Great MS Debate Review: Discussing Evidence for High Efficacy Therapy in RMS Patients

This educational program is sponsored by Novartis Pharmaceuticals Corporation.

The speakers in this video are being compensated by Novartis to conduct this presentation.

DR COYLE:

Hello and welcome to our discussion around the evidence for why the use of high-efficacy therapy in RMS patients is important.

My name is Patricia Coyle. I'm Professor of Neurology and Vice Chair in the Department of Neurology at Stony Brook in New York and I direct Stony Brook MS Conference of Care Center.

DR NICHOLAS:

Hi. I'm Dr. Jacqueline Nicholas, and I'm an MS specialist and I run the MS Center at OhioHealth in Columbus, Ohio.

DR COYLE:

For today's topic, Dr Nicholas and I will present some insights and opinions on responses that were given by MS experts during the first and second Great MS Debate events this summer. The Great MS Debates addressed some uncertainties surrounding MS, which have led to differences in opinions regarding the management and treatment strategies. The panel of top MS experts challenged each other's perspectives on different management approaches for patients and discussed how patient preference has a role in the shared decision-making process.

Since I participated in the second event of the Great MS Debate, you will see me sharing some of my perspectives in footage from that event itself. In addition, Dr Nicholas and I will provide further insights from our own clinical experience and we will comment on the topics that were discussed during the debates.

So let's get started with a brief introduction to current MS management.

DR COYLE:

MS is a chronic, progressive disease with a variable disease course1,2

A goal of managing MS is to preserve neurological function and slow down the accumulation of disability3

DR NICHOLAS:

August 2019, of the approximately 235,000 patients with MS treated, 28% (approximately 66,000) initiate or change to new treatments annually4

Of this group, 55% (around 36,000) who received a new prescription were switching their disease-modifying therapy4

What might be driving these rates of treatment switching? This is a question that lends itself to further discussion on current treatment approaches that we will explore in our conversation today.

DR NICHOLAS:

We will now hear from several esteemed MS specialists about this and many other topics related to the management of MS.

Our first question is:

What are patients and clinicians looking for?

DR RILEY:

I think neurologists and MS patients have, you know, some overlap in terms of what they're most concerned about. But the differences are important. So while neurologists note that control of relapsing, control of disease progression, as well as safety as among their top concerns, patients are more likely to say that they're interested in sort of the impact in their daily life that a medication will have. So potentially some tolerability issues, and they rate that relapse control and disability progression a bit less highly. So I think we have to keep it in mind that we may come from, you know, with some different goals and try to meet our patients where they are, as we talk about what immunotherapy is best for them.

DR VARTANIAN:

I think, you know, I found that when the patient is very involved in the decision-making process that outcomes are better and that's for a number of reasons. One is that the patients really want to understand what the adverse events are. You know, what potential risks they have for medication. They certainly want to understand efficacy and relative efficacy, and they need to understand what the monitoring involves, and why that monitoring is being done.

A number of studies have shown that when patients are more involved with the decision-making, when the physician is giving them more information about not just efficacy, but about adverse events and monitoring, that they are more invested in their therapy, they're more likely to be adherent and outcomes are better. And I think the other important point is that this is an ongoing process, because stuff happens. There is a relapse or there is a disease progression, and it's better if all of that has been explained before, so that there are no surprises, or if there are surprises, at least can be explained.

DR COYLE:

I think what MS patients want is the ability to have a normal life, so not have their MS limit them at all to be able to start families, to have careers, to go on vacation when they want, to have a routine, good quality of life, that means controlling the MS damage process, but in a good way maintaining a quality of life not having pain and suffering, and I think we can play a huge role in allowing our MS patients to have a normal life, I do think that means we need to get them on appropriate treatment very quickly. And that means a recognition that this is a treatable disease but in shared decision-making with their physician, you need to come up with what are the best choices for them. And this is an educational approach.

