Voiceover: 

Welcome to The Raw Nerve, the official podcast of MS Australia, a conversation space for all things multiple sclerosis. Join us for news and views on the latest research, treatments and advocacy efforts, as well as candid and informative interviews with our community, those living with MS and their families and carers, together with leading clinicians, researchers and advocates.   

Tennille Luker: 

Welcome to The Raw Nerve. I’m Dr Tennille Luker, Head of Research at MS Australia and I’m joined today by my colleague, Dr Julia Morahan, Deputy CEO at MS Australia.  

Recently, we attended ECTRIMS 2025, the world’s largest MS research congress held this year in Barcelona. With over 9,000 delegates from more than 100 countries, the event brought together the global MS research community to share the latest breakthroughs in diagnostics, therapeutics, and precision medicine.  

In this episode, we’ll unpack the most exciting developments, clinical trials, BTK inhibitors, updated diagnostic criteria and more. We’ll also reflect on what these advances mean for the future of MS care and the people it impacts. So, let’s dive in.  

This is the first ECTRIMS Congress I have attended. And I must admit I was quite overwhelmed by the sheer amount of research that was going to be presented there. But once I got there, it was actually really cool, and everything was streamlined and really nice. What did you think, Julia? 

Julia Morahan: 

I thought this was a fantastic ECTRIMS and was very excited to be able to share this with Tennille. Honestly, so wonderful to be able to have an Australian presence at these big international conferences. I think ECTRIMS 2025 didn’t disappoint. We have lots of exciting results that we want to talk about today and contextualise for you. Really, really fantastic conference. 

Tennille Luker: 

Yeah, completely agree. It was, was really awesome. So, the theme for this year’s conference was a new era of precision. So, this emphasises personalised care, early diagnosis and targeted therapies, which is definitely what we saw there this year.  So, the first session we wanted to talk about was the updated McDonald criteria. So as many of you know, the McDonald criteria is used to diagnose MS, and it’s gone through a few iterations of being updated and it was recently updated and published in Lancet Neurology. There’s been quite a few articles um by us about that. And I think it’s going to provide an opportunity to diagnose MS earlier. Julia, did you want to talk about one of the talks that you thought was really good there?  

Julia Morahan: 

Yeah, so I think we know as an MS community that in fact the McDonald Criteria was presented at ECTRIMS last year, ECTRIMS 2024. So, people kind of have known that this is coming and the publication is now out, which is fantastic. But it also gave clinical teams who were involved in the update to the criteria, the opportunity to see how they performed, I guess, in the real world.  

So, we saw a presentation from Luca Bollo from Spain, where he looked at around 300 people, who were being checked for MS. They were doing the work up and he compared the new 2024 criteria, compared to the previous, 2017 criteria and found that the new criteria allowed doctors to diagnose MS in more people, so that the numbers were 71% versus 47, which is fantastic. That’s exactly what the committee was after when they were doing the revisions. And really means that there’s a wider range of tests that doctors and clinical teams can use and new brain scan features. So, people don’t have to wait as long for a diagnosis. So fantastic to see that actually pan out in the real-world setting.  

Tennille Luker: 

Yeah. I think Wallace Brownlee from the UK presented very similar findings where he was testing the new criteria in real-world clinics. So, his team looked at nearly 200 people who were being checked for MS in a real clinic. And the new criteria meant more people were diagnosed with MS right away and fewer were left in that ‘maybe’ category. 

So, it’s quite clear that the new criteria are very good at catching MS early. But there’s also that risk of overdiagnosis. So, I guess we’ll kind of see that down the track and what that means.  

So, in summary, when it comes to the updated McDonald Criteria session, this updated criteria means more people can get a clear MS diagnosis sooner but making sure everyone has access to the right test is still a challenge worldwide as well.  

Julia Morahan: 

Exactly. So, I think we also wanted to talk about, it was a really, really interesting session about moving away from our classical phenotypes of MS to a more mechanistic characterisation of MS. And what we mean by that is we’ve had these very long-standing categories, subtypes of MS, things like relapsing remitting MS, primary progressive MS, secondary progressive MS that we’ve been using for a very long time.  

But really, we think we now know enough about the disease mechanisms that we could possibly change the way that we think about disease course and focus on maybe using new tools like MRIs or machine learning or blood tests, to look deeper and really understand what’s happening in the body and in the brain of people that are living with MS, giving us a clearer picture of the disease and a better way of describing it, which ideally gives us the chance to have better predictions about outcomes and importantly, a much more personalised treatment pathway, I guess, for people living with MS.  

