Unpacking MS Progression and BTK Inhibitors

Unpacking MS Progression and BTK Inhibitors

Episode 194 – Podcast Transcript

[(0:24)] Stephanie Buxhoeveden:Welcome to the Can Do MS Podcast. I’m your host, Stephanie Buxhoeveden. I live with MS and I’m also a clinician and MS researcher. Today, we’re joined by Augusto Miravalle, who is a neurologist and serves as the chief of the MS division at Rush. Welcome Augusto. I’m really looking forward to diving into 2 really big topics today, uh, one being MS progression and the other being what some people are calling the next big thing in MS which is BTK inhibitors.

[(0:50)] Augusto Miravale: Thank you, Stephanie. It’s truly an honor being here, and I’m excited to talk about these 2 very important topics.

[(0:55)] Stephanie Buxoviden: Awesome. There are several times, um, during my own MS journey when I was anxiously awaiting this sort of next big thing on the horizon, the new therapy to be approved, wondering if that was the one that was gonna finally stop my relapses and change sort of the, the trajectory of my disease early on. Um, and I remember that feeling of having to be on these early injectable medicines, they weren’t working, uh, and then the excitement of moving to oral medications as they came to market and then later, um, to an infusion that became available, which I first accessed off-label and then after it was FDA approved. So, I can’t help but wonder, you know, and think about the people out there who are now awaiting this next exciting big thing on the horizon. And, I’d love to just have you today give us sort of start with a big picture. BTK inhibitors are getting a lot of attention right now. So, can we start by explaining what they are and what makes them so unique?

[(2:00)] Augusto Miravale: Absolutely. And, you know, you’re correct. If we reflect back into how new therapies have been introduced in the last 2, 3 decades, in a sense they, um, they brought a different mechanism of action that in a, was resulted in better efficacy in stopping relapses or preventing relapses and, you know, acute inflammation. Uh, but if you look at all of the currently approved medications, they, for the most part, affect one part of the MS pathology, which is acute inflammation. That inflammation that, you know, in a sense is triggered by with those, we don’t know yet what triggers MS, but we know that the immune system gets activated and learned to go after myelin in the brain and spinal cord and that results in lesions and lesions results in relapses in MRI activity. Uh, this new class called, uh, BTK inhibitors or Bruton’s Tyrosine Kinase inhibitors, they introduce a new, uh, target for MS pathology. Uh, and the hope is that not only they will address acute inflammation, but also another type of inflammation that we call chronic or smoldering inflammation.

[(3:10)] Stephanie Buxoviden: Yeah, and that smoldering MS, that’s a term we’re hearing more and more. I’m sure many of our listeners have heard it being thrown around. And as you said, that’s that kind of slow, steady inflammation, degeneration that’s causing damage even when relapses are controlled. And those of us living with MS know firsthand that we tend to get worse even though we’re not relapsing, and quote unquote, our MS is well controlled. Can you break down what’s actually happening in the brain during that process and how these BTK inhibitors are going to help?

[(3:44)] Augusto Miravale: Sure. And that’s a, that’s a critical area to understand. So our current understanding of MS pathology is, you know, as I mentioned before, when these immune cells get activated in the periphery, meaning outside of the central nervous system, they learn to target myelin. And by doing that, what they do is they try to find myelin. So they’re going to get to this, to the brain and the spinal cord. And they enter the brain and spinal cord through a barrier that we call, we call the blood-brain barrier. So once they get inside the central nervous system, they’re gonna target myelin, and they’re going to try to react against or destroy myelin and that results in lesions, which are these focal areas of demyelination. That’s kind of like the acute inflammation. However, that inflammation gets resolved and, and that’s why we see that usually lesions, uh, you know, in a sense they cause symptoms early on, but the symptoms may resolve over time, meaning the relapses usually improve.

However, not all immune cells that reach the, the brain and spinal cord, they’re going to exit. And some immune cells will stay within the central nervous systems, but also some immune cells will continue to cause this chronic, ongoing smoldering inflammation. And there is a, one type of cell that we particularly are paying attention these days which is called the microglial cells. And those cells reside in the brain. Um, they are, there trying to fight inflammation or trying to kind of control these reactions. But in the presence of this influx of other immune cells, they might become activated, and they might actually cause more inflammation. So microglial cells, even though they’re supposed to be there to clean up inflammation, under certain circumstances, they might get activated and do the opposite, which is to cause more inflammation.