DR NICHOLAS:

So I agree with you Dr. Coyle. I think that our patients

really, if they didn't ask to have this disease and once they do accept that they have multiple sclerosis, they want to figure out a way of, all right, how can I manage this with the least interruption possible into the lifestyle that I want to have. And so I think starting out with understanding what are their goals what's important to them, and then making sure that we offer them treatment options that we think are going to be effective enough for their disease but also that we think they're going to be options that fit into their lifestyle, and are they things they're going to be able to tolerate and hoping to empower them to make that choice because, again, giving them a choice to control their disease is incredibly important when they had no choice of whether or not they would develop MS.

DR COYLE:

Now, let's go into our next question,

How have management strategies for MS evolved?

DR VARTANIAN:

So I think the two major treatment strategies are escalation and beginning with a high-efficacy therapy upfront. So let's talk about escalation therapy first. I think the rationale between, the rationale about using escalation therapy is really one centered on safety, and so the idea here that people who use this strategy are thinking is that high-efficacy drugs often have more serious adverse events associated with them.

The idea with high-efficacy therapy upfront is to recognize that for the most part once the damage has been done to the CNS, it's irreversible, or partially reversible. And so we're trying to prevent that damage from happening at all. High-efficacy therapy upfront is our best chance of protecting the nervous system from injury, and therefore, our best chance of limiting the probability of disability in patients' long term. It's something that I think most MS specialists do.

DR COYLE:

Well, this escalation versus high-efficacy controversy has been going on for some time. And the issue was that the high-efficacy agents, which sound great -- and who wouldn't want a high-efficacy agent? -- were considered safety risks. They were considered to be more dangerous. So you had to be very, very selective. Even the AAN 2018 practice guidelines said if you had highly active MS, you should use a high-efficacy agent, you should not use an escalation strategy. The whole escalation strategy was knocked for a loop when we began getting high-efficacy agents that were pretty safe. So the safety issue was being taken away. So now the argument for not going with a high-efficacy becomes much more convoluted. And the other issue is the literature is increasing in tempo to really support how critically important the efficacy is very, very early on. Remember our paradigm of MS: accumulating permanent damage to the most valuable body organ, the central nervous system, so that the individual will not age well.

We are getting more and more data that says the first window of opportunity, the early stage of MS when it clinically declares itself, is key. And if we can treat it really well then, it will pay dividends for, likely, decades. And I think there's increasing data to support high-efficacy.

DR COYLE:

Well, I really think that what I said, I mean. This is a debate that has been going on. It would be very accepted by experts that a high efficacy agent is very important if you have what is considered significant MS disease. As we get high-efficacy agents we've had for longer periods of time and we've realized that they seem to be quite safe and they have a very friendly delivery system, then you begin to kind of not have the same concern about safety and then you're looking at efficacy, do you choose a modern efficacy or a higher efficacy agent that may be a very convenient formulation. Suddenly, the high efficacy agent becomes much more desirable. I think it's an important shared decision-making point to bring up with a patient, how much do they value efficacy? And I think if a patient tells me that that's important to them, then really that does favor using a high efficacy agent from the very beginning.

DR NICHOLAS:

So, again, Dr. Coyle, I couldn't agree with you more. I think that when we think about multiple sclerosis, which is a neurodegenerative devastating progressive disease in which, once that damage is done, you cannot turn back time, why wouldn't we use a high-efficacy therapy when we have such good safety profiles for most of these therapies? I think that it's really important to talk to our patients about the differences of these approaches and also the treatment options that we think will be most effective for them, but also how that's going to help them to maintain that quality of life that they want in the long run. And so, again, I think that we need to do our best job as early as possible to control this disease, and that gives our patients the best chance of having the best quality of life for the remainder of their lives. I think that most clinicians are starting to think in this way especially because we have many high-efficacy treatments which can be very safely managed. Fortunately there are two clinical studies that are ongoing currently called deliver MS and treat MS which are actually going to help to answer this question in the long run about what is the difference in terms of the long term outcome or patient starts on high efficacy treatments first versus low to moderate efficacy.