So, Tennille, what were your highlights from this session?  

Tennille Luker: 

Yeah, so there was a couple of talks that I found quite interesting.  

So, one of them was focusing on identifying MS subtypes using MRI based machine learning. So, machine learning is a type of artificial intelligence. This was presented by Alessia Bianchi. And what they did was use machine learning to analyse MRI scans from people living with MS, which revealed hidden subtypes and stages of MS. And the two main MRI based subtypes they found was one with lots of lesions very early on, and another with widespread brain shrinkage, but with fewer lesions. 

And they found that these subtypes matched up with how advanced the disease was. So, by using this machine learning technique along with MRI scans, this can help clinicians better understand, classify and track MS, which could lead to more personalised care and better predictions about how the disease will progress.  

There was also a talk by Paola Valsasina, again, using machine learning. And so, what the researchers did here was they used machine learning to analyse MRI and clinical data from over 1,500 people with MS and 500 without MS. And they found that machine learning can accurately diagnose MS, tell subtypes apart, and predict disability using, and predict disability.  

So, the models could tell MS from people without MS with up to 95% accuracy and predict disability scores reliably. And the most important factors of predicting these disability scores were brain lesion volume and the size of certain brain regions. So, these MRI features, along with this clinical information, helped the machine learning models accurately predict how much disability a person with MS might have. And so, these tools could help support earlier diagnosis and more tailored treatment for people with MS.   

Julia, what were your highlights from this session? 

Julia Morahan: 

Yeah, so I really liked a presentation from Ahmed Abdelhak and it was about serum proteome changes in pre-symptomatic MS, which essentially just means changes to proteins in the blood. Is there a way that we could have a blood test that is looking at protein changes, but in those people that maybe don’t even have MS yet, so in the almost pre-early stages of MS. And I think really this is part of our ongoing push globally and in Australia, of course, about the earlier that we can diagnose MS or start tracking people that might develop MS, the sooner we can get the treatments in front of them and hopefully improve their outcomes.  

So, this presentation was pretty incredible. They had blood samples from people, years before they developed MS that showed signs of myelin damage up to eight years before they developed symptoms followed by nerve injury and then changes in support cells much closer to the symptom onset. And then further, they took that, and they identified a set of blood proteins that could help spot people at risk long before the symptoms start.  

So, I think the key takeaway is really that this brain injury in MS starts much earlier than the clinical symptoms that we see. And the goal honestly is that one day we might be able to have a blood test that can help clinicians and healthcare teams identify and treat people with MS…at risk of MS, I should say, really much sooner.  

Tennille Luker: 

I was going to say eight years, picking up that damage eight years before is insane. Absolutely incredible. So that’s very exciting work.  

Julia Morahan: 

Very promising. And I think a really important step towards our arsenal of being able to really get in there as early as possible. And I think really, this whole session, the cutting-edge technology that they’re using with the MRIs, with the machine learning, with the AI, with the blood tests. It’s really about trying to predict MS, predict the prognosis of MS, better monitoring. With honestly, the goal of early detection and trying to get more precise treatment for people and improve their outcomes. So overall, a fantastic and very encouraging session. 

Tennille Luker: 

Yeah, I completely agree. So, I think one of the, one of the, my highlights as well was the session on emergent therapies and MS and related conditions. So, there’s a lot of new therapies coming into play here. A lot of them still in clinical trials and not just for MS, but also for MS related diseases.  

So, one of the talks I found quite interesting was on frexalimab in relapsing MS. And this was presented by Patrick Vermersch. And frexalimab is a new type of immunotherapy that works differently from current MS drugs. So, it’s an anti-CD4L antibody as opposed to the anti-CD20 antibodies that we see. And what they found was that after two and a half years, most people had no relapses and very few new MRI lesions. And the side effects were mostly mild, like simply colds and headaches.  

And I guess this matters because frexalimab could become a new, effective and well tolerated option for people with relapsing MS. And as we know, people respond to MS treatments differently. Everyone has different symptoms and finding the right treatment for people is of high priority. What about you, Julia? What was your highlight at this session?  

Julia Morahan: 

I’m going to talk a little bit about fenebrutinib which is a BTK inhibitor that’s been on the scene for a while. But I also just wanted to mention that I was actually really pleased to see Xavier Montalban present a negative study in this session.  

So, we do know in kind of scientific literature and conferences and things, there is a natural bias towards all of these studies that work… that have positive results, but in fact, it’s really important to know when things don’t work as well and potentially try and figure out why they’re not working.  

