Professor of Neurology, MedStar Georgetown University Hospital

Robert K. Shin, MD

“As we've seen at AAN and other meetings, data using different biomarkers, whether it's optical coherence tomography, serum neurofilament light, other biological markers, volumetric MRI, other more investigational MRI markers—what's the common theme? We're seeing that neurodegeneration occurs from the beginning of the disease process, if not probably before the patient's even aware or the providers are even aware of the diagnosis. I would say, rather than two different stages, we now see them almost as overlapping. We see that there is a progressive neurodegenerative component that is occurring, as best we can tell, probably from the beginning of the disease process that is punctuated by relapses.”

In the three decades since the first multiple sclerosis (MS) therapeutics were introduced in the 1990s, much progress has been made in developing effective and disease-modifying therapies (DMTs) for the disease. Now, even more novel approaches, such as those targeting Bruton tyrosine kinase (BTK) inhibition, or those with varied dosing options, are being explored to improve upon other aspects of disease management—particularly quality of life.

Despite this progress in improving treatments, though, many patients still utilize older drugs. Often, this can be related to their disease status, or to reduce the risk of unwanted adverse effects, or other reasons. Shared decision-making between patient and physician helps to result in a goal of treatment: optimization. That has also driven conversations about induction vs escalation strategies for the use of DMTs, and although the field appears to lean more toward induction—beginning with aggressive, high-efficacy treatment—a furthered understanding of the disease pathology has somewhat muddied the waters.

For Robert K. Shin, MD, professor of neurology, MedStar Georgetown University Hospital, the conversation about the state of treatment for MS is reflective of a shift in thinking from the field. In a conversation with

, he spoke about the changes in thinking that have occurred since the 1990s and what trends are appearing in the approach to disease management.

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The professor of neurology at MedStar Georgetown University Hospital shared his perspective on the trends in thinking about the treatment of MS and how an improved understanding of underlying processes has led to a shift in the field. [WATCH TIME: 5 minutes]

The State of Multiple Sclerosis Therapy and Trends in Thinking: Robert K. Shin, MD

Actually, it's more than a quarter-century as I think about it, right? We're approaching 30 years—3 decades—of having approved therapies for multiple sclerosis. And some of the medications that were approved in the early 1990s are still being used today, which is kind of amazing. However, I think that with some of the data that that's been presented now, we're doing more and more head-to-head studies with active comparators. I think we can say that certainly for patients with active MS, we can see that there's a difference. That some MS therapies are more effective than other therapies, I think we should just be honest about that. They're not all created equal. And it doesn't really matter whether we focus on relapse rate or MRI parameters, disability progression, or combining them together into a metric like No Evidence of Disease Activity, whether it's NEDA-3 or, if you incorporate other components, NEDA-4. For the first time, we can say, Oh, if I use drug X over drug Y, I'm going to have a greater chance of seeing no evidence of disease activity. 

I think that MS might be not totally unique, but unlike in some other fields of medicine, we have not agreed upon a firstline therapy. We don't have a consensus that when somebody is diagnosed with MS, we should start with drug X, and then if that's not tolerated. That kind of thing, which is common in other disease spaces. We just haven't come to a consensus in this space. But I think that if we look at studies that we're seeing reported out today, and what I think you can really see is that we should be honest and say that there are therapies that are more effective than others, there are strategies that will be more likely to result in shutting down of the disease process than others. Again, in our field, we're still debating sort of the timing of that optimization of our strategy. 

But I do think that maybe there's an increasing shift, a recognition, that with the advent of therapies with greater efficacy, at least that option exists. I think more and more people are looking at using them earlier in the disease course rather than waiting until disability is apparent. And so to me, this is a positive shift. One thing I think that's kind of changed even how we think about MS, in terms of its clinical course, is the different disease processes. Because I do think in the past, we really thought in a very binary way. We thought that people would present with a relapsing form of the disease, and you know, heaven forbid that you transition into phase 2, like a progressive form of the disease. As if there's sort of this wide gulf between the two. Hopefully, you would never cross over in that regard. As we've seen at AAN and other meetings, data using different biomarkers, whether it's optical coherence tomography, serum neurofilament light, other biological markers, volumetric MRI, other more investigational MRI markers—what's the common theme? We're seeing that neurodegeneration occurs from the beginning of the disease process, if not probably before the patient's even aware or the providers are even aware of the diagnosis. I would say, rather than two different stages, we now see them almost as overlapping. We see that there is a progressive neurodegenerative component that is occurring, as best we can tell, probably from the beginning of the disease process that is punctuated by relapses.

