Emerging Therapies in the Treatment of Progressive MS

Podcast Transcript

Alex Rae-Grant:  Neuro Pathways, a Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Welcome to another episode of Neuro Pathways. I'm your host, Alex Rae-Grant, neurologist in Cleveland Clinic's Neurological Institute. In an effort to explore the latest advances in neurological practice, today we're talking about emerging therapies in the treatment of progressive multiple sclerosis. I'm very pleased to have my friend, and a pioneering researcher in the field, Dr. Bob Fox, join us for today's conversation. Dr. Fox is Vice Chairman of Research in Cleveland Clinic's Neurological Institute, and a staff physician in Cleveland Clinic's Mellen Center for Multiple Sclerosis. Bob, welcome to Neuro Pathways.

Bob Fox:  Thanks, it's great to be here.

Alex Rae-Grant: Bob, I'd like our listeners to get to know a little bit more about you. Tell us a bit about yourself - where'd you come from, where'd you train and when did you begin your career at the Cleveland Clinic?

Bob Fox:  I grew up in New Jersey, on the east coast. I did my training at Johns Hopkins Medical School and the University of Pennsylvania for my neurology training, then came out here to the Mellen Center for Multiple Sclerosis at the Cleveland Clinic for a fellowship in 2000, and I've just stayed on here ever since.

Alex Rae-Grant:  Very good, we're glad to have you here. So Bob, let's talk about progressive MS. How do we define it, and how does it differ from relapsing MS?

Bob Fox:  We've made a lot of advancements in the last few years in understanding MS, and particularly in understanding how it differentiates from relapsing MS. What we've learned is that initially MS usually starts with episodes, the relapses, and it typically transitions to progressive MS. They're not two separate and independent diseases of manifestations, but they're actually overlapping. What we generally see is that the frequency of relapses and new lesions in MRI will decrease over years, and instead is replaced by a gradual, little-by-little decline. The little-by-little decline is most commonly manifest by walking, by decreased ability or duration or abilities to sustain walking. It can be seen with long distance walking, like a patient walking around the block.

It can also be seen climbing the stairs, where the patient may have been able to climb the stairs with a box in his or her hand in the past, but over time soon had to just walk up without anything in the hands, would have to stop at the top of the stairs, and eventually has to stop a few times up the stairs. The hallmark of this is a gradual, little-by-little decline. There can also be a decline in arm function, coordination, ability to do things with the arms, as well as cognition, memory and concentration, although the cognition part tends to be relatively non-specific, and that is very commonly reported by patients all across the spectrum of MS. It's really the gradual, little-by-little decline in the arms, and particularly the little-by-little decline in the legs, that is what is manifest as progressive MS.

Alex Rae-Grant:  So Bob, are there then different types of progressive MS, or do we think of them all as one? How do we classify progressive MS today?

Bob Fox:  Again, we used to think of them as two distinct diseases, or manifestations of MS. And now we see them as overlapping. In that overlapping, we have developed two different ways of characterizing progressive MS. One is whether there is the underlying progression, that little-by-little worsening in function, most commonly manifest in walking, but also arm and cognition. The other aspect is the active inflammation. It's what we think of with relapsing MS, the episodes, the clinical relapses, and the new or active lesions in MRI. So, in addition to the progression component, is their progression or is there not, is there active inflammation? Is there evidence of relapses in the last year or two, or new, enlarging lesions in MRI? Now, exactly how far back one goes to define the active part of progressive MS is not quite clear, but most people will think, “In the last year or two, have there been either relapses or new lesions in MRI?” That is what defines the active progressive MS. And if there haven't been relapses or new lesions in MRI, then we call that without active inflammation, or inactive progressive MS.

Alex Rae-Grant:  So Bob, talk to us a bit about the kinds of technologies we can use in monitoring people with multiple sclerosis. You mentioned hand function and walking function, but are there other things we can do to monitor over time the course of the disease?

Bob Fox:  Yeah, there are two main directions of measuring the progress and measuring the performance with progressive MS. One is what the patient is doing. It used to be the most sensitive thing that the neurologist used was measuring motor strength on exam, and measuring coordination on a direct finger-to-nose test, things like that, tapping the index finger on the thumb. What we've come to find is that that is a very insensitive way of measuring the progression or the worsening of function, and instead what we've adopted is functional measures, functional measures of how the patient is functioning out in daily living. Its simple things such as how fast a patient can walk a 25-foot walk, and how long it takes them to put nine pegs into a pegboard and then taking them back out, and a cognitive test of converting symbols into digits. What we've found is by measuring MS in that way, rather than the typical neurologist exam in the exam room, we have a much more sensitive, reproducible, and dynamically changing over time ability to measure the progression of MS. We also have new technologies as well.