So, Xavier presented something called a RIP K1 inhibitor, that has a long, complicated name of a SAR 4, 4, 3, 8, 2, 0. But, in fact, it didn’t improve the nerve damage markers or improve the MRI scans. So, I think while it always very disappointing to hear about these kinds of studies, because we all have such hope that everything will work beautifully and fast track everything, just really pleased to see that that was on the agenda to let everybody know how it went.  

But I think fenebrutinib, I’m very excited to see this study read out. And I think we’ve talked a lot to our MS community about the BTK inhibitors as a new class of oral MS drugs. And they work a little bit differently from our current treatments and they target specific immune cells, both in the blood and inside the brain, rather than suppressing the whole immune system.  

So, it’s really a bit more of a precise approach, which is good news because you get fewer side effects and really, they could be very useful for treating forms of MS that are harder to control with today’s medicines. It’s something that we can add to our treatment arsenal. We’re very, very keen on how we’re going to go with the BTK inhibitors in the progressive MS space. But G1O at ECTRIMS also presented the fenebrutinib study phase two in relapsing MS and it looked very good, I have to say. So, after two years, nearly 80% of people had no evidence of disease activity. So, no relapses, no new MRIs, no worsening of disability. And 92% were relapse-free and no new active MRI lesions were seen.  

So really very, very effective treatment for this relapsing cohort. And the side effects were mild, similar to what Tennille said, minor infections, no serious adverse events were seen, which is great news.  

So, the next step after something like this is to go into a phase three study, which is essentially a much, much larger study in a bigger group of people that are probably a bit more diverse, to make sure that we’ve tested it in enough people to say that we think it’s safe to go out into the world. But this result as a phase two study was excellent and very pleasing to see.   

Tennille Luker: 

Yes, it is very exciting. The BTK inhibitors and there a couple coming into play soon, including tolebrutinib, which is currently going through a fast-track FDA approval process. So hopefully there’ll be positive results from that as well.   

Julia Morahan: 

So, my absolute favourite session at ECTRIMS every year, and I’ve been incredibly fortunate to go to a number of ECTRIMS conferences over the years, is the ‘late breaker’ session. And it is a special session where the absolute, most recent, high impact research findings are presented. And they’re often so new, or usually so new, that they are not available at the time of the regular abstract submission deadline.  

So, people get up, and they say, this is stuff that we only saw a couple of weeks ago, or we have literally just drawn this graph. It’s extremely exciting and it just feels like very cutting edge.  

And we’ve been incredibly fortunate as a community that for the last few years in MS, because we have been very fortunate with our treatment pipeline, that this is where the big clinical trials read out. So, I love it. This is my favourite bit. And we were not disappointed this year with what we saw.  

And so, I am going to ask Tennille to talk a little bit about some findings around ocrelizumab, which is a drug that is already on the market. So, very interesting to see it in a number of settings to try and kind of expand its applicability and really fantastic work from everybody to get these clinical trials over the line. So, Tennille.  

Tennille Luker: 

Yeah. So, in terms of ocrelizumab, there were quite a few studies um and I agree, it was my favourite session of my first ECTRIMS. So, I really did enjoy it.  

So, as we know, ocrelizumab has been approved for both relapsing MS, relapsing remitting MS and primary progressive MS in Australia, but it’s only available on the PBS for relapsing remitting MS. And it was quite interesting. Gavin Giovannoni presented the ORARORIO-HAND study, which is looking at ocrelizumab in primary progressive MS.  

So, in this study, ocrelizumab was tested against a placebo in people with primary progressive MS, including those with more advanced disease. Again, a phase three study, this showed that ocrelizumab significantly delayed disability progression and worsening of hand function compared to placebo. And this is incredibly exciting because as we know, having hand function is absolutely vital. And if we can do anything to at least stop the progression of worsening of any form of disability, that’s fantastic.  

Julia Morahan: 

I completely agree, Tennille. I think given that this clinical trial was in people with much higher EDSS scores and perhaps a group of people that are not necessarily always included in clinical trials and the cohort was also much older. So, really wonderful to see the inclusive inclusion criteria of this study. 

And as Tennille mentions, hand function is so important. So, these people are wheelchair bound. That was the criteria. So, hand function is super important. It’s about their ability to manoeuvre the wheelchair. In some cases, it’s about their ability to transfer in and out of the wheelchair. And often if they’re not able to use their legs effectively, your hands become, become paramount.  

