The professor of neurology at the University of Colorado spoke in-depth about the treatment landscape, the biggest unmet need, and some of the challenges of research in progressive MS.
John Corboy, MD
The treatment landscape for multiple sclerosis (MS) has drastically changed for the better over the last several decades, which has opened the doors to new treatment options and provided clinicians with additional therapies. While all of the medications are approved for relapsing forms of MS, only 2 are technically approved for progressive forms: mitoxantrone (Novantrone, EMD Serono), and more recently, ocrelizumab (Ocrevus, Genentech).
For John Corboy, MD, one of the greatest unmet needs is understanding progressive MS, however, there has been a lot of work done in the last several years focusing on understanding its pathology and pathogenesis in order devise interventions that would address the underlying causes.
To further explore progressive MS, it's challenges in research, among other topics, NeurologyLive spoke with the professor of neurology at the University of Colorado, in an interview.
John Corboy, MD: John Corboy, MD: The treatment landscape for MS has become substantially more complicated over the course the last 26 years since the first medication was approved for use with multiple sclerosis which was interferon beta-1b. Depending upon how you count, we have certainly over a dozen disease-modifying therapies now and they come in all different types, mechanisms of actions, routes of delivery, durations of effectiveness and degree of effectiveness, side effects, long-term risk, etc., and it's just become a much more complicated circumstance. In addition, all of the medications are approved for relapsing forms of MS and technically 2 are approved for progressive forms mitoxantrone (Novantrone, EMD Serono) was approved many years ago and in Europe interferon beta-1b (Betaseron, Bayer) was actually approved for some people with progressive MS, but in the United States more recently in 2017, ocrelizumab was also approved for primary progressive MS.
In addition it's become more obvious that early aggressive intervention, especially for newly diagnosed individuals, especially for younger individuals who are very responsive to these therapies, has become ever more important in that context to make sure that we get an early diagnosis and an accurate diagnosis, and both of those things are important—early is good, but accurate even more important. Use of these medications has become much more prominent when interferon beta-1b was first approved in 1993. There was to be a lottery to actually get this delivered to patients because the concern was that the company would not be able to make an adequate amount of the drug and there were so many people around the world that wanted the drug, and yet, interestingly, the lottery lasted a few months because, in fact, very few people were actually injecting the drug in part because the physicians were quite conservative about its use and the patients were very conservative about its use. We've come sort of full cycle on that now where there's a great expectation that when you are diagnosed with MS that you are going to be treated and the only question is with what and for how long.
The landscape has changed dramatically over the last 26 years, all to the good, but in addition, just more complicated and much more challenging discussions with patients when they're newly diagnosed, and things are often very confusing. I would also say that all of the presently available disease-modifying therapies are all in one way, shape, or form, affecting the immune system, they are suppressing it, modulating it, altering it in one form or another, with the hope that you can turn down or turn off the acute inflammatory events that occur especially in younger patients with MS.
There remains an incredibly great unmet need to deal with those individuals with progressive MS, in which case MS is much less of an inflammatory disorder and an autoimmune disorder and much more of a neurodegenerative disorder. There has been a great deal of work done in the last several years focusing on understanding the pathology of progressive MS, understanding the pathogenesis, that is how do you get to the pathology, and then trying to devise interventions that might address the dropout and death of cells in the brain and the spinal cord that appear to occur almost independently from inflammation or at least the type of inflammation that's associated with the acute attacks when patients are younger. There's clearly ongoing inflammation inside the nervous system but it is not the same as that which is seen when patients are younger and have these acute inflammatory plaques that are very common and our response of it appears to all of these different medications, whereas those with progressive MS, the nature of the inflammation is not particularly responsive to the presently available disease-modifying therapies.
The landscape has gotten incredibly more complicated, but that's all for the good, and how this plays out over time as we add different types of therapies such as neuroprotective therapies or remyelination strategies or replacement strategies if we can ever hold some promise that stem cells and other things that might actually either induce the creation of better cells or directly replace damaged cells remains to be seen.
The greatest unmet need from a treatment point of view remains trying to help those individuals with progressive MS. The majority of disability that accrues in patients with MS occurs during progressive phases of the illness. The recent new demographic study that looked at the numbers of individuals in the United States who actually have MS, not only more than doubled the previous estimates as to the number of individuals who actually are diagnosed with MS, but also identified the populations especially, based on age, and for people 18 years of age and older with multiple sclerosis in the United States, 46% of those individuals are 55 and older—this is the population of progressive MS for many people, not all have progressive MS, but many do.
