Ataxia Series: Treating cerebellar ataxia in 2026 - What's new?

Dr. Liana Rosenthal: Well, Thank you so much for having me. I'm glad to be here.

Prof. Orlando Barsottini: Liana until recently ataxias, especially the genetic forms [00:01:00] were considered untreatable disease. To begin our conversation, do we have reasons for optimism or not?

Dr. Liana Rosenthal: So Orlando, I think we do have reasons for optimism. There's a number of different things I'm actually really excited about. As we think about our treatments for the different genetic ataxias. In the time that I have been working with and helping to treat and manage people with ataxia, so it's been about 10 to 15 years and over that time, I have just seen in incredible growth in our ability to think about and understand the pathophysiology, apply that to identification of new biomarkers.

And then also I've seen incredible growth in pharmaceutical companies' interest in treating ataxias. And so I think that combination is really gonna be very exciting moving forward. And in addition, you take all of that [00:02:00] growth that we're seeing in ataxia, and then you also throw in the success that has happened in other areas in terms of gene therapies.

And so this idea that other diseases can successfully have gene therapies treating them, I don't see why we can't hopefully soon have similar treatments in the world of ataxia. And then finally, the other thing I'm really excited about in terms of optimism for ataxia is the approval of omaveloxolone for Friedrich's ataxia. So I think that together is a lot of reasons for optimism.

Prof. Orlando Barsottini: Yes. As you mentioned recently omaveloxolone was approved for Friedrich's ataxia. Could you tell us a little bit more about this drug? And my second question in this topic, is this drug indicated for all patients with Friedreich's ataxia or we need some selection of patients?

Dr. Liana Rosenthal: [00:03:00] So first lemme tell you a little bit about the drug, and I don't wanna get too bogged down in mechanism of action conversations, but I think it is useful because this i dea that some understanding of the mechanism of action is what allows us to say this drug is gonna work and then we test it in patients and sure enough, it helps.

So I think that pathway is a really good one to think about. So essentially in folks that don't have Friedreich's ataxia, there's this NRF2 protein and when it goes to the nucleus it will activate anti-inflammatory pathways. We can leave it at that. It's obviously much more complex than that.

But what happens though is in people with Friedrich's ataxia, this protein will undergo degradation leading to increase in oxidative stress. So instead of going to the nucleus and promoting anti-inflammatory pathways, it will degrade and it won't do its job. And omaveloxolone, we believe stops this degradation.

And so therefore, by [00:04:00] stopping the degradation, the protein can go to the nucleus and do what it's supposed to do. So there was that basic science background, and then of course you had to move over to the clinical studies. And in the largest study the MOXIe study patients with omaveloxolone were better at 48 weeks than those on placebo.

And they were better using the mFARS, the Modified Friedreich's Ataxia Rating Scale. And further they did additional analysis. Not only were patients better at 48 weeks on drug than on placebo. In addition, then there was a delayed start analysis showing that at 72 weeks, people on omaveloxolone were better than placebo.

And they also did an analysis and even longer study compared to natural history data. And again, people on drug were better than placebo. And then finally, when you stopped omaveloxolone, some of the patients got worse. So if you put it all together, the idea is that this drug seems to [00:05:00] be certainly helping symptomatically and is likely disease modifying in terms of individuals with Friedreich's ataxia, which is of course very exciting.

Right now, to get to your question of is it indicated for all patients, which I think is a really important question. Right now it is approved for individuals age 16 and older. And that was that approvals in at US FDA, Europe and many other countries as well, I believe. And that I would need to check. Right now they are doing a study to look at omaveloxolone and people age 2 to 15.

We are not gonna know the results of that study for at least a couple years. They just started enrolling patients little less than a year ago. So we're not gonna know the results of that for a while. So I think there's a discussion and there's a reasonable discussion to be had about the value of off-label use of omaveloxolone in kids who are under 16, but it's [00:06:00] off-label.

The concerns really focus around liver function, and so the question is dose dependent. What is a dose that's appropriate for kids? Making sure we're not causing more than a transient elevation in liver function testing, which we know that the drug can cause this transient elevation in LFTs. And so I think these are the questions about safety that need to be looked at.

And then also efficacy for the younger kids. I think the question is, people who are really comfortable with the drug, would they be comfortable prescribing it for someone who's 14 or 15? But then the next question, of course, would insurance even cover that? So those are the sort of issues going on about off-label use.

But right now is for folks 16 and older.

Prof. Orlando Barsottini: Okay. Thank you. Liana, moving now to spinocerebellar ataxias. We know that troriluzole was not approved by [00:07:00] FDA. Are your expectations regarding the use of antisense oligonucleotides in ataxia? Do we already have any positive results with this therapy?

