've had in the past.
Primary progressive MS is when you just sort of have this slow accumulation of symptoms and disability without any of these relapses where a new symptom appears and then eventually resolves or partially resolves. And so most of our medications that we have have been developed to target the immune system because as abnormal or aberrant inflammation, where immune cells somehow get into the brain and spinal cord and cause damage seemed to be the initiator of what's going on in MS. And so most of our medications really are targeting things that happen outside of the brain and spinal cord within the blood and the immune system to change how those immune cells are acting and to stop them from getting into the brain and spinal cord and causing damage.
And so when it comes to progressive disease, there have been many, many studies over time trying to see whether these immune modulator treatments would also affect progressive symptoms, and for the most part they have not. But we now actually have with Ocrevus (ocrelizumab), which was tested specifically for primary progressive MS in the ORATORIO trial, to reduce the proportion of people with disability progression. So with someone who is diagnosed with primary progressive MS, we have a good medication to go to right away.
When Siponimod was approved, that was the first time that one of the disease modifying medications were approved for what's called active secondary progression. And what that means is, although it wasn't directly tested for that, that even though a particular person with MS was experiencing progressive symptoms, that if you are also having signs of inflammation, either new lesions on MRI or signs of inflammation, like gadolinium-enhanced lesions on MRI or new clinical symptoms that's considered active despite the co-occurrence of progression. And so it turns out that all of the new medications that are being approved at this point are also indicated for active progressive disease.
So what that means is we're sort of rich in options for people with MS that here at Penn we actually have a whole visit just to discuss all of the options and what people feel comfortable with for safety lab monitoring and adverse effects and how often and what type of administration of drug that they are most comfortable with. And usually we can, I personally like to come up with a plan and then a backup plan if anything comes up.
How do you determine treatment selection and sequencing?
That really involves a discussion with an individual person and the doctor. And we do it as a team. I also incorporate nurse practitioner and the pharmacist and together you know we go through so the these are your baseline lab testing. This would mean you'd have to get this we you know we'd be more comfortable with making sure you had hepatitis B vaccination status before starting this. How comfortable do you feel starting an immune depleter in a COVID-19 pandemic, you know that sort of thing. And something with like Tysabri for example, you know highly effective medication, but there is that PML risk. So we just sort of go through the pluses and negatives of each medication to decide what is the best option for the person sitting in front of you and what they feel most comfortable with.
What’s the role of non-pharmaceutical strategies like diet or exercise?
Right, so that’s a huge portion. Maybe in my first conversation with someone we might not be able to get to everything. But certainly in all follow up discussions I want to know how much someone is exercising, how often? What are they doing? How much time per exercise session are they doing and how it makes them feel, how it affects their sleep and their energy throughout the day and their mood. So those are all different aspects of getting someone to feel better and do the things that they want to do that give them joy, right? And all of those things are possible no matter where you are on the scale of mild or more severe disability.
From the standpoint of a subjective how well an individual person feels due to exercise, there's both clinical data and individual person data that people feel better once they incorporate that into their daily life patterns. But there's also from the basic science perspective, which I also do. I studied re-myelination in my lab. That there do seem to be some benefits to promoting the cells that form myelin to becoming mature cells so that we haven't figured out the link between how much exercise, which type of exercise when, and how much to do for any individual person. So essentially when I talk to patients about this, it's more of a conversation of what do you think you can do and that you can do regularly, and then we can build on that from there.
How does the treatment of progressive MS move forward?
Like I said, we have so many medications that target the immune system. But what that means is we're able or we try to prevent the formation of new lesions or lesions at all, right? But what about the lesions that are already there? How do we reverse them? Repair them and fix the damage? So we do not have a treatment that directly targets that and it's complicated and why we haven't found it yet. There are many, many labs from around the world that are coming at this from many different angles and many different types of approaches that I think we're actually we're on our way there to to get an understanding what the targets need to be to actually re-myelinate and repair the brain. And the parts that make it complicated is something that affects the white matter might not work the same way as it does on the Gray matter, which is where I I study, but it seems to be what underlies part of progressive disease in ways that we don't understand because we don't have the right biomarkers to follow in clinic. So the other big thing that we really need to develop is a clinical biomarker that tells us that repair has occurred in the brain directly because of an intervention we did. And so again there are many people that I work with and also around the world and myself that are trying to figure out how can we identify, develop, and use biomarkers from the blood from imaging to say we have intervened, we have fixed the lesion, and this will make this person’s life better.
