Conversations in Progressive Multiple Sclerosis

Patients with multiple sclerosis and depression are at an increased risk for vascular disease and mortality, according to a recent study published in Neurology. 

Barbara Giesser, MD, neurologist at Pacific Neuroscience Institute in Santa Monica, California, who was not directly involved with this study, spoke with MD /alert about the study findings, as well as her own experience treating multiple sclerosis patients.  

When treating a condition like multiple sclerosis, Giesser says, it is imperative to look at the whole patient. This holistic view is the key to improving clinical outcomes with multiple sclerosis especially with this well-established link to depression and an increased risk of vascular disease and death. 

What was the background for this research and what did the study examine? 

I think this is a very important study. It’s a very well done study, and the authors have a very distinguished track record of doing work in this area. One of the senior authors in particular, Dr. Ruth Ann Marrie, has published quite a bit of work in the area of MS and comorbidities in vascular disease. This particular study had the merits not only having very skilled and experienced investigators, but it was a very large population study with just under 85,000 people in this study, and they followed the people over almost three decades.  

The main conclusion of the study, the main thing that was determined was that, unfortunately, there seems to be an additive effect between having MS and being depressed in terms of having an increased risk of dying. What they also determined, some of which had previously been described, is that there was an increased risk for vascular disease (cardiovascular disease, atherosclerosis)., MS increased that risk, and being depressed increased that risk. So we have an interplay between a couple of risk factors here. 

What are your thoughts on these findings?  

Again, we have had some work in this area, it's been known that there's a higher incidence of vascular comorbidities, in people with MS. There's also literature that depression seems to increase the risk of vascular events. We sort of had some background for this. This is one of the first studies to put everything together and look at if there's any synergistic effects. Unfortunately, there do seem to be, again, independent of other variables that might contribute to vascular disease, or dying. 

What role do these synergistic effects play in someone with multiple sclerosis? 

There seems to be an increased risk of death if you have MS and depression, as compared to if you just have MS, or if you just have depression, so they seem to be working in concert. It's not entirely clear why. The authors have some speculation about this. We've known for a while that if you have MS and if you have a vascular comorbidity, that you have worse neurologic outcomes. This paper just added in the effects of depression. I think the very important take home message from this paper, there are a couple, one of which is that it's very important to screen for depression and treat it appropriately in people with multiple sclerosis.  

I think the other take home from this paper is that, and the authors have alluded to this, you can't treat MS in a vacuum, you can't ignore other medical conditions, again, particularly in this case, vascular comorbidities, and you want to really address the whole person and not just focus on the neurologic condition or just focus on a medical condition. One of the obvious areas for future research, which are pointed out in the paper, is that if in people with MS if the depression is appropriately addressed and treated, can this improve vascular and mortality outcomes down the line. One would think it might, but that research needs to be done. I think that this may lead us into a discussion of the importance of treating the whole person, the importance of lifestyle factors in persons with MS.  

What do you think are some next steps to continue this research? 

A sort of obvious next step would be to do a trial in people who had MS and depression and perhaps cardiovascular risk factors, and very aggressively treat the depression and see if the cardiovascular outcomes and the overall neurologic outcomes were improved just by treating the depression. I think you could also do the flip side of that and see if people with MS and depression who have very well managed cardiovascular risk factors if they have better psychological outcomes. I think the practical message for healthcare professionals is how important it is to screen for and treat depression and look at people with MS as a comprehensive whole and take together medical management, lifestyle management, management of other medical conditions. 

Disclosures: Giesser did not declare any financial ties to drugmakers. 

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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.

Photo Credit: Getty Images

Tolebrutinib, an oral BTK inhibitor, significantly reduced new lesions among patients with relapsing and progressive forms of multiple sclerosis, according to a 12-week, placebo-controlled phase 2 trial.  

Robert Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis and Vice Chair for Research at the Neurological Institute at Cleveland Clinic, discussed the results from the randomized, dose-finding trial with MD /alert, saying this new medication could improve inflammation control.  

Of the four doses studied, the 60 mg dose was found to be most efficacious and was well-tolerated.  

What was the idea behind this research? 