Dr. Liana Rosenthal: So to my knowledge in ataxia, we do not have any positive results for ASOs. There was a SCA3 ASO study that was stopped due to safety concerns. I'm actually really enthusiastic about the ASOs as a concept for treatments in ataxia, and there are a number of different clinical trials that are ongoing that seem to have addressed some of these initial safety concerns and that they're ongoing.

Right now, they're still early phase though, and so it's hard to say when the ASOs are going to really become a true potential treatment versus early clinical trials. But right now I'm excited about the [00:08:00] idea that there are a number of companies doing these early clinical trials with the idea that the ASOs may be a really great treatment in the future.

Prof. Orlando Barsottini: Okay. You know many patients with ataxia may have cerebellar and non motor symptoms. For example, with sleep disorders, fatigue, neuropathy, and cognitive dysfunction. Could you tell us about your clinical approach to these specific symptoms? 

Dr. Liana Rosenthal: I think a couple of things are important in terms of the symptomatic management. The first is really in many ways to recognize the symptom that the patient's having this problem, and many patients don't realize that their fatigue or their neuropathy or their cognitive dysfunction is related to their ataxia.

So I think the first step is actually even just asking the question to the patients and letting the patient know that, yes, this may be related. And then the next [00:09:00] step for all of these symptoms that I try to do is I try to think about for each symptom first is it, how much is it bothering the patient?

And then furthermore, how much is it affecting their function? And then also, what are all the things that we can treat as it relates to that symptom. So while right now we can't change the underlying pathophysiology of their ataxia. Some patients have sleep disorders, not only because of their ataxia, but also because of other problems.

So making sure that you're looking at and thinking about all the other causes. So are you looking at things like sleep apnea? Are they exercising? For neuropathy, would they benefit from gabapentin? Would they benefit from other type of medications? For cognitive dysfunction, I always spend a fair amount of time thinking about all the other things. So cardiovascular risk factors, are they cholesterol well controlled, blood pressure well controlled. If they have a hearing loss, are [00:10:00] they wearing their hearing aids? Has their hearing loss even been assessed? Are we looking at sleep disorders in terms of cognitive dysfunction as well?

Are we looking at mood and mood symptoms in terms of cognitive dysfunction and in terms of quality of life? So a lot of these symptoms have medications, of course, that we can use, but then also making sure that we're thinking about all the other causes. So while we can't help the ataxia part of it, if we can help with the other 5, 10, 20% that's contributing to the symptom, it will at least improve how the patient feels.

So that's how I think about it for each of these different symptoms and then educating the patients that it is indeed part of their ataxia. So I like to think of it holistically that way.

Prof. Orlando Barsottini: Liana, today we know the importance of exercise in neurogenerative disease such as Parkinson's and Alzheimer's disease. What is the importance of exercise [00:11:00] in patients with ataxia, and do we have any ongoing clinical trials on this topic at this moment?

Dr. Liana Rosenthal: So there have been a lot of clinical trials looking at exercise in ataxia. There's two that I always tend to talk about. One study that came out of Hopkins from Amy Bastian's group and Jen Keller. What I really liked about this study, it was a smaller group, but what it showed directly is that the intensity of the exercise matters.

So patients who found the exercise more challenging to them, had more benefit from it, and so I really liked to discuss that with patients because I think it's directly applicable in terms of if you make sure that you're pushing yourself. Safely pushing yourself is the key point there, but pushing yourself, you are gonna have more benefit from the exercise.

The other study I was really excited about because [00:12:00] patients always ask what exercise should I do? And so the other study was a study that just came out of the group up at Columbia is published in JAMA back in 2025, so just last year. And what was exciting about that is it looked at home-based exercise therapy. So home-based, high intensity aerobic training compared to balance training. And it was 62 people. So it was a reasonable number of people. And what they actually found is that the aerobic training achieved greater improvements in even balance scores compared to the balance training.

And we could certainly sit here and discuss at, a different time all of the nuances of that finding and how I still would maintain that balance training is important and balance training can be helpful for our patients. It also speaks to the importance of aerobic exercise and again, of challenging people with their aerobic exercise. And the other thing the JAMA study found, which I thought was really important, is that [00:13:00] sustained training adherence was really important to maintain benefits.

So in other words, even amongst the people who exercise great for the first six months, if they stopped exercising, the benefits trickle down. But the people who kept exercising had continued maintenance of the benefits of that exercise. So it speaks to what I imagine most of us are telling our patients, which is it's really important that you keep exercising and you should do it often, and you should do it with a reasonable intensity.

And I think these are really important ideas and there are always additional exercised-based therapies that I see. If you look on the, if you look@clinicaltrials.gov, there's always a few other additional exercise studies, but they all basically say that same concept, which is great.