Any views expressed above are the author's own and do not necessarily reflect the views of MD /alert. This transcript was digitally generated and edited for clarity.
Video: The Challenges of Diagnosing and Treating Progressive MS
Progressive MS is characterized by progressive worsening of neurologic function that can either onset with or without a history of relapsing/remitting MS.
According to Stephen Krieger, MD, Associate Professor of Neurology at the Icahn School of Medicine, progressive MS presents numerous challenges related to diagnosis and treatment.
What are the biggest challenges that need to be addressed when it comes to treating progressive MS?
Well, you know we've made so much progress in relapsing MS in the past 20 years. And I really think that MS is almost a tale of two cities at this point. If someone walks into the office or comes in for a telehealth visit with early relapsing MS, we have more treatment options than can possibly talk to her about -- a real abundance of choice. The ability to personalize treatment, the ability to use great data that guide what we do for her. But when a patient comes in, who has longstanding and progressive multiple sclerosis, someone who has already accumulated a lot of disability for instance, our choices narrow down really profoundly, and we have far less data to guide what we can offer. We have far less assurance that we can stabilize the disease process and turn it around.
And so it really is two opposite problems. It's almost as though we live in a modern era for relapsing MS. But we still fall back on very few options for progressive disease. And you know to go one step further with that. the categories of relapsing remitting and secondary progressive and primary progressive MS have been incredibly useful for the past 20 or so years in defining these phenotypes, organizing our clinical trials, and giving us outcomes that we can use to measure the success of our treatments. But, in reality, in clinical practice, I think it's often very hard to know what kind of MS someone has. Do they still have relapsing remitting MS? Has someone begun to develop signs and symptoms of progression? When does that transition point between relapsing remitting and secondary progressive MS even happen?
This is something I've tried to address with the work that I've done modeling MS disease course with something called the topographical model of MS, which really suggests there's a huge overlap between these different types and that individual people with MS may have some relapse activity and some progressive disease. And it's sort of up to the clinician to elucidate which things are driving that patient's disease course. So in point of fact, it's not always obvious who has progressive MS, how fast they are progressing, and how that's going to guide our treatment options. So there's certainly unmet needs, and treating progressive diseases is also unmet needs in knowing how to recognize progression when we see it, and ideally stop it from happening even before we see it, before it manifests clinically In an above threshold way that the patient is very aware of. And then of course we have the challenges of meeting to develop and have approved medicines for progressive disease that will truly stop the gradual, insidious progressive process.
What are the diagnostic challenges associated with progressive MS?
Well, everyone learns that multiple sclerosis often begins with relapses, and it often does. Episodes of optic neuritis, brainstem symptoms, spinal cord attacks that evolve over weeks and recover. But when someone presents with just gradual neurological deficits, insidious progression, the differential diagnosis is just much wider. Those patients don't come in with the sort of calling card of multiple sclerosis, so it is often a windier diagnostic path where someone who has progressive onset at mass, what we call primary progressive MS, may see their primary doctor 1st and then an orthopedist if they think it's a bone problem or a joint problem or a leg problem before they finally get to a neurologist that then will initiate a work up for perhaps progressive weakness, which itself is a pretty broad differential diagnosis within neurology.
It's only when the work up is done. MRI scans reveal lesions that are characteristic of MS, perhaps a Spinal Tap is performed to show the CSF findings of multiple sclerosis oligoclonal bands, for instance, that a diagnosis of progressive onset MS, Primary progressive MS, is made. So that initial diagnostic process is a bit of a conundrum often and takes a little longer to happen.
On the other end of the spectrum, someone who has relapsing remitting multiple sclerosis, their diagnostic process is not over. So I always tend to think that the neurologist needs to continually reassess is this patient experiencing relapsing remitting MS with disease stability? Do they have disease activity? New relapses or lesions? Or are they starting to develop insidious progression which invokes this phenotype transition from relapsing remitting to secondary progressive MS? Or the way I tend to think about it, a loss of reserve that is occurring it is gradually unmasking the burden of disease that they have accumulated and manifesting in a gradual, progressive way. So I think the diagnostic process for progressive MS happens at the beginning, but it also happens anywhere along the way with somebody's MS diagnosis and management.
