A few organizational remarks. Please note that all participants will be in listen-only mode, and this event is being recorded. After today's presentations, there will be an opportunity to ask questions. The Q and A session will be held at the end of the event. In addition to the Immunic team, our two experts will stay online and be available for questions. If you join the webcast via the Zoom platform, there are two ways to submit questions. You can either submit your questions in writing via the Q and A tool of the Zoom portal, or if you would like to speak with us directly, please use the raise hand function of the Zoom portal to queue your question. As always, before we begin, I would like to remind you that this presentation may contain forward-looking statements.
Such statements can be identified by words such as may, will, expect, anticipate, estimate, or words with a similar meaning, and such statements involve a number of risks and uncertainties that could cause Immunic's actual results to differ materially from those discussed here. Please note that these forward-looking statements reflect Immunic's opinions only as of the date of this presentation, and it undertakes no obligation to revise or publicly release the result of any revision to these forward-looking statements in light of new information or future events. Please refer to Immunic's SEC filings for a more detailed description of the risk factors that may affect Immunic's results and these forward-looking statements. Let's move on to today's actual agenda.
I'm super excited that two internationally renowned experts will be speaking on the call today, Dr. Jiwon Oh from the University of Toronto, and Dr. Maria Pia Sormani from the University of Genoa in Italy. Moreover, we will have our Immunic management team presenting, including Erik Lundgren, CEO, Dr. Hella Kohlhof, CSO, Dr. Mike Panzara, CMO, and Jason Tardio, President and COO. During today's event, the group will discuss the key unmet needs in progressive MS and the persistent needs for innovative approaches to the development of therapies that target novel mechanisms associated with neurodegeneration and MS progression. Immunic management will highlight the potential expansion opportunity for vidofludimus calcium in progressive MS, including the clinical and scientific rationale supporting the initiation of a phase III progressive MS trial. With this, I would like to hand over to our CEO, Erik Lundgren, to kick things off. Erik?
Great. Thank you, Jessica, and thank you everyone who's joining us live and/or anyone who watches the recording after the fact. Really appreciate your interest in Immunic, in vidofludimus calcium, and in our very important efforts in progressive MS. Next slide, please, Jessica. I'll be quick. I just want to set a little bit of the context here. It's an extraordinarily exciting time at Immunic. We're really in a pivot, so pivoting towards a fully integrated commercial company with a real laser focus on multiple sclerosis. While we're going to spend the vast majority of today talking about our efforts in progressive MS, which I think represents the greatest unmet need in multiple sclerosis, it would be remiss of me to not mention that we also have a very near-term catalyst in relapsing MS.
And so we have two phase III studies, the ENSURE-1 and ENSURE-2 studies that are reading out in December. Everything is on track for that. We look at that as a near-term value inflection point for the company. If those studies are successful, allow us to submit an NDA next year and reach the market in 2028 with a relapsing indication. That will allow us to really establish our presence commercially, further advance and mature the company, and ultimately get to profitability so that we can support the next value horizon, which is truly defined by the topic of today, which is progressive MS. This is, as I said already, arguably the largest unmet need in MS today, and it represents progress in this space, represents tremendous value for the MS community, most importantly for people living with MS, and of course, for the company as well.
So, truly excited about the moment that we're in here, sitting on the cusp of data for our relapsing indications and simultaneously preparing for and initiating our studies, our further study, phase III study in progressive MS. It really is an example of what we're trying to build here, which is a leading organization focused on MS and people living with the disease, both in terms of how we're building ourselves, but also, I think you'll see in the presentations today, a reflection of us really starting with the patient and listening to what they value, what they struggle with, and ultimately, what would be meaningful for advancing and improving their lives. Next slide, please, Jessica. As you can see here, we have a lot going on, but in green, we're going to be talking at the bottom of the slide.
You see our phase II progressive MS study called the CALLIPER study. This study has been fully read out, and Dr. Mike Panzara will walk through some of the detailed findings of that study that enrich our hypothesis and thesis around our ability to really meaningfully move the needle in progressive MS, and that phase II data is a big part of the basis of that confidence as we move into, as I said, a phase III study in progressive MS. That study is in preparation and being initiated now, with a plan for the first patients to be enrolled in the first half of next year. Next slide, please. Last setup here, as I walk through, right now, it's about building the foundation for a commercial organization laser-focused on MS. That work is happening as we speak.
In this middle period, following an FDA approval based on the ENSURE data set in relapsing disease, we start to scale. We really establish ourselves in the MS community. We're generating cash and getting to sustainability from an operating environment and balance sheet environment in that middle period, all setting up for and in preparation for becoming truly a global leader in MS on the back of both the ENSURE data, but also the progressive MS data that we'll talk about here. As I said, extraordinarily exciting time here at the company. We feel so privileged to have an asset like this and an opportunity like this to lean in to advance care across the full spectrum of multiple sclerosis. With that, let's get into the topic of the day. It is my distinct pleasure to have the opportunity to introduce Dr. Jiwon Oh.