DR NICHOLAS:

When is the right time for a high-efficacy treatment approach?

DR COYLE:

MS is an organ-specific immune-mediated disease. There's clear data from rheumatoid arthritis and other disorders that, in a situation like that, quickly treating the disease effectively is key, because it decreases late damage. And the treatment has to be very effective to really create minimal disease activity. So if we truly have this critical window of opportunity early on in MS, that is the time to use high-efficacy therapy, particularly if it's really fairly safe. I think that -- I quoted some of the studies. You get the biggest bang for the buck by treating with a high-efficacy agent early as opposed to delaying it a couple of years. And, remember, there is subtle damage ongoing that's going to impede the ability of the MS individual to age properly. We want to control the disease, we want to control it quickly. We don't want epitope spread, which is likely a factor in the MS disease process. We really need to optimally treat early. And this is a disease where there's a lot of hidden damage, that even though the patient looks well, we may not be aware of. That's a risk with escalation therapy.

DR. VARTANIAN:

There is a significant percentage of patients that seem to be doing well on modest efficacy, low risk medications. And -- and so, you know, part of the challenge is figuring out who those patients are, which we really have a hard time doing. I think the other part of the equation though is the adverse event and safety profile of these agents. So, you know -- and that becomes part -- that's a complicated equation, because there is the patient decision-making, the patient, you know, how risk averse or how much of a risk taker the patient is, and then there are comorbidities.

So sometimes we see these adverse events appear after we've started a high-efficacy drug and they become almost intolerable, so we have to revert back for our modest efficacy drug.

DR NICHOLAS:

So I think the right time is early, and at the time of diagnosis. The reason why I recommend starting high efficacy agent from the beginning is because we really don't have a way of knowing each individual's -- what their course would be like. Certainly there are prognostic factors that can help us to predict that, but we don't know who's going to respond to a low or moderate high efficacy agent. And so if we use a therapy that's believed to be more efficacious early on, we have a greater chance that their disease is going to be controlled as best as possible. And again, once that damage occurs, we can't get it back. And so just like in the field of stroke, you know, time is brain, and although it happens a little more slowly in MS than it does in vascular etymology, I think that we should think of it the same way. I think that there is a place for modest and low-efficacy treatments in certain situations, but I think that those should be more reserved for individuals where we are de-escalating therapy because of age or potential risks or adverse events that have occurred. What do you think, Dr. Coyle?

DR COYLE:

So we really have multiple MS disease modifying therapies and we want to match them appropriately at the patient right from the beginning. That's why you put so much thought into what's the ideal treatment for the patient. And we want good quality of life. We want a well-tolerated agent. I would not choose a disease-modifying therapy that I expected not to be well tolerated. You can always run into surprises but that's why, for a disease like MS, a high efficacy, safe, expected to be well-tolerated agent, becomes so attractive, particularly for a disease like MS where there's hidden occult damage ongoing and you're in it for the long term. You're in it by treating optimally now to try to help them for the next 30 years. And I think a high efficacy well-tolerated agent becomes very, very attractive in that scenario. Well, of course, there may be circumstances where an alternative agent is the best for that individual and you counsel them and you follow them closely, et cetera. That's key.

A high efficacy agent is particularly attractive when it's well tolerated, and I think that's what we're really beginning to see available in our MS armamentarium, so it's very attractive from that point of view. And if we think about the aging issue, in MS that there's evidence that MS involves accelerated aging, you may really want to control the damage process as effectively as possible as early as possible it really makes a strong argument for using the high efficacy agent early on.

DR COYLE:

Now that we've heard about when it may be appropriate to start a high-efficacy treatment, let's now look into what the evidence says about using a high-efficacy treatment approach sooner?