We have some immunotherapies that decrease the frequency of the immune system attacking the brain and the spinal cord, but we're still looking for a better combination of efficacy, safety, and tolerability. This is a new line of treatment for multiple sclerosis. The BTK inhibitors or the Bruton tyrosine kinase inhibitors, which are just now being evaluated for whether they may be helpful in slowing down the inflammation that's involved in multiple sclerosis. So, this drug has two potential advantages, one as a BTK inhibitor, it can decrease the involvement of that molecule in the immune response in the peripheral immune response.  

But this molecule also crosses over the blood-brain barrier into the brain and spinal cord and can have actions directly within the brain and the spinal cord. And so we think multiple sclerosis starts as a disease of the immune system in the periphery, but then also goes and evolves within the brain and spinal cord to be an immune disease within the central nervous system. So, by having a drug that also crosses the blood-brain barrier and goes into the brain and spinal cord, it may have some actions there that may have relevance not just for the relapsing early stage of MS, but we're hoping also the later stages that we call progressive MS.  

What we found is that the highest dose, the 60 mg a day, was the best dose in decreasing new lesions on MRI. And in fact, compared to placebo, it reduced new lesions by 85%, so quite a robust reduction similar to what we see with our very highly effective anti-inflammatory therapies.  

Do you have a sense of whether this dose would be ideal for all patients but not all? 

It did seem to be the best. It was the best looking at… using statistical models to evaluate that dose-response and to look at the dose-response curve. And it was by far the most effective. And fortunately, it was a very well-tolerated dose.  

One of the tradeoffs we sometimes have to make is something working well, but it has a safety or side effect profile. And fortunately, this highest dose had a very favorable safety and tolerability profile like the lower doses as well. So, it does seem quite compelling that this is the right dose. Could there be an even higher dose? Well, maybe, but once you have an 85% reduction in the new lesions on MRI, it's hard to do much better than that.  

What did you see in terms of safety? 

In terms of the side effect profile, there really wasn't much that was seen more commonly in the treated patients than in the placebo-treated patients. So, there wasn't much of a signal. Now, one of the challenges with these studies is that they're very short duration, and they've enrolled a relatively few number of patients. With the highest dose, there may have been a higher rate of headache amongst patients treated with that higher dose, but it didn't seem to be associated with an early discontinuation of the drug during the trial. So, the safety and tolerability looked very favorable. But of course, we'll need to look at it in a larger number of patients, followed over a longer period of time. 

What about tolebrutinib makes it a compelling option for further study?  

It's a new line of treatment, so a new class of treatment. We don't have approved therapies that leverage the BTK inhibitor family of drugs. This is going down a new pathway that does not have any FDA-approved therapies. It is an oral drug, but we do have oral drugs. We do have oral drugs that have good efficacy. But we're still looking for that ideal combination of a very strong efficacy, good safety, and good tolerability.  

In addition, we have a very big unmet need in developing treatments for progressive MS for stopping the gradual little by little decline in neurologic function that patients often report after 15, 20, 25 years of having the disease. And so, because this drug does cross over into the brain and spinal cord and has activities that we think may be beneficial in multiple sclerosis, both relapsing and progressive MS, it is being studied not only in phase 3 trials in relapsing MS, but is also being studied in phase 3 trials in progressive MS, secondary progressive MS, and primary progressive MS.   

Disclosures: Fox receives consultant fees from Sanofi. He has received  personal consulting fees from AB Science, Biogen, Celgene, EMD Serono,  Genentech, Genzyme, Greenwich Biosciences, Immunic, Janssen, Novartis,  Sanofi, and TG Therapeutics. I have served on advisory committees for AB  Science, Biogen, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG  Therapeutics, and received clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. 

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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.

Photo Credit: Getty Images

The National Multiple Sclerosis Society recently put out guidance saying that patients with MS taking disease-modifying therapies should receive an additional dose of the mRNA COVID-19 vaccines. Julie Fiol, MSW, BSN, RN, MSCN, Associate Vice President of Healthcare Access with the Society, told MD /alert that an additional dose of the vaccine is different than a booster dose which has been discussed and encouraged for people who have already been vaccinated.  

In their guidance, the National MS Society encourages patients to talk to their health care providers about an additional dose of the vaccine, which are now available, as well as the optimal timing in relation to MS treatment and previous vaccination doses.   