[(5:35)] Stephanie Buxoviden: Right. So these, these immune cells are tricky because they have a purpose, and they, as you said, can be helpful or they can cross a line and become harmful. So these, uh, medications, they’re not just stopping them from forming or completely depleting them, right? They’re actually modulating how they behave.

[(5:54)] Augusto Miravale: Absolutely. And that’s how we are becoming more nuanced with the therapies in Multiple Sclerosis. You know, if you reflect back to the anti-B cell therapies, right, so the infusions that we, we have, you know, we learned, once we learned that B cells play a critical role in MS, we thought, well, let’s go after them and kill them, right? And, you know, we, we get a lot of benefits from doing that, which is, you know, we substantially reduced inflammation. But we can’t do the same with microglial cells, because, as you said, they also play a good role in the brain. They are critical to help fight inflammation. So what we need to do with these cells is we need to modulate them. That means, you know, instead of going and killing these cells, we have to retrain them to do what we want to do, which is in a sense decrease or, or stop inflammation.

[(6:46)] Stephanie Buxoviden: And that’s really where BTK inhibitors can fill that important gap, right? Because they’re the first drugs that can get into the central nervous system and do what you’re describing.

[(6:51)] Augusto Miravale: Right. And why don’t we talk about what is BTK? So BTK stands for Bruton’s Tyrosine Kinase. So the kinase means it’s an enzyme. And that enzyme is inside the cells and mostly immune cells. So it’s inside the B cells in the periphery, but it’s also inside the microglial cells in the brain. Uh, and this enzyme plays a critical role. So once a, an immune cell gets activated, it needs to activate this enzyme in order to proliferate, meaning in order to expand the number of B cells, in order to produce, for example, immunoglobulins, kind of like to amplify that inflammatory response. So without this enzyme, even though the B cells or the microglial cells may be activated, they can’t truly, you know, cause inflammation. So learning how to stop this enzyme is key because then, you know, even though the signal that activated these B cells and microglial cells is there, if we block this enzyme, they cannot proliferate and they cannot amplify, um, you know, inflammation. So what BTK inhibitors do is they bind to this enzyme, called the Bruton’s Tyrosine Kinase, and they stop the enzyme from being activated.

[(8:08)] Stephanie Buxoviden: And, you know, there’s a lot of technical terminology there, I think, um. So what does all of that mean for people living with MS?

[(8:18)] Augusto Miravale: Yeah. So, a couple of things that are unique about BTK inhibitors. So first of all, they target cells that are part of the 2 processes that we discussed before, right? The acute inflammation outside of the brain, and we call that, you know, mostly through the B cells, but also they target the chronic or smoldering inflammation that is inside the brain and, and also spinal cord, we call that, that smoldering inflammation through microglial cells. So one of the unique features of BTK inhibitors as a class is that they target 2 types or potentially target 2 types of inflammation. That’s unique. The second thing that I think is, is common in all options within the class of BTK inhibitors is that because they are oral, they cross the blood-brain barrier. So they can get inside the central nervous system. Which, you know, some of the therapies that we have now, particularly those infusions, they are large monoclonal antibodies and they do not cross the blood-brain barrier. So with these oral therapies, uh, we expect that the efficacy is going to be driven by their actions outside of the central nervous system as well as inside. So, those are I think the 2 characteristics that we can say we can generalize that all BTK inhibitors have. Uh, which is again narrows down to they ac- al- altered acute and chronic inflammation, and they could also affect, uh, processes inside the brain.

[(9:44)] Stephanie Buxoviden: Yeah, and I think that’s the big takeaway and the most exciting thing about this next step or this next phase in research is exactly what you just said. We haven’t to this point successfully had a disease-modifying therapy that truly gets through the blood-brain barrier into the brain. And we’ve gotten extremely good at controlling relapses. Many patients have near-complete relapse or inflammation suppression, um, with these more powerful drugs, but that progression, that smoldering piece, uh, that’s where a lot of the, the slow disability accumulation occurs. And that’s what, you know, I get the most frustrated with because my MRI doesn’t change, right? And my MRI hasn’t changed in over 8 years, but still losing mobility over time, cognitive challenges over time, certainly the fatigue. I think that’s the, the hope of this new class of medicines is that we’re finally going to be able to target that other side of MS.