This particular population has already accrued disability and for many of our patients who are diagnosed prior to the introduction of interferon beta-1b in 1993, they've been carrying a disability and/or developing disability for many years, so it remains the greatest unmet need from the disease-modifying therapy point of view and also from the point of view of just symptom control. Ultimately what we care about is that individuals will have the greatest quality of life possible, and that means all the different things that are related to symptom control, disease-modifying therapies, addressing comorbidities, and other things that are associated with quality of life, and so addressing all of those from multiple different points of view is extremely important.
For progressive MS patients the concept that you can wake up in the morning and feel confident that you're going to have a reasonably good day and not have to worry about dealing with any of a variety of different symptomatic problems, that would be the ultimate goal, to give people quality of life and focus on how they feel when they wake up in the morning, and when they go to bed at night—that's our main issue. The way we think about it in our institution, is we talk about lifelong brain health, and brain and spine health, and ultimately that is reflected in people living the quality of life that they want to.
The major challenge in research related to progressive MS is understanding the nature of it. We know a lot about what it looks like clinically, but understanding the underlying pathology, the pathophysiology, or pathogenesis that is how is it that whatever the inciting cause somehow leads to the pathology, and how do you interrupt that cycle and interrupt the nature of the drop out of cells over time, is really the biggest problem. In the last several years, the Progressive MS Alliance and others, have focused a great deal of energy on trying to understand these very fundamental questions and it appears that there may well be power failures, if you will, inside cells. Energy is required for all of the activities of cells throughout the body including in the nervous system, and if you have an inadequate energy supply then that can certainly be associated with death of the cells, similarly, there are things that may be actively participating in damaging cells and oxidizing agents or free oxygen radicals are likely participating at a high level in damaging and having ongoing damage to cells within the nervous system. If that is accurate, those are 2 approaches that might be available as treatment options, if you could somehow enhance energy production inside cells or if you could perhaps use antioxidant approaches. There are other approaches as well that would help delay or diminish the likelihood of cellular death overtime and we know that there’s cellular death because there's significant progression of brain and spine atrophy that's seen in progressive MS; it starts very early, even before progression, for those who have secondary progressive MS it begins perhaps even before the first relapse that someone has when they're in their 20s or 30s, but it is persistent throughout the lifetime of the patient the drop out of cells. Early on it seems to be quite associated with these acute inflammatory events, but as patients age and as they go into a slow progressive mode, there is less relationship with these acute inflammatory plaques that occur when patients are younger.
The biggest issues with regard to the research related to progressive MS is understanding how these cells are dropping out, the degeneration that occurs over time, what are those mechanisms and what are ways that we might try to limit the damage that is done and/or to maintain those cells so that they continue to act in a proper fashion and people don't have progression of disability.
There are several things that are important with regard to treating a patient with progressive MS. One is to be clear with the patient as to what the nature of the progression can be, it's often manifested by progressive gait disturbance, imbalance, often also associated with cognitive impairment, perhaps weakness throughout the various limbs, and even some other things bowel, bladder, sexual dysfunction, mood disorders, are also prominent. It's often the case that there are multiple different issues that need to be addressed and that leads to not only telling that to the patient but then addressing those issues. From a symptomatic point of view, it's extremely important to find out what's important for the patient and to try to address those so that their quality of life is maximized—that doesn't necessarily mean that you have to give a drug or do something else for every single one of the symptoms that may be occurring, but you have to at least address all of those different things, find out what's important for the patient, and address the ones that are most important to the patient so that you can improve the quality of life.
On the point of trying to use disease-modifying therapies, this whole concept that progressive MS is somehow a different disease than relapsing MS also needs to be addressed. It's really not a different disease, it's not something that occurs by flicking a light switch and you go from relapsing MS, into progressive MS, especially for those individuals who never had relapses, such as with primary progressive MS or progressive onset MS.