So, this is something that we have been talking about that Gavin Giovannoni, to be fair to him, has been championing for a long time. So, really excited to see this clinical trial finally come to completion.   

Tennille Luker: 

Perfect. Brenda Banwell also presented findings on an ocrelizumab clinical trial compared to fingolimod in paediatric MS. So, as we know, treatment options are quite limited for children living with MS. In Australia, we really only have fingolimod and natalizumab.  

So, what was presented here is the first head-to-head trial of ocrelizumab versus fingolimod in children and teens with relapsing remitting MS. And this phase three study tested whether ocrelizumab is at least as effective as fingolimod in reducing relapses and MRI activity. And it was successful. It was very exciting. It was highly effective. It was definitely as effective as, as fingolimod. And this is really important because this might be another, another high efficacy treatment that will be available for children living with MS. so, I mean, I think this was the most exciting result for me in the ‘late breakers’ to be perfectly honest.  

Julia Morahan: 

That’s fantastic. And I think we, we know, you know, children like adults need early intervention and treatments as soon as possible. It’s very difficult to do clinical trials in children. So, another fantastic effort to get this clinical trial done and show that it is now an official option for children living with MS who we know reach their disability milestones faster. So, anything we can do for this cohort, it’s just brilliant. We don’t always see results for clinical trials in paediatric MS. So, I agree Tennille, awesome moment for paediatric MS and the field. 

I’m going to talk about a study that came out of the University of Cambridge and was presented by Nick Cunliffe. And I really also thought this was very promising, but for slightly different reasons.  

So, it was looking at metformin, which is a drug for diabetes, and clemastine, which is an antihistamine, in combination to try and promote remyelination in MS. So, we’ve had hints before that metformin might be a good product in a repurposed way. It might have some remyelination or neuroprotective effects. And we’ve also had some hints in previous studies that clemastine might be useful. 

Clemastine has been tested before and unfortunately was not clinically useful, I guess, in isolation. And so, the idea between, for this study was to combine the two, to see if when our powers combine, we can get a result for remyelination, which is something that we have been chasing for a long time and remains one of our greatest unmet needs.  

So, they designed this trial as phase two. So, in, in people, and they particularly looked at something called visual evoked potential tests, which is a way of measuring how quickly you can get nerve signals between the eyes and the brain. So, they, they did that, and they did find in fact, slightly disappointingly that over the six months, the signal stayed the same in the people taking the medication. So that’s good. The placebo group, the signal slowed down.  So, it’s really small, but it was there, it was significant. But the disability and the vision tests really showed no difference between the groups.  

So, I think there’s a couple of things that we can take away from this. One is that in this particular kind of setting or clinical trial design, it was not clinically relevant, which was upsetting, not great, but there was actually definite difference. So, I think what we’re looking at here is a proof-of-concept study; that people with MS could have a medication that is able to remyelinate in the first place, which I think is (a) really, really, really important piece of information to definitely have now.   

But I think what we need now is how do we kind of take what we’ve learned from this and move it into something that makes clinical difference. But I think from a, the reason I kind of loved it was that we showed, well they showed, I didn’t show anything. They showed that it’s possible. This is a definite positive proof-of-concept. And I think you’ve heard me talk about a lot about the unmet need for progression and the unmet need for something that can repair myelin or repair damage. And this really showed us that it’s possible and it’s out there. We just need to find a better way of getting to it.   

Tennille Luker: 

I completely agree. I mean, yeah, progressive MS is…medications for progressive MS is definitely an unmet need. And this shows promise at least. It’s a stepping stone to get us there.   

The last thing I want to talk about was the patient community day, which happened on the final day of ECTRIMS. So, this is a special part of ECTRIMS designed for people living with MS, their families and advocates. And the first session focused on the patient journey from diagnosis to emerging therapies, rehabilitation and lifestyle modifications. It also highlighted the critical role nurses play throughout these stages. And that’s something we’ve identified in our MS Nurse Care in Australia Report as well.  

Session two dove into cutting edge research presented at ECTRIMS covering biomarkers, smouldering MS, cognition, genetics, imaging, AI, infections and vaccinations. So, I just want to say if you missed it live, you actually can watch the full program online and we’ll include the link in the show notes.   

So, Julia, thanks for joining me on the podcast and sharing your perspective of ECTRIMS. And until next time, thank you.   

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Thanks for listening to The Raw Nerve, the official podcast of MS Australia. To hear more, subscribe to our podcast today at msaustralia.org.au/podcast.