[(10:44)] Augusto Miravale: Yeah. And, and you know, and, and to, to follow up on these, you know, like the benefits for the class itself. So we talked about both peripheral and central inflammation. We talked about, um, penetrating the central nervous system. And the third one that is important for patients to understand is it does not deplete cells. So it does not decrease the amount of immune cells. Which that in a sense, relates to perhaps a more favorable safety profile when it comes to infections or, you know, any consequences of having decreased, you know, number of immune cells. So I think those are the 3 characteristics that we can say apply to all of the options within the class. But as we are going to talk next, there are substantial differences between all of these options, right? And those differences, I think, matter. As a matter of fact, I will say if the audience can remember one thing from this podcast is that not all BTK inhibitors are created equal.

[(11:42)] Stephanie Buxoviden: Yes. And that, that is a big change. Again, we have a lot of medications in the same class, B-cell depleters, et cetera, et cetera. For the most part, they have pretty equivalent safety and efficacy. So we’re going to dive into sort of why that’s a little bit different in the BTKs. Um, so there are, to give an overview, quite a few in development, tolobrutinib, fenibrutinib, evibrutinib, remibrutinib, orlibrutinib, lots of brutinibs. And people, as you just said, may have heard that not all of them have performed the same way in trials. Um, so can you walk us through what we know so far?

[(11:59)] Augusto Miravale: Yes. And I think that’s critical to remember because we’ve seen data from the first of the BTK inhibitors that was studied in a phase 3 clinical trial, Evobrutinib. And unfortunately, that data was not that favorable. We were disappointed with the medication, I mean it was good, but it was not better than the comparator arm, like, uh, you know, Teriflunomide. So in a sense, we got disappointed by the fact that at least in measures of acute inflammation, meaning relapses and lesions, was not superior. That doesn’t mean that was completely ineffective, but it was not superior. However, once we understand that all of these options have very different ways in which they, they, bind to the enzyme, for example, the selectivity for the enzyme, meaning, meaning, you know, you have a medication that was designed to bind to BTK. But not all molecules are perfect. So some options within the BTK inhibitors also bind to other enzymes in other parts of the body, like liver, heart and, you know, uh, other places. So being able to be selective, meaning you only bind to the enzyme that we want you to bind is critical to, um, prevent the medication to cause side effects in other organs. So we call off-target side effects. So of all the options that you mentioned, the ones that are most selective to binding only to BTK are Fenebrutinib and Remibrutinib. So what we expect from these 2 options is that they will have less, uh, off-target side effects. So that’s one big difference. Um…

[(13:59)] Stephanie Buxoviden: And off-target side effects, meaning like liver damage or…

[(14:04)] Augusto Miravale: Exactly. So the, the on-target will be we want them to get to the brain and target, you know, microglial cells, right? We don’t want them to mess around with, you know, heart cells or liver cells or other things. Um, so being more selective is desirable because you want them to just do what you want.

[(14:22)] Stephanie Buxhoeveden: Mm-hm.

[(14:22)] Augusto Miravalle: Another difference, which is again a, a very nuanced, subtle difference but very important, is how they bind to the enzyme. And this is when becomes a little bit more scientific, um, than what we want, but I think again, remembering that not only the target being more specific but also how they bind, whether it’s reversible or it’s irreversible, it matters. Uh, because, you know, not only the dose frequency may change but also, you know, as many things in life and in human body, mutations can happen. And mutations in the enzyme in BTK can happen. And these mutations may alter how the medication binds to the enzyme. So the type of binding, whether it is reversible or not, may be more or less influenced by certain mutations, leading to more or less efficacy in the clinical outcomes.

[(15:16)] Stephanie Buxoviden: Interesting. Yeah. It’s, uh, we’ve all got a lot to learn, I think about this class coming up. It’s going to be really interesting, but I think it’s very unique how the way in which each of these individual molecules, um, binds exactly how you said, really affects potentially how well they work, maybe how well they work for certain people versus others, um, and safety. Let’s spend some time on something I know every person with MS worries about. And that’s their disease getting worse or progression. You know, that might look like, uh, not bouncing back from relapses like you used to or fatigue and mobility have worsened even though you haven’t had any relapses in the recent years. And it’s really hard for me as a clinician and an MS researcher to know whether what I’m experiencing is true MS related progression or maybe it’s just deconditioning, cuz I’m not doing as much physical activity as I used to, I’m more fatigued, um, really, how can someone tell the difference?