We had been disappointed that MRI wasn't capturing the progression of progressive MS, or to put it another way, a patient will come in and will be very frustrated that the MRI didn't show any new lesions over the last few years but the patient says, “I know I'm getting worse,” and I can see the patient getting worse over time. We are starting to move beyond measuring new lesions. It's still a very important part of measuring the inflammatory aspect of MS, but it doesn't characterize the progressive part of progressive MS. So we have shifted to using the MRI in different ways. Some of the things that we're using is whole-brain atrophy, how much brain shrinkage is going on. That is a measure of the underlying injury or destruction of the brain tissue. Also looking at the spinal cord area, at the cross-sectional area of the spinal cord, and looking at that shrinkage over time. There's also some advanced MRI methods, like diffusion tensor imaging which measures the diffusion of the water within tissue, magnetization transfer imaging which is looking at the transfer of magnetization from the surrounding water into the tissue structure itself. We know that, as the disease progresses, magnetization transfer will go down as there's less tissue to receive the magnetization.

We also have new ways of measuring pathology, not just to the white matter that we traditionally have thought have been involved in MS, but also the gray matter, looking at gray matter pathology. Some using the methods I just mentioned, like magnetization transfer imaging, but also other things like PET scan to look at some of the components within the tissue, measuring how they dynamically change over time. We even have a non-MRI method called optical coherence tomography. That is a way that a light beam will shine into the back of the eye and will measure the thickness of the retina. We can measure that thickness gradually thinning over time, which is reflecting the neurodegeneration that we think is really driving the progression of progressive MS.

Now, these advanced technologies, the MRI and the OCT, whole-brain atrophy, diffusion tensor imaging, and optical coherence tomography, they are not ready yet to apply to individual patients. We're using them in clinical trials, and gaining experience, and looking to see how well they can measure the potential of neuroprotective therapies. But at this point we're not quite ready to apply the two individual patients and counseling them in individual patient visits.

Alex Rae-Grant:  So let me go back, Bob. I hear from the patients quite often this idea that, “Gee, my doctor says I'm doing fine because my MRI is steady and I'm not having relapses, but I know I'm getting worse.” You touched on that, are there ways we can explain, ways that doctors can explain, to their patients a little better how to think about that, how to put that into their head and their thinking?

Bob Fox:  I have struggled with the same thing, the same exact thing of the patient saying, “Doc, I'm confused. I know I'm getting worse, but you tell me my MRI is stable.” What I find helpful is explaining to patients the two underlying components of MS, the active inflammation that's manifest by relapses and new lesions in MRI, and then this neurodegeneration, or an accelerated neurodegeneration, which is accelerated by the previous injury of the MS, the relapses and the lesions in MRI. Even though we may have been able to turn off the inflammation, perhaps with a therapy the patient is on, an anti-inflammatory therapy, even though we stop the inflammation and they don't have relapses and they don't have more new lesions in MRI, the degeneration is still going on. So I've found it helpful to explain to patients those two different components, and how the conventional MRI only measures the first component, the new lesions on MRI. It's the corresponding MRI signature for the relapses that most patients are familiar with, but that gradual, little-by-little decline is not measured by the new lesions. That's why, even though they don't have inflammation, they're still degenerating. By explaining that, I can often get patients to understand those two different facets of their disease.

Alex Rae-Grant:  Yeah, Bob, it does seem to be important for us to validate their experience of change over time and recognize that we just haven't quite gotten there in terms of monitoring that fully.

Bob Fox: It's true, and to be transparent with our shortcomings. We can measure the active inflammation quite well with MRI; we don't measure the gradual, little-by-little decline, the degeneration that we know is the driving force behind the progression of progressive MS.

Alex Rae-Grant:  So Bob, let's change gears here at this point, let's dive a bit into the therapies for progressive MS. Can you talk a bit about how these therapies came about, including your research work, and where they're headed, and how we might use the available agents going forward?