Progressive MS really represents a phase of the illness presumably in which the compensatory capacity of the brain and the spine is being superseded by the drop out of cells, the loss of cognitive reserve that occurs over the lifetime of the patient and is manifested pathologically with drop out of cells and shrinkage of the brain and spine then manifested clinically by the slow worsening that we see. The simple fact is that the medications that are presently available as disease-modifying therapies are very effective when patients are younger and have acute ongoing intermittent inflammation but unfortunately have been substantially less effective for progressive MS and those older individuals. Just to be clear, progressive MS affects individuals who are relatively older, the median age of onset of symptoms for relapsing forms of MS is late 20s, early 30s, the mean time of onset for progressive MS is probably in the mid-40s and so these older patients are having a different type of pathology that's ongoing than say a newly diagnosed 25-year-old. Consequently, we need to be honest with patients as to what role the disease-modifying therapies have in these patients. Importantly though, just because someone has a label of progressive MS, does not mean that they should not be treated because the medicines are relatively less effective, it means that we have to identify what our goals are for the patient and the importance of treating those patients who have ongoing inflammation in addition to neurodegeneration. This all then gets back to the same general concept that MS may be the manifestation of multiple things that ultimately lead to what we see clinically, but the reality is that this is all a combination of degenerative disease as well as inflammatory disease and we need to treat the inflammatory disease component as aggressively as possible when it has the greatest impact, which is typically in patients when they are younger regardless of whether or not we call it progressive MS or relapsing MS—setting expectations, being honest about what the goals are, and then treating aggressively as appropriate, all make sense. In addition, as part of that, it should also be part of the discussion as to how long is it appropriate to continue to use disease-modifying therapies. At present, there are no good studies that answer the question as to whether or not it is safe to discontinue disease-modifying therapies or deescalate disease-modifying therapies as people age but is well-known that the medications are most beneficial in those who are younger, and the benefits are more difficult to define as people age.
We're in the middle right now of what we call the DISCO-MS study, the discontinuation of disease-modifying therapies and MS, which is looking at older individuals with relapsing or progressive MS and asking the question if they have not had a relapse for at least 5 years, and a scan change for at least 3 years, and are over the age 54, that is 55 and older, is it safe in that context to discontinue their present disease-modifying therapy. We should have the answer in a couple more years, but it's an important question given potential risks associated with various medications, the fact that risk may increase with age, and of course the cost of the different medications which are exceedingly high, and so trying to understand the nature of medications, what they actually do, when it is appropriate to start them, and when it is potentially appropriate to consider stopping them, are all important questions that we should ask every time we see a patient for the first time.
The biomarker issue is a very important one. In some respects, we have a biomarker of some form, we have the MRI scan, but biomarkers can come in blood, urine, cerebral spinal fluid, in scans and potentially in other contexts, and they can be useful potentially from a diagnostic point of view, from understanding the severity of the disease point of view, from the point of view of response to therapy, perhaps even from the point of view of determining whether or not someone needs to continue to use a disease-modifying therapy.
Presently though, the best biomarkers we really have, have to do with MRI scans, but there's been a great deal of interest of late in blood biomarkers. The leading contender right now as a biomarker potentially of disease severity and perhaps for response to different disease-modifying therapies would be neurofilament light, which is a component of the nerve cable, the axon itself, and if there is damage then you can see leakage into the cerebral spinal fluid, and more recently, with more sensitive techniques this can also be measured in blood. Multiple studies have shown that this marker, which is not specific to MS, but it's just specific to damage, may be useful not just in MS but also in concussion and brain trauma, may perhaps be of interest in a stroke, and a variety of other different contexts.
In MS it has been shown to be associated with a variety of different things, it tends to increase with age, it tends to be a little higher and progressive than relapsing MS patients, it's probably higher during acute relapses when there's damage that's occurring, and it may be a marker of response to therapy if indeed it can be shown conclusively that there are drops in neurofilament light with therapy.
That's one example, there are a variety of other examples as well that are being looked at, and the hope is that we'll be able to develop a significant collection of these biomarkers that will give us an idea of all those different things from a diagnostic and prognostic, and responsive therapy point of view. Right now, today in 2019, probably none of these are really considered standard of care and it's not easily available to get, for example, neurofilament light testing, it's possible to probably see that in the next couple years though where it's more routinely used. The hope is that once we somewhat break the barrier with use of a standard molecule such as neurofilament that others will also be developed that are equally, if not greater, sensitive and specific perhaps for MS.
Transcript edited for clarity.