[(16:19)] Augusto Miravale: Yeah, that’s an excellent question, and I think now more than ever that we may have options to treat progression. It’s critical for patients and healthcare providers to truly understand the difference between progression versus deconditioning. So let’s start with progression. So we, we define that as this ongoing damage to the central nervous system that is due to inflammation. And that clinically manifests as patients having this persistent, gradual decline in neurological function. And just to give an example, if we choose ambulation, being able to walk. Uh, patients might say, well, 2 years ago I was able to walk, you know, 2 miles. And then I have this foot drop on the right, and that weakness in lifting the foot becomes chronically worse. And now I can only walk, you know, 50 feet without having to stop. So that will be a classic example of progression, right? So you gradually lose function, um, that appears to be permanent. There are no fluctuations. And that results in limitations in functional abilities.

So that will be an example of progression, and that usually represents that MS or at least the inflammatory portion of MS is getting worse or is not being properly controlled. On the flip side, deconditioning is something that may feel sometimes similar to progression to patients saying, well, you know, I’m tired and I don’t want to exercise. And if I walk for more than, you know, 20 feet and my legs give up. And so how do we distinguish the 2? Well, usually deconditioning doesn’t represent, you know, ongoing activity or inflammation, but it just simply means that your body is out of shape. And usually the symptoms fluctuate. So patients may say, I have good days and bad days. Or they may say, you know, I wake up in the morning and my legs feel fine, but towards the end of the day, I feel that they become consistently weaker. Or they say, you know, I try to exercise for 2 weeks and I was feeling really well, but then I stopped, you know, and, and then now I feel that I cannot even do half of what I was doing. Well, that is not progression. That is deconditioning. Um, so a, the other thing will be fatigue. So if you feel that the symptoms worsen with fatigue or, let’s say, heat intolerance, that is usually more deconditioning than progression. So, but as I said before, sometimes it’s hard. So I, I always recommend if patients feel that their function is getting worse, please check with your neurologist, with your healthcare team, because we can do assessments, we can do physical exams, MRI, sometimes blood work to try to help deci- tease out whether this is true progression or deconditioning.

[(19:01)] Stephanie Buxoviden: Right. And that’s why when you go to your office, they like to walk you up and down the hall and do all these tests and take a really close look and compare you to where you were one, two, three years ago, right?

[(19:14)] Augusto Miravale: But the good news there, Stephanie, is that regardless of what causes this, whether it’s deconditioning or progression, exercise and physical therapy helps. Helps both, right? Um, so I always say, well, yeah, you know, we can do something. And usually the first step is let’s start with an exercise program. Let’s start with a physical therapy program because, regardless of the cause, usually the symptoms improve in one way or the other.

[(19:39)] Stephanie Buxoviden: Exactly. I’ve definitely noticed that. And you live with MS for the rest of your life. You’re going to go through periods where you have time to treat your body well. And then you have periods where maybe you don’t have the time you need to pay attention. But, um, it’s an iterative process, always remembering to incorporate it. And at Kendo, I know we have a lot of resources that help people with that. And we can link to some of those in the description. So this brings us to a really practical part of the podcast, which is the BTKI class is coming, hopefully soon. Um, at the time that this podcast airs, we might be close to an FTA decision. Um, in the meantime, people can start to talk to their doctors about progression. And what do you, what advice would you give to somebody who feels like their MS is changing and they’re worried, but their doctor might be brushing it off because their MRIs look stable?

[(20:38)] Augusto Miravale: Yeah. So I, I think you have to be very clear and explicit in your concerns. And, and these are important conversations to have. And it has to be addressed. So the first step will be come prepared to the visit. And that means, you know, have your questions written and also have data to provide your healthcare providers. So be your own researcher in your life, right? So try to periodically check on you. Say, well, how, how am I doing with walking? How am I doing with thinking abilities? Uh, and am I, am I similar to what I was 6 months ago or perhaps I noticed some, some trends. Ask your, your, um, life partners, uh, your, your, you know, friends to kind of give you feedback about certain things. Particularly when it comes to cognitive function, sometimes people living around us pick up in those things before we do. You know, things like attention, concentration and things like that. So come prepared, uh, but also don’t leave the room until your questions have been answered. Because these are important questions to address.