What is the difference between an additional dose of the vaccine and a booster dose? 

Last week the national MS Society put out guidance for people living with MS to know when they should get an additional dose of the vaccine. But at the same time, the FDA and CDC started talking about boosters which apply to everyone.  

So, an additional dose is sort of what it says. It's an extra dose of the mRNA vaccine, so a third dose for people who have conditions that compromise or attenuate their response to the vaccine, saying they need an additional dose to help them have a similar level of protection from COVID-19 from the vaccine for those who do not have compromised immune systems. And the booster is what everyone will be eligible to receive, and that is because the effects of the vaccine have been seen to be waning over time.  

So, starting in September, everyone who has been vaccinated with two doses of an mRNA vaccine would be eligible to receive a booster dose or a third dose of mRNA vaccine 8 months after they had their primary series of vaccines. 

What was the goal of the release from the Society? 

The goal is to make people aware that there is an additional dose authorized for people who have compromised immune systems. And particularly when we think of people with MS… MS is not a condition that in and of itself compromises the immune system. It doesn't weaken how the immune system behaves or it doesn't change the immune system's ability to mount a response after vaccination. But some of the disease modifying therapies that we use in MS can do that. So, it was important for us to let people with MS and their health care providers know that an additional dose is available to them. 

What we're seeing in the data from vaccine response for people with MS who use certain disease modifying therapies, we are seeing that they do not mount the same response as the healthy controls or people who are not living or taking disease modifying therapies and do not have conditions that are compromising their immune system. So, we wanted providers and patients or people living with MS to know that this additional dose could be needed and that they are eligible to receive it now.  

How important is the COVID-19 vaccine for people with MS? How can providers best guide their patients during uncertain times? 

COVID-19 can be very serious. It can be fatal for people, particularly those, there are particular risk factors for people living with MS for worse outcomes from COVID. Some of those are very similar to the general population; Having older age or having other health conditions that they're living with.  

For people with MS being on a particular disease modifying therapy has been shown to lead to worse outcomes. Not necessarily death from COVID-19, but a more severe course. Even people who have mobility challenges, impaired mobility, or walk with assistance of a cane or a walker, or who use a wheelchair have worse outcomes. So, vaccination for all people, regardless of whether they live with MS is critical. It’s critical for public health and public safety. But it’s particularly important for people who live with MS.  

And it’s especially important for those who live with MS and have risk factors for worse outcomes. Hence why it was critically important to the Society to make people aware of this additional dose and encourage them to speak with their health care providers to find out if they're eligible to receive it. 

Are there more questions to be answered when it comes to COVID-19 vaccines for patients with MS? 

Absolutely. A lot of the data we’re seeing are showing us the antibody response to the vaccine. And what we’re seeing in people with MS is that some of the disease modifying therapies are attenuating their response, the antibody response. But what we’d like to learn is what does that mean in terms of protection from COVID-19? Is there a cellular response to the vaccine that will offer protection? And so, if somebody has an attenuated response to the vaccine, perhaps they're still protected. We need to learn more about all of the different disease modifying therapies, and larger studies, more numbers of people to confirm which ones are attenuating their response to the vaccine.  

And I think the most important thing is what really confers protection from COVID-19? Is it the antibody response? Or, as we're starting to see there is one study that shows a T-cell response, a robust T-cell response for those who do not, who have an attenuated antibody response to the vaccine. So, does that mean that people with MS are protected from COVID-19?  

We need to learn how many… is an additional dose necessary and the best data that we have so far tell us yes. But, how, you asked, should they have a fourth dose. And so, we need data to show whether they need a fourth dose. And so, there is still much to learn in terms of the response and the protection for people who live with MS, use of certain or any disease modifying therapy, and how protected they are from COVID-19 after vaccination.  

How can patients with MS find out if the vaccine is giving them the needed amount of protection from the virus? 