DR. BAR-OR:

Observational studies that have lasted longer may give us complementary insights. One example is another UK study that ran for approximately 16 years in some patients and what they did is they considered the time to sustained accumulation of disability or disability progression in a cohort of patients who started either with a high-efficacy therapy or with a lesser efficacy therapy, and they found that some five years out, it took about twice as long, or half the proportion of individuals to achieve this sustained disability progression in the higher efficacies as compared to the lower efficacy groups. So this study again is limited in the sense that it is a nonrandomized trial, but it does give some window of insight into longer term consequences of starting with high-efficacy therapy.

DR. RILEY:

Well, I think it's very interesting to look carefully at some of observational studies, because I mean you're just really limited by the design, you know, for example, the last study you mentioned, it ran for 16 years. You know, when you adjust for the baseline covariance, that difference between the time to sustained disability accumulation falls away. And so I think that some of the current efforts, and there are two large PCORI studies going on right now evaluating, in a randomized fashion, these two strategies. I think those are going to be really important to see, you know, if in at least in the medium term, is there a true difference in how people are doing neurologically in ways that matter to them, and then our best measurements and our best biomarkers, you know, do they support that as well.

DR COYLE:

I would make stronger statements than both of the that we just heard from. The data is becoming stronger and stronger and clearer and clearer on the importance of early treatment and effective treatment. I don't think there's any doubt and that's how we should be counseling our patients we should be sure we inform them that there's different degrees of efficacy of the disease modifying therapies, how much do they value a high efficacy agent particularly if it is pretty safe and very well tolerated I think it's important in shared decision-making to bring that in. But if you really think about it, isn't it appealing to use a safe convenient high efficacy agent in the gamble, the crap shoot that we have, with MS.

DR NICHOLAS:

So I would agree with Dr. Coyle, I think the two previous physicians were really speaking to the observational study and certainly there are flaws in that data, but I do think we have good data that already shows a difference in patients who are treated with high-efficacy therapy early versus later. Again, we know what happens if this disease is not controlled effectively in the first few years of the disease, we need to educate our patients on this and make sure they are aware of the differences in efficacy and treatments and make sure that they know that when making their choice because some people don't and they're educated to, you know, start the one treatment that that doctor shares with them and, unfortunately, using an escalation approach oftentimes can result in significant disability and, you know, I think that we need to really be clear about that from day one.

DR NICHOLAS:

We've had the opportunity to listen to a variety of perspectives on the use of high efficacy therapies in MS. Before we end, we'll take this chance to add our own voice to the conversation and respond to the question: would an early high-efficacy treatment strategy optimize disease management for your MS patients?

DR NICHOLAS:

What do you think, Dr. Coyle?

DR COYLE:

Believing that there's more and more data to say there's

a critical window of opportunity, early treatment

in that window of opportunity appears to be key, and then the second factor is the effectiveness of the treatment that we choose. And I think a high efficacy safe agent is extraordinarily appealing as a first choice

agent in that window of opportunity.

DR NICHOLAS:

Well, certainly in my clinical experience, I find that the early use of high-efficacy therapy does impact the quality of life and outcomes for my patients. And this is certainly a treatment pattern that I endorse, and I talk with my patients about it because, again, once the damage is done, we can't do anything to repair that damage or to, you know, repair Q1 hyperintensities or areas of holes in the brain. These, each and every lesion is brain damage and spinal cord damage, and with time, with normal aging, we know that the brain shrinks and in MS, the rate of brain atrophy and spinal cord atrophy is actually much faster than that of normal aging. So even this damage that happens asymptomatic, ultimately, in the long run, will catch up with our patients in the form of cognitive dysfunction and/or physical dysfunctions, and so giving them the best chance for the best quality of life and being able to reach all their goals and do everything they always wanted to do up into their senior years is key, and I think the best way to

give them that opportunity is to give them the highest efficacy treatment as early as possible.