[(21:41)] Stephanie Buxoviden: Yeah. And I love the point about sometimes the people around you taking note of it. I know that’s, that’s definitely the case. Um, I also tend to I think minimize my concerns when I’m in, in front of the doctor. Um, luckily my neurologist knows me well and calls me out on that. [Laughter] Um, but sometimes just the most valuable thing you can do is describe how your daily life has changed, right? Even if it seems like a small change. And that gives your doctor or your healthcare provider real information to work off of. And so for somebody in the room having that conversation, especially if and when BTK-is are now available, what questions should they ask about them?

[(22:24)] Augusto Miravale: Well, number 1 is understand the data from the clinical trials. Right? So clinical trials is our way to look at efficacy and safety in a pooled population of patients. And, so for, number 1, understand what are the benefits and what are the risks? And how they compare to my current therapy. Um, so that’s one. Two is understand, you know, how am I going to measure if this medication is doing what I want or what we want. So understanding how to monitor the signs of progression, how to also complement the benefits that I might be getting with this medication with other interventions. And, you know, one of the good things about MS these days is that we are moving away from a reactive type of approach, saying well if someone is having new lesions or new relapses or progression we need to change, to more of a proactive approach. Saying well, we know that certain interventions will benefit people regardless of your situation. Why don’t we adopt in those strategies now? And with that, I mean usually lifestyle interventions, exercise, diet, proper sleep and things like that. So I think with any change, that also brings the opportunity to say, well, in addition to this medication, let’s look at everything else we can do to maximize the benefits that you may get from this intervention.

[(23:49)] Stephanie Buxoviden: Yeah. So before we wrap up, what gives you the most hope about the future of MS treatment and where we’re heading?

[(23:56)] Augusto Miravale: You know, one of the things that is becoming very exciting is that we are learning more about MS as we observe how these different mechanisms affect disease processes. Um, so in a sense, simultaneously, we are learning about MS as we develop new therapies. So I hope that this is going to allow us to continue to expand our knowledge and develop therapies that are going to be not only more targeted to the what we want, but also to reverse the damage. Like things like remyelination and repair, uh, will continue to evolve as we continue to understand these processes that are leading to demyelination

[(24:34)] Stephanie Buxoviden: Yeah, I have to completely agree with that. I think knowing what causes MS is still largely unknown, as you said in the beginning of this podcast, but we are making huge strides in terms of understanding it. And once you understand something, you can really effectively treat it. Um, so I think, you know, for everyone listening, it just means that we’re closer ever to therapies that don’t just stop relapses but may actually slow that hidden inflammation and that degeneration that’s really driving long-term disability. So to sum it up, there are 2 big takeaways from today’s conversation. Right? So first is understanding progression and how talking about it with your healthcare team is absolutely crucial. And that the earlier you raise concerns, the sooner you can explore options. And those include, as you mentioned, lifestyle changes, rehab, new therapies as they become available. And then second, these BTK inhibitors are exciting. They’re a brand new class of MS treatments. Uh, they’re really designed to target that inflammation that’s been hard to reach inside of the central nervous system. That smoldering, slow-burning kind that’s driving progression. And I just want to thank you so much for joining us today and is there anything else that you’d like to share before we say goodbye?

[(25:54)] Augusto Miravale: No, thank you for the invitation. It’s been a pleasure being here. And no, if anything, just convey the message to patients that we have more options and these options continue to expand the way that we can help, um, help you and with your life. So I know that MS is hard, and sometimes you feel defeated, and sometimes you feel kind of like in a place that you don’t know your way out. So please know that there are many ways out and, and you know, even now in, in understanding progression and being able to hopefully address that, I think it’s an exciting time.

[(26:28)] Stephanie Buxoviden: Thank you so much. And thanks to everyone listening. Again, this is a very evolving field. Um, so to learn more about BTK inhibitors and to stay updated on the latest MS research, we recommend the National MS Society’s research webpage as a good resource to turn to. Thank you so much. Thank you for listening to this episode of the Can Do MS Podcast. If you like this episode, please leave us a rating and review on Apple Podcasts or Spotify. We appreciate your feedback. We’d also like to thank all of our generous sponsors for their support of this episode of the Can Do MS Podcast. Until next time, be well and have a great day.

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