Prof. Orlando Barsottini: Liana, we know that invasive and non-invasive brain stimulation is a hot topic in the movements disorders field. In your opinion, what is your role in invasive or [00:14:00] non-invasive brain stimulation in patients with cerebellar ataxia and in my particular question, how safe are these therapies for ataxia patients?

Dr. Liana Rosenthal: So I actually think they're safe. I think we need to do a lot more research to truly answer that question. Let's be clear. W hat the data I have seen thus far is very encouraging, I would say, towards them being safe. And I think the question that we have to figure out, has to do with efficacy and how to optimize that efficacy. As you know, Orlando, there's good studies looking at TMS in ataxia, so transcranial magnetic stimulation. There are also some studies looking at direct current stimulation, and then there's a few small trials doing dentate nucleus DBS. And in each of these studies, the TMS studies in particular [00:15:00] and the very small dentate nucleus studies, they're showing improvements in SARA scores and other scores and improvements in cerebellar tremor.

But we need to learn how to optimize it, and we need to learn why it works. And I'm also really excited about the idea of transcranial direct current simulation. The data on that right now is more variable. I still think each of these has a role to play in our treatment of patients. We just need to understand it better, and we need to be able to look better at its efficacy and safety.

Prof. Orlando Barsottini: Liana. Now another hot topic. What is the importance of biomarkers, even neuroimagings of biofluid for monitoring treatment response or disease progression?

Dr. Liana Rosenthal: So I think as you know, Orlando, objective measurements are absolutely needed. I think the, right now we have [00:16:00] some really good candidates for markers of disease progression. In many of the ataxia, we are lucky in the sense that diagnostic markers are not necessarily what's needed and that a genetic test can tell us if a patient has a specific genetic ataxia.

So now sense of diagnostic markers for the genetic ataxia are many of that is done. I think, as we learn more and we identify new genes, we'll get even more diagnostic markers. For the progression is where it really starts to matter. We have some really good candidates, so we have things like pons size that seems to be a good measurement of disease progression on imaging.

There's also some interesting MS type measurements in imaging that we can look at for progression I think are really intriguing. And then NFL levels in terms of biofluid biomarkers. Also really interesting. The thing with NFL levels is, as they'll go up prior to diagnosis and [00:17:00] prior to symptom onset, then they seem to stabilize a little bit.

So those may not be the best progression, but they may be really good markers of target engagement. And so I think that's where the other interesting question comes in. I think that an objective biomarker is one of the key things that we need. Multiple, probably objective biomarkers are the key things that we need to develop treatments more rapidly.

So we are getting there though we are making progress on this. We as a community and regulatory agencies have not yet coalesced around, we are going to accept these markers as endpoints and so I think that's part of what we all need to work toward.

Prof. Orlando Barsottini: Okay. Thank you. Liana, this is my last question. Probably the most difficult question, but what is needed to fasten the development of new treatments? And tell me more about your perspectives for the future.

Dr. Liana Rosenthal: I think [00:18:00] there are a number of things that are needed, and I think the key though is how can we do these concurrently? How can we make sure that we are working on each of these and getting it all to move together well. So I think a couple things we absolutely need sensitive and validated, is the key word there, outcome measures that we can look at in clinical trials. And these validated outcome measures then need to be accepted by regulatory bodies. In terms of, endpoints for these clinical trials. So it's a bit circular, but we need the validated endpoints to then be accepted to then be tested, and we need to be able to move forward on that because I think we have some good candidates, especially in terms of target engagement. The other thing I think we need is we need more adaptive trial designs. So especially in these rare diseases, where there's a maximum number of patients that come to our attention. [00:19:00] These adaptive trial designs, things like platform studies and other designs, will really allow for multiple interventions to be tested more efficiently, but to really optimize that efficiency, again, we need these outcome measures.

So kind of all that circles back and we are working on improved understanding of the pathophysiology of the disease, and it is that basic science backbone that will then tell us which drugs we need to be testing potentially even then that ties to which outcome measures. Because different drugs may work on slightly different ways to then help guide which outcome measures and which biomarkers we wanna use.

All while making sure the regulatory bodies are going to accept what we're doing in terms of drug approval in the end. If that's a complicated answer, perhaps. But I think that's where we're going and I think that we can do all of those things together in order to hopefully get new treatments in the future.

So I'm optimistic to go back to his first question, but I still think [00:20:00] there's a lot more work that needs to be done.

Prof. Orlando Barsottini: Thank you, Liana, for sharing these insights and thank you to our listeners for joining us. We hope this episode helps you approach ataxia treatment with greater confidence and procedure. Thank you.

Dr. Liana Rosenthal: Well, Thank you for having me. It's been great talking with you.