The FDA has urged clinicians to not order antibody testing because we just don’t have the data to show whether or interpret the results after somebody receives a vaccine and gets antibody testing. The antibody tests were designed to show if someone was exposed to the virus, but not necessarily to indicate the level of protection. So, clinicians are… people are getting their antibodies tested. But we don’t necessarily know if that means they’re protected or not protected. So, that explains some of the anxiety people have. Or someone with MS on a disease modifying therapy that attenuates their antibody response to the vaccine gets an antibody test and sees that they don’t have antibodies. So that creates a lot of anxiety, a lot of questions that there still aren’t answers to.   

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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.

A new study has identified a possible cause of progressive disability among patients with multiple sclerosis. Researchers examined patients with one of three demyelinating diseases and found that patients with MS have areas of inflammation which can cause scarring that may lead to slow worsening disability. 

Eoin Flanagan, MB, BCh, a professor of neurology at the Mayo Clinic spoke with MD /alert about the study.  

By further studying related demyelinating diseases where inflammation tends to reverse and scars do not form, researchers may be able to identify new treatment targets for MS.   

What was the idea behind this research? 

I think we have not really studied very well, you know, what happens to these, lesions or white spots on the brain that we see during attacks of MS and these related diseases: the MOG antibody associated disease and aquaporin 4 positive NMO spectrum disorder. And we had recognized that with this new diseases, MOG antibody disease, that patients would often have areas of abnormality that would come, and then when we'd follow them up, all of the areas would be gone away. And with MS, what we tend to see is that when a new lesion comes, it tends to stay, and that's why we monitor MRIs in patients with MS to see if there are new lesions that have come because they tend to stay and leave a little scar, I suppose on the brain. 

So that's part of the reason why we do the MRI's every so often. But with this MOG antibody disease, what we recognize is that the lesions tend to go away completely. And that fits kind of with these patients having a good prognosis and in the long term not developing any of this progressive disability. So, what we're wondering is in MS, and this is somewhat speculative, but we're wondering if those areas of scarring and those lesions that stay there contribute somewhat to the patients developing that progressive course of disability. Because we think that if they resolved completely, then maybe they would not get that. 

How did you conduct the research? 

What we did was we looked at the three diseases: the patients with multiple sclerosis, with the MOG antibody disease, and with the aquaporin 4 positive antibody positive NMOSD. And we took their MRIs from when they had an attack, an acute episode, and then we looked at the MRIs and follow up more than six months later.  

And what we found was that the MS areas when they had an acute episode there would often be a large lesion there or a moderate size lesion and then it would leave a moderate size scar or residual lesion. While with the with the aquaporin 4 positive NMOSD it also would leave a small scar, small residual lesion. But with the MOG antibody disease, what we found in follow-up is that the vast majority of the areas of abnormality resolved completely. So this was kind of what we studied. And then we looked also at the size and the reductions in size of those areas of abnormality, and the reductions in size seem to be greater in this MOG antibody disease and the aquaporin 4 antibody positive disease versus MS, where they didn't reduce in size as much.  

And what we think, but this needs further research, is that that might give some insight because we what we know with the aquaporin 4 positive NMOSD and the MOG antibody is that they don't have that slow secondary progressive course that we see with multiple sclerosis, so we think that's some of those areas or lesions that are leftover may contribute somewhat to that disability.  

What does this mean for patients with MS?  

I think you know what it suggests is that you know the importance of treatments because what we know is the treatments for MS in patients with relapsing remitting MS is that if you treat them with some of our very effective medications that we have now available, that it reduces the number of some of those new lesions coming and it reduces the number of attacks. And we think if you can prevent those lesions, then the patients will likely have a better outcome in the long term. So, the idea would be prevent new lesions developing and then prevents cards from forming. And then we hope in the long term that that will help prevent against the disability developing. 

Could this change the way imaging is used or read in the treatment of MS? 

Doctors were already looking at this in MS. You know, we tend to monitor MRIs in patients with MS even when they're not having symptoms to make sure they're not developing those new lesions that might suggest that the medication is not effective enough. Because if they're developing new lesions, even if they're not having new attacks, we sometimes will change our treatment based on that to try and prevent, you know, those lesions from happening. So, this this was happening in MS. But in the MOG, antibody disease and these and the aquaporin 4 positive NMOSD, we weren't really looking at this as much. So, I think this tells us that those diseases are different and how these areas of abnormality evolve over time is very different. Because with the MOG, most of the lesions go away completely, which you know we would think should be a good thing if they resolved completely, that suggests that the body does a better job in repairing those than it does in MS. 