Dr. Oh is a Staff neurologist, Scientist, and Medical Director of the Barlo MS Program at St. Michael's Hospital at the University of Toronto. Her research focuses on developing advanced MRI techniques for the use in clinical settings, the development of large data sets, and of course, her work as a clinical trialist. She leads the MRI research program at St. Michael's Hospital and is the principal investigator on numerous local and international multi-center collaborative studies. Dr. Oh is deeply committed to caring for people with MS, educating future generations of clinicians and scientists, and contributing to scientific developments that will drive the MS field forward. So with that, it is my distinct pleasure to welcome Dr. Jiwon Oh.
Thank you, Erik, and hello, everybody. I am going to, in the next 10 minutes, just set the stage for much of the discussion today and talk about what the greatest unmet needs are in MS and how important progression is throughout the entire disease course. I would say in the last 10, 15 years, what is becoming abundantly clear in the MS field to MS neurologists, to people living with MS, as well as scientists, is that MS really is a disease spectrum. We used to think that relapsing disease was really what happened at the beginning of disease in almost everybody. There was really very little progression until much later stages of disease or in people who are initially diagnosed with primary progressive MS.
But in part because of the successes of our treatment of relapsing disease biology, we are recognizing more and more that MS really is a disease spectrum, and there is this huge overlap of both relapsing and progressive disease biologies from the very beginning of disease until the very end of disease. Because of this recognition, international think tank groups like the International Advisory Committee on Clinical Trials in MS is publishing papers like this, which suggest that we really need a new mechanism-driven framework to describe the entire MS disease course. Probably the best pieces of evidence that illustrate this concept of MS as a disease spectrum and that both relapsing and progressive disease biologies are at play across the entire disease course is this publication of the first systematic description of progression that is independent of relapsing activity, or PIRA, as we like to call it.
This was first done back in 2020 by Ludwig Kappos and colleagues, and this was actually a post-hoc analysis of the pivotal phase III clinical trials that looked at ocrelizumab versus interferon beta-1a in people with relapsing MS. Like most contemporary relapsing MS clinical trial populations, this was a relapsing MS population that was very early in the disease course, so within a few years of diagnosis. When these investigators looked at this concept of PIRA, which was essentially progression or disability worsening happening well outside of the context of any clinical relapse, they were actually surprised to see that despite the fact that in our heads we always think that progression really does not happen in people with relapsing MS, they found that actually PIRA happens very commonly in people with relapsing MS very early in the disease course.
When you look at the disability worsening events in these clinical trials that happened, the vast majority, so nearly 80%-90% of them, were due to PIRA. This was a bit of a moment in the field when we recognized that, you know what? Progression that happens outside of the context of relapses is not something that only happens in progressive forms of MS or in the later stages of disease. It absolutely happens and happens very frequently from the very beginning of the disease. In addition, when you look at contemporary MS clinical trials that looked at purely progressive forms of disease, again, we think if based on that prior framework, that in these people, there should be very little evidence of relapsing disease activity.
What we see, say in ORATORIO, that looked at primary progressive MS and ocrelizumab, EXPAND, that looked at SPMS and siponimod, and HERCULES, that recently looked at non-relapsing secondary progressive MS and tolebrutinib, when you look for gadolinium-enhancing lesions, which we think is the MRI equivalent of relapsing disease activity, you very clearly see that even when you're trying to look at purely progressive populations, you have actually a substantial portion of people that even at the beginning of the trial show evidence of relapsing disease activity based on MRI features. All of this shows us and clearly illustrates that MS is a disease spectrum and that both relapsing and progressive disease biologies happen across the entire disease spectrum. You might say then, what does this mean for the field?
Well, we're at somewhat of a crossroads, you might say, because this whole framework that we use to describe MS and to recruit for clinical trials is clearly problematic, and we're recognizing this again because in a way, we've been so successful with treatments that can really get rid of any evidence of relapsing disease activity, and it's clear that we need to figure out a better framework to move forward. This is exactly where that International Clinical Trials Committee is really trying to play a role in driving this forward.
Very recently, the Clinical Trials Committee published this paper talking about a roadmap of how we might transition from that old framework that we've used until now towards a more biologically informed description of MS disease course, which is very clearly needed in the field, first for drug development, because in clinical trials, we need to figure out how to do these trials better, and that we're not relying on that prior framework. In clinical practice, because there probably are emerging treatments in the next number of years that address aspects of progressive disease biology, we absolutely need to figure out how to describe MS more accurately. In that paper that was just published, there's a whole bunch of statements indicating what we might do as a field, but the take-home points really are that we can't describe MS based on clinical features alone.
It's really clear that a multimodal assessment of MS is needed and that this needs to be done across the MS disease course. We can't just say someone has relapsing MS based on the fact that they have clinical relapses. We need paraclinical evidence of relapsing disease as well, whether that's using MRI or blood biomarkers, and we need to take into account functional status and modifiers. As you can see from the figure on the right, this is again because this has huge implications, not just for the science in MS, but also for drug development as well as clinical practice. You might ask then, other than that, what is the greatest unmet need in MS?