My opinion of why we were, I guess, misled is because of the existence of reserve, right? The ability of a young healthy person to compensate for the early stage means that it created the illusion that everything was fine until reserve runs out, and then the progression is more obvious. So to me, this has been the biggest shift in our understanding of the disease process because what this means is that we are developing a heightened sensitivity to any signs of progression. In other words, rather than waiting until somebody suddenly needs to use a cane or walker, what's the focus? Everyone's interested in things like cognition and biomarkers and different things to recognize this component as early as possible, really setting the stage for theoretically, hopefully, another class of therapies that will be to be particularly helpful for that. So there's been this shift, I would say, in sort of our thinking about MS, which I find very exciting because I think this maybe bodes well for the future. But as we discussed earlier, there are still some important steps that are necessary before we'll know how to best address that.

Discussing the progress made in therapeutic approaches to multiple sclerosis, Robert K. Shin, MD, shared his perspective on how the focus on treatments has shifted in the community.

Progress in MS Therapeutic Development and Shifts in the Landscape

I think one thing that's been happening in the MS space is that we continue to make progress in terms of our treatment options for multiple sclerosis. So it's been now, about a quarter century of therapeutics, but new classes keep being developed. And if we're honest, we keep getting increasingly effective at treating, at least, the relapsing form of disease. It does seem like there is an increased interest in also figuring out how we can prevent accumulation of disease progression over time. 

I could say, as a general statement, that there has been a lot of interest in a new class of potential treatments for MS, the Bruton's tyrosine kinase inhibitors—the BTK inhibitors. We're hearing a lot about them. We're seeing posters and more research, preliminarily, as well as the recruitment for the next phase 3 studies to look at the efficacy of this class of medication. That's really what I've been most interested in, is seeing where we're going to go in the future. With BTK inhibitors, I think what's interesting—and maybe takes us to a place we haven't been before the MS space—is multiple companies are developing multiple versions of BTK inhibitors, more or less at the same time. Some products are a little bit farther in development than others, but it's kind of remarkable to see 4 or more BTK inhibitors being actively looked at and evaluated at the same time. 

Now, I would have to say that although there's a lot of promise in this class, we don't know if it's going to pan out. For example, we are seeing in the earlier studies an effect on, let's say, MRI parameters, right? Those are markers of active inflammation, or if you will, markers that certainly typically correlate with the relapsing component of the disease. But the promise of BTK inhibitors, the possibility that they can act centrally on things like microglia, or do things that might reduce progression over time, perhaps treat the focus on compartmentalized inflammation or smoldering—whatever term you'd like to use for that. That promise has yet to be realized. We will have to find out. 

Another challenge in evaluating the class of BTK inhibitors will be things like the tolerability of these medications. A lot of the studies seem to be showing a dose-dependent relationship, meaning the higher dose, the more effective the medication seems to be. But, also with higher doses, there is a potential for tolerability or safety issues. We've seen that in other spaces where BTK inhibitors have been evaluated other than MS. So, I would say it's exciting as a possibility, but we're really going to have to wait for the data to find out if they are all effective, if some are better than others, if some are effective in one way and others in another. This is yet to be established.

Robert K. Shin, MD, offered his perspective on the novel therapies being developed for multiple sclerosis, highlighting the potential of Bruton tyrosine kinase inhibitors for progressive disease.

Robert K. Shin, MD

Articles

The State of Multiple Sclerosis Therapy and Trends in Thinking: Robert K. Shin, MD

Progress in MS Therapeutic Development and Shifts in the Landscape

BTK Inhibitors and Novel Approaches to Multiple Sclerosis

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