What is the future of your research? 

Well, I think we want to understand a little bit more about you know how do these areas resolve in the MOG antibody disease because all of these diseases are what we term demyelinating diseases, so they remove the covering from the nerves. And what we would like to know is how do these MOG antibody disease, how is it that their lesions resolves and you know, does that suggest that they put back on the covering of the nerves or what we term re-myelinate the nerves better than in MS? Or what are the reasons behind that?  

So I think we need to look further. But for now, it can help us, you know, diagnostically. If we see a patient in the clinic and we've seen them in follow up and all of their lesions resolved, then we might think well, maybe this is more the MOG antibody disease than it is MS where the lesions usually stay and never go away.  

Disclosures: Flanagan reports advisory boards roles for Alexion, Genentech and Horizon Therapeutics; speaker honoraria from Pharmacy Times, and royalties from UpToDate. Flanagan is member of the medical advisory board of the MOG project. In addition, Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. 

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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.

MRI use is a valuable and well-established tool for diagnosing multiple sclerosis. Mike P. Wattjes, MD, of the Department of Diagnostic and Interventional Neuroradiology at the Hannover Medical School, in Hannover, Germany and colleagues recently published updated recommendations for universal MRI usage guidelines in MS. 

Dr Wattjes discussed what prompted this position statement and how it differs from previous recommendations.  

Can you describe what prompted the need for a position statement and recommendations for MRI use in MS Patients? 

There were previous guidelines published by the Magnum Group and the CMSC Group in 2015 and 2016. Since then, our new developments have been published focusing on spinal cord imaging. But, in particular, there are issues around the accumulation of elemental gallium in the deep gray matter structure of the brain. In addition, there were new data [published] on pediatric MS, on progressive MS. So, altogether, this was motivation for us to reconvene to revise the previous guidelines published in 2015 and update the guidelines.  

But also to bring several groups together. So, the initial guidelines were established by separate organizations like the Magnums Group and the Consortium of MS Centers, but the aim of these guidelines was to combine and to harmonize the guidelines established by CMSC from North American Imaging, and Magnums, to one worldwide global transatlantic guideline paper. So, these were basically the motivations for us to reconvene and revise the guidelines.  

What were the most significant new or revised recommendations? 

The first big issue is the standardization of the image acquisition, not only from the brain point of view, but also focusing on the spinal cord. So, we stress the fact that 3-D flare sequences are basically the core sequences that should be used for brain MRI.  

But we also gave an update on image acquisition of the spinal cord in particular, focusing on sequences in addition to late echo T2-weighted. Proton density stir images were also an alternative from a highly T1 weighted 3-D sequences of the cervical spinal cord.  

What has changed the most since the last guidelines were released? 

I think we made a big step forward in terms of implementation of quantitative MRI techniques. And so, we use already quantitative or more techniques in the clinical trial setting. Also automated image analysis made a big step forward. So, I think we are pretty close right now to get this implemented in the clinical routine setting. At the current stage, we do not recommend the use of automated image analysis on a regular basis, also based on standardization issues. But I think in the next couple of years this recommendation might be revised that quantitative MRI techniques and also automated image analysis might enter the clinical routine for certain MS patients who need these more, this better phenotyping of microstructural damage.  

Where does MS diagnostics go from here? 

I think in terms of diagnosis, so, we basically reached now the plateau. So, we are extremely sensitive facilitating a very early MS diagnosis. In terms of treatment monitoring, we have good markers to detect subclinical disease activity. And so we have also markers to assess neurodegenerative changes. So, this means volumetric measurements.  

But the next step will be to assess neuronal repair and remyelination. And that’s a big issue because there is limited data on how to assess remyelination neuronal repair in vivo. So, there are a couple of quantitative measures used in the clinical trial setting. But this once again needs to be validated before this can enter the clinical routine settings. I think this will be our monumental task to get this implemented in the clinical routine setting in order to assess the potential effects of specific drugs on neuronal repair and remyelination. 

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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.

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. 

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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.

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.

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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.

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.

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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.

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.

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Photo Credit: Tisch MS Research Center

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.