Bob Fox:  Sure. Let me start with ocrelizumab. This is a drug that was approved a couple years ago for primary progressive MS as well as relapsing MS. Ocrelizumab is a monoclonal antibody that targets a certain type of immune cells, a certain type of white blood cells called B cells, and it knocks them out of the body, it kills them. This is an important component of the immune network that drives inflammation, and by knocking out these cells we can reduce the active inflammation very, very effectively. So we dramatically reduce the number of new lesions in MRI and dramatically reduce the number of relapses in relapsing MS. Now, as I mentioned, this drug was also evaluated in primary progressive MS. This was a phase 3 trial with a primary outcome looking at confirmed progression of disability in patients with primary progressive MS.

What this study found was a 24% reduction in the probability, or in the rate of progression of disability in patients with primary progressive MS. So this was indeed very encouraging. Now, 24% is not 100%, so it's still only partially effective, but it was 24% more than the 0% we currently had for treating primary progressive MS. Now, an important component of this study was looking at patients who had active inflammation at the beginning of the trial versus patients who didn't have active inflammation at the beginning of the trial. When that subgroup analysis was evaluated, what was found was that the patients who had active inflammation before the trial, or at the start of the trial, meaning they had gadolinium enhancing lesions at the start of the trial, they were much more likely to respond to ocrelizumab than the patients who did not have active inflammation.

There still may have been a modest benefit in those without gadolinium enhancing lesions at baseline, but it was still quite modest compared to those with. Now, this may not be surprising because ocrelizumab is a robust anti-inflammatory therapy. If one looked at the group of patients that were enriched for having active inflammation, one would expect it to have more efficacy. Another important component of this trial is that it enrolled patients who were quite young relative to primary progressive patients in my practice. It enrolled patients that were under age 55, and indeed we don't know how effective it is in patients who are older than that because they really weren't studied. The upshot of that is it does seem effective in primary progressive MS, but its efficacy seems to be limited in patients who don't have active inflammation. So I think patients who are perhaps older and don't have active inflammation at the time that one is thinking about ocrelizumab, it's very unclear if those patients will actually benefit from this drug.

Alex Rae-Grant:  So Bob, you'd say there's still room for other new approaches to treatment in the progressive population?

Bob Fox:  There absolutely is, and particularly drugs that are not targeting anti-inflammation, but drugs that may be targeting something else. We don't necessarily know what that something else is in progressive MS, but it appears that we need to target something other than active inflammation in order to slow down the progression of progressive MS.

Alex Rae-Grant: Do you want to talk a little bit about the research that you and others have done on ibudilast?

Bob Fox:  Sure. Ibudilast is an oral therapy, it's a pill, that was approved in Japan almost 30 years ago for asthma, and also some post-stroke symptoms. It's been used in humans for quite a period of time, and so its safety profile is relatively well-known. It was studied about 10 years ago in relapsing MS, and was found not to be helpful in relapsing MS in that it didn't reduce new lesions in MRI. But what it was found to do was to slow the progression of brain atrophy, or brain shrinkage, and do it in a dose-dependent fashion. So that raised the question of whether ibudilast may be useful in progressive MS, where we think inflammation is less of a driver of the pathology of progressive MS. The SPRINT-MS trial was a trial I was fortunate enough to lead, funded by the National Institutes of Health. It was a phase 2 placebo-controlled trial that enrolled both patients with primary and secondary progressive MS. What this trial found was that over two years in 255 patients, randomized at either ibudilast or a placebo, the patients treated with ibudilast had a slowing in the progression of brain atrophy, or brain shrinkage, over the two years.

That slowing was 48%, it almost cut in half the progression of brain atrophy in the ibudilast-treated patients compared to placebo. Now, there's a number of different biologic mechanisms where ibudilast acts, and which of that is responsible for its slowing of brain atrophy we really don't know. And whether the findings of brain atrophy in this phase 2 trial will translate to a slowing of disability progression in a phase 3 trial we really don't know. But this does establish a proof of concept, that this can slow the progression of brain atrophy, which is the most embraced outcome for a phase 2 trial in progressive MS at this point anyway there were also promising results from some of the other measures, particularly magnetization transfer ration, or magnetization transfer imaging, in cortical atrophy. There were encouraging findings there supporting benefit of ibudilast. So this is a drug that doesn't appear to be driven through an inflammation pathway, and has some evidence from a phase 2 trial showing that it may be beneficial in progressive MS. But phase 3 trials are needed to really evaluate the next stage.