How does treatment for progressive MS differ from treatment for relapsing/remitting MS?
Well, you know, obviously there's been a lot of work and discussion of the need for development of medicines that fundamentally treat in a disease modifying way progressive MS. We have medicine that has had successful phase three trials and approval for primary progressive MS with ocrelizumab. We have medicine that had a successful trial and secondary progressive MS which is siponimod. It was approved for relapsing forms, but the data is that it worked in a secondary progressive MS population. And then we have this notion of treating active SPMS with our relapsing agents. But there's an understanding there that we're not fundamentally necessarily stopping progression itself. So I do think that's a huge unmet need. But your question is about what we do for the progressive MS patients, and I think that's an important question.
All of our talk and research into disease modifying therapies is very future focused. Preventing future disability which is important to be sure. But, how we treat our progressive MS patients now, I think largely involved what can we do to improve their quality of life today and address their symptoms, and optimize how they navigate the world with MS in whatever way MS is effective. So I tend to think that symptom management is important always. But it takes an added relevance in the context of progressive MS, because these are people who have symptoms to treat and disability or other limitations from their multiple sclerosis that need to be handled. And so this includes everything from fatigue, which is a huge symptom and huge cause of morbidity and disability in MS. So fatigue is important. Gate limitations, weakness, spasticity and the various ways that spasticity can limit someone's quality of life with multiple sclerosis. Pain and sensory symptoms from MS, Cognitive symptomatology with multiple sclerosis, which is being increasingly recognized. An unmet need also in terms of treatment, but needs to be better evaluated, studied, tracked, addressed for people with this disease and a whole host of other symptoms.
I just I really encourage neurologists and primary docs and anyone else who's looking at people with their MS, particularly progressive disease, to focus not only on what we hope to be able to do for them for the future, but what we can do for them now and to help their quality of life now. And so when I give, you know, talks at national meetings and the like, when I give talks in national meetings I I really try to focus as much on symptom management as I do on disease modification because I think it's what matters to our patients now and also will increase their trust in their providers. Because you know, if we, as neurologists are focused only on the MRI scan and the metrics for future performance, we might miss opportunities to help somebody that are right in front of us. And so I try to look for them.
Video: Mesenchymal Stem Cells Appear Safe, Effective for Progressive MS in Early Trial
In a phase 1 study released earlier this year, researchers found that autologous mesenchymal stem cell-derived neural progenitors appeared safe and effective among a small group of patients with progressive multiple sclerosis.
Saud A. Sadiq, MD, FAAN, co-author of the study, and director and chief research scientist at Tisch MS Research Center of New York, discusses the ongoing phase 2 trial and how this therapy may provide a much-needed option for patients with progressive MS.
What does the current body of evidence say regarding stem cell treatment for the treatment of MS, especially progressive MS?
We’re still unsure of whether stem cells have a role to play in regeneration and restoring disability in patients with progressive MS. So just to just to restate in progressive MS by definition, almost there's some level of disability in these patients, whether they're primary progressive or secondary, progressive MS. And so one of the strategies that we've been interested in and other people who have been using stem cells is to see if they can use terms of therapy to repair. And it's still at the clinical trial stage in every sort of legitimate clinic that's doing it. There's a lot of places in the world in that they profess to give stem cells in various parts of the world where it's unregulated. I'm not counting those clinics. But where people are sort of, the scientists are doing trials, I don't think it's a proven therapy, but there are phase one phase two trials going on that will establish what their exact role is.
How does the therapy work?
The basic principle is the same and I just want to make one point which is very misunderstood and you I just think I want to get that out of the way first. There is a stem cell treatment so called in inverted commas. If you want to put it, that's how you know HSCT, which means you ablate, the immune system and reset it and use hematological or blood stem cells to repopulate the immune system. That, sometimes at least by patients is often confused with what we're doing. I just want to point out that is nothing to do with what I'm going to talk about. That's as far as I'm concerned that is a very radical but maybe effective treatment in, and there's an MS Society information page on it and a directive. And it's like the ultimate disease modifying treatment with its own risks. So I'm not speaking about, you know, using immune therapy. This is a reparative therapy.
So the challenge is that the CNS provides is that it's not cartilage, it's not cardiac tissue, it's really neurological tissue. So where you deliver that is a problem. And how do you deliver them, and what kind of stem cells do you want to deliver that will actually induce neurological repair? It's not like because some of the stem cells that we use and they are derived from either the fat or the bone marrow, or we don't use embryonic stem cells because of regulations, they these cells by nature, they called mesenchyme of stem cells taken from the bone marrow of patients or fat. They readily form bone tissue or cartilage and you don't want that kind of so called ectopic or in a location in the central nervous system so there is some challenges that the central nervous system presents if you're going to use them, but the basic principles you could say are the same.
How does this approach compare to currently available treatment?
What's available now is basically effective ways of treating relapsing remitting multiple sclerosis so that you don't get a secondary progressive stage. If you're really ideally you've got no disease activity, or They call it NEDA, no evidence of disease activity in an early diagnosed MS patients. But for as you get more progressive, in some patients with the disease, modifying agents will become less effective and certainly for primary progressive MS, even though there are drugs that have been just approved, it may not be that effective in preventing for real progression. And so the disability accumulates and for that group of patients where there's disability there's nothing yet at the moment in the therapeutic arsenal that's FDA approved that can actually not only stop disability, but perhaps it gives some sort of repair.
What do you see as the future of stem cell therapy for MS treatment?
So there are a few centers doing it. Very few that are FDA approved. We have one of them and the other centers are pretty much at the same sort of stage of development. So the first phase is usually a small trial that we did a few years ago that was monitored by the FDA to establish safety and efficacy. In our case we use stem cells taken from the bone marrow that have been changed into what we call neural progenitors, or cells that will only make neurological cells hopefully, and then we injected them into the spinal fluid and we give three treatments every three months, and that is a phase one trial that established safety. Investigators in the Cleveland Clinic, Johns Hopkins and not Johns Hopkins, Israel at Hadassah, and at a few of the one of the centers have shown that that was safe, and I think the safety and even tolerability of this approach has been really established in multiple places.
We moved on under the guidance of the FDA to a phase two study which is to establish efficacy. It's a four year study with 50 patients. All of them are going to be getting placebo and or treatment is a crossover design or a parallel group design where they'll get six injections of placebo and six injections of stem cells that during year one or year two and then they crossover and get the alternative and then. But it's 50. because of how low capabilities are. It's a four year study that started in 2018. It's double blind. We haven't done an initial analysis. And in 2022 we should hear whether it works or not. It included secondary progressive and primary progressive patients and we have them at various levels of disability. There are patients are ambulating without any assistance to patients were ambulate with either a single support or bilateral support, so we'll get an idea of whether it works at all in secondary progressive or primary progressive, whether it works in patients who are very little disabled or not, or whether it doesn't work at all. So in another year and a half, we should have a good idea about at that from our study. There is some studies that are coming out of Israel and elsewhere in the United States. One of the centers that is almost at the same kind of stage of development.
Photo Credit: Tisch MS Research Center
Video: Developing Better Treatments for Progressive MS
The mechanisms of progressive multiple sclerosis (MS), unlike the relapsing form of the disease, are not well understood and effective treatments are limited.
Robert Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis and the vice chair for research at the Neurological Institute of the Cleveland Clinic,
discusses the difficulties of developing effective therapies for progressive MS and how researchers are approaching this challenge.
How does treatment for progressive MS differ from treatment for the relapsing stage?
Well, MS, in general, has an embarrassment of riches in that we have over 15 FDA approved therapies for the relapsing stage. The early stage of MS. And we really have been able to get that disease, that stage of the disease under very very good control in the vast majority of patients.
Now, there's then this later stage called Progressive MS. When it follows the relapsing stage, we call that secondary progressive secondary following relapsing. But some patients go right into progressive from the very beginning, and we call that primary progressive MS. Well, those two forms of the disease, we have a lot less effective therapy available right now. And part of our error was we took effective therapies for relapsing MS, and we just slapped it into progressive MS Trials and expected them to work, and they didn't work. They didn't work, hardly at all. And so we had to scratch our heads and say, alright, well, why is that?