Alex Rae-Grant:  Sure. Any other potential therapies that could target the progressive MS population that we should talk about?

Bob Fox:  Well, just recently we had approval of two therapies for secondary progressive MS. One is siponimod, this is a sphingosine receptor modulator, so it's a cousin of fingolimod, which has been approved for many years for relapsing MS. Siponimod is a cousin in that it works on the same receptors, but works on a different subset of the receptors. This drug was evaluated in a trial of secondary progressive MS, the EXPAND trial. It was a very, very large trial that enrolled over 1600 patients from over 30 countries that followed patients over several years. And what it found is that it slowed the progression of disability, or the sustained progression of disability, by 21% compared to placebo. So again, 21%, it's not the 100% reduction that we look for in therapies, but 21% is 21% more than we have for secondary progressive MS at this point. Like with ocrelizumab, siponimod was also found to have greater activity, or greater slowing of disability progression, in patients with active inflammation at baseline. That was defined as either having gadolinium enhancing lesions at baseline or having a clinical relapse in the two years prior to enrollment. Those patients seemed to respond better than patients who didn't have active inflammation.

And in fact, based upon that subgroup analysis the FDA approval in secondary progressive MS was for those with active secondary progressive MS. The FDA didn't define what they meant by active secondary progressive MS, so it's left us having to interpret that ourselves, but most people would consider that patients who have had either a clinical relapse in the last year or two, or new MS lesions in MRI in the last year or two. I also mentioned cladribine. This is a drug which was also approved for active secondary progressive MS. The surprising thing about this drug is that it actually wasn't studied in patients with secondary progressive MS.

This appears to be a regulatory decision where they have lumped relapsing MS together, and have included active secondary progressive MS in a general categorization of relapsing forms of MS. So this is a drug that, although it's approved for active secondary progressive MS, it hasn't been studied in secondary progressive MS, so we really don't know how this drug will work and how beneficial it will be in secondary progressive MS. But it's certainly an option that we can consider, and will merit further study to understand how this drug really does work in active secondary progressive MS.

Alex Rae-Grant:  So Bob, just to summarize a bit of what you said, it really sounds like we've moved from hard categorization into relapsing versus progressive, and really thinking more about how much inflammatory activity does this individual have, and how much does that set the stage for them to have active medication treatment. Would that be a fair summarization?

Bob Fox:  It is, we have overlapping pathologies. We have the active inflammation that we think is coming from infiltrating immune cells which are attacking the brain and the spinal cord and the optic nerve, and in parallel to that, and to varying proportions in different patients, we have a neurodegeneration which is probably set up by the previous injury, but continues separate and relatively independent from new active inflammation. Our current therapies are most effective in patients who still have active inflammation, although we have some promising directions for new therapies that may work outside of the anti-inflammatory pathways of our previous therapies.

Alex Rae-Grant:  So we talked a lot about medication for progressive MS. Anything else besides medicine that we do in the clinic, or that we suggest to people who have progressive MS for their care?

Bob Fox:  Yeah, we often forget, at least as a neurologist I often forget, that there are many symptom aspects of progressive MS which go along with progressive MS, and almost all of the symptoms of progressive MS have some treatment options, some treatment modalities we can consider. Going from the top to bottom, that can be mood disruptions like depression and anxiety, it can be spasticity, pain, pins and needles, swallowing difficulties, speech difficulties, bladder and bowel and sexual problems, walking difficulties. All of these have treatment modalities that we can offer to patients. Some are medicines, some are therapy, either physical therapy or occupational therapy, or health psychology counseling. With very few exceptions, all of the symptoms that arise from progressive MS do have some management strategies. Now, those management strategies don't allow us to completely remove the symptom from patients, but in the majority of cases we can reduce the symptoms and we can improve the patient's functions through a number of different modalities, again, either medications or therapy or assisted devices, walking devices and braces, helping devices in the patient's home. There are many things that we can do, beyond giving a medicine to slow the progression, that can really improve patients' quality of life.

Alex Rae-Grant:  Well, thanks Bob. Thanks for joining us, and thanks for your words about progressive MS. It was a great pleasure.

Bob Fox:  It's been great being here, thanks Alex.

Alex Rae-Grant:  This concludes this episode of our Neuro Pathways podcast. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Subscribe to the Neuro Pathways podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word, that's at C-L-E Clinic M-D on Twitter. Thank you for listening. Please join us again soon.