And we had a couple that worked a little bit, and indeed we have one that's now FDA approved for primary progressive MS. But where we saw successful studies in progressive MS --- either primary or secondary progressive MS --- it was at the very early stages of those diseases. And the benefit was predominantly in patients with active inflammation. They either had ongoing clinical relapses, or they had new or active lesions on their brain MRI. So it is that kind of left shift towards the very beginning of progressive MS when aspects of the relapsing form of the disease was still present.
So, what we've come to realize now is that progressive MS is probably a very, very different disease from relapsing MS.
Why have effective progressive MS treatments been harder to develop?
Well, I think for a while we were looking in the wrong place in that we were saying, hey, we got a therapy for relapsing MS slap it in a progressive MS trial and it should work an almost always they didn't and when they did work it's because they were progressed to patients that had enough active inflammation persisting or superimposed that an anti-inflammatory therapy would work. But I think the main issue is we don't really know. We don't really know what is driving progressive MS. And like many diseases, when you don't know what's really driving it forward, it makes it really hard to develop a therapy. If you don't know if it's compartmentalized inflammation, if it's accelerated aging, if it's metabolic exhaustion, depending on what the right answer is, that can get you in a very, very different direction in terms of treatment.
How are researchers approaching developing new treatments for progressive MS?
Well, there are a number of different ways this is being approached, and this is definitely a very, very active area of research. One is basic scientists have leveraged different models, which we think recapitulate what's going on in progressive MS and have been leveraging them to test out different molecules. Now, are they the right models? We don't really know. We're hoping they are. But they may not be so. But you gotta do something. You gotta start somewhere. So basic scientists are leveraging different models which they think are recapitulating what's going on in progressive MS.
Secondly, people are trying to develop better biomarkers for use in proof of concept clinical trials. Right now, what we're stuck with is doing a big phase three trial with 1000 or 1500 patients and saying did it work or not. And when it doesn't work, we say wow, OK, well that was a loss of 100 million or 150 million dollars. Not a good way to develop drugs. So what we want to do is develop sensitive, responsive biomarkers to apply in shorter, more focused phase two trials, what we call proof of concept trials that can be done more quickly and can be done with fewer patients and lower costs, which will then allow us to do more trials at once to identify potentially promising therapies.
And that said, there are still many groups who are just diving in who are saying, you know what, I think I have enough data to go forward with the phase three trial. And so there are several groups that are doing phase three trials, even though there isn't the compelling data, just because we don't know how to develop compelling data to do those trials. So in a number of different ways, from the basic scientists to the translational scientists, to actually doing the clinical trials, the work is still carrying forward.
With limited options, how do you approach treating patients with progressive MS?
It's tough. It's difficult to tell these patients you know what right now we don't know how to stop the gradual little by little decline in your function. Now, there are things we can do. And these patients tend to have a lot of different symptoms that are disrupting their daily function. And with almost all of those symptoms, there are things we can do to help relieve their difficulties. Relieve the leg stiffness, help with their bladder dysfunction with sexual dysfunction with walking difficulties with pain, with tingling. There's a lot of things we can do to help patients.
Now some will say, well, that's just a band-aid. Well, it may be a band-aid, but if it's making your day go better. If it's making you have to go to the bathroom less frequently and not have accidents, probably that's a good band-aid, So there are ways that we can improve patients’ quality of life. And that's where we're focused right now until we can identify a therapy that will truly slow the gradual little by little decline in progressive Ms.
Are you optimistic about where treatment will be 5-10 years down the road?
Absolutely. When I came into this field 20 years ago, we had two FDA-approved therapies for relapsing MS, and both of them were only modestly mildly effective. And then we got a third. And then it's just blossomed since then. We now have generic preparations for many of the drugs, which have brought down the cost and made it more accessible for patients to get on these therapies. So we really have had dramatic success. But the way we had dramatic successes, we understood the biology of relapsing MS. We had good laboratory models of that biology, and we had a good Phase 2 proof of concept marker. To try out new drugs. If we can make that progress and progressive MS understand the biology, develop good laboratory models, develop sensitive, dynamic, and validated Phase 2 proof of concept marker, then I think that will open up the floodgates for us to test a lot of therapies and find things that work.