Clearly, we need a better framework as to how to describe MS, but truly from a clinical perspective, the greatest unmet need in clinical practice are treatments for progression that can definitively alter the trajectory of disease. We have currently two treatments actually that are approved for progressive MS, ocrelizumab and siponimod, but we know in the field that these treatments are modestly beneficial at best, and very importantly, they actually do not target the disease processes underlying progression that's independent of relapsing activity. I'm displaying here again that study, that first systematically described PIRA. That study not only illustrates this concept of MS as a disease spectrum, but very clearly shows us that even when you use our highest efficacy therapies, progression still happens, and the progression that happens is related to PIRA.
It's very clear that this is truly the greatest unmet need in clinical practice. You might then ask, why is it so difficult for the field to address this unmet need? Why has it taken so long? Why do you have 20+ treatments that can address relapsing disease biology, but very few, if any, that actually definitively can address progression independent of relapsing activity? This is because the mechanisms underlying progressive disease biology are really complicated, and this is an illustration of the various different pathophysiologic processes that we understand are relevant, but there probably are many different disease processes that we don't understand as well. This is an area in the scientific field that is being intensely studied.
In addition, another major reason why we have not been able to definitively address this unmet need is because progression is actually very difficult to measure accurately, particularly in a complex chronic neurologic disease like MS that lasts decades, if not a lifetime. This is a huge problem that we have because in clinical trials, we're still focusing exclusively on some of these clinical measures that we know are problematic, like the EDSS, which is a scale measuring global neurologic disability, but we know that it is both insensitive to subtle neurological change, and it's insensitive to aspects of MS that are most important to patients, including cognition and fatigue.
The field has moved towards composite endpoints, but they are still problematic, as recent clinical trials have illustrated, where we were including things like Timed25 ft W alk and the 9-Hole Peg Test, but it turns out the Timed 25 ft W alk, because of its variability, may not be ideal to include. Many people are moving towards using EDSS and the 9-Hole Peg Test, which is a measure of manual dexterity. Then in the clinic, similar to clinical trials, this is a problem as well, because there are patients that we see, we know they are progressing, but the EDSS every year is completely stable, and so we often rely on what the patient tells us in the clinic to understand whether they are progressing or not. This is another huge reason why it has been difficult to find better treatments for progression in MS.
It is because the measurement tools that we have and that we rely on and that regulators actually force us to rely on in clinical trials are limited. This study just really quickly illustrates the fact that the EDSS is inadequate. This was a study done by Stephen Krieger and colleagues in New York, but they looked at people with MS who had EDSS scores of zero, so absolutely no objective evidence of disability. Their Timed 25 ft W alks were stable. But when they got these patients to do these high-challenge tasks of balance and upper extremity function, they found that these patients clearly had deficits. Just an illustration of the fact that our EDSS is inadequate and that we clearly need better clinical tools, including possibly digital tools that include both passive and active monitoring that may be useful.
Again, this is where it is very clear that in clinical trials and clinical practice, we need to move away from exclusive reliance on clinical tools and include better clinical tools, but also paraclinical tools like imaging measures that are relevant and blood biomarkers that are relevant. This is where, in the future, I envision that we may, as long as we can convince regulators, be able to move towards composite multimodal endpoints that more accurately reflect the clinical endpoints that we care about. This is an example of what, say, a relapsing composite multimodal endpoint might look like, a progressive multimodal endpoint might look like.
I hope I have been able to just set the stage to illustrate to you how MS disease course descriptors are clearly outdated, and we need a better way to describe MS and not rely on these categorizations that we did in the past. The greatest unmet need in clinical practice truly are treatments that target progressive disease mechanisms, and it is complicated to figure this out because progressive disease biology is complicated, and it is very clear that we need better clinical endpoints, which will need to include composite multimodal endpoints. Thank you very much for your attention.
Thank you very much. I'll go on here, and I'm happy to present vidofludimus calcium differentiated mode of action by being the first direct Nurr1 activator which was ever tested in multiple sclerosis. Next slide, please. What is Nurr1? Nurr1 is a member of the NR4A family of orphan nuclear receptor transcription factors, and it's expressed in microglia, astrocytes, and the neurons, and there it regulates transcriptional programs which are involved in neuronal maintenance and in survival. Therefore, Nurr1 can be associated with different neurological diseases. Via its expression in midbrain dopaminergic neurons, cortical and subicular glutamatergic neurons, Nurr1 is associated with different neurological diseases beyond MS, such as Parkinson's disease, Alzheimer's disease, ALS, schizophrenia, and other neurodevelopmental disorders. This could allow a broader indication spectrum for the use of vidofludimus calcium in the future. Today, we focus on multiple sclerosis.
In studies of relapsing MS, it was shown that reduced Nurr1 expression is associated with higher relapses rate and higher EDSS scores, and Nurr1 expression normalizes during pregnancy, coinciding with reduced MS disease activity. There's valuable research supporting the relevance of Nurr1 in progressive MS. The Pansieri publication showed that in post-mortem MS motor cortex, higher Nurr1 expression is associated with greater neuronal preservation, supported by higher neural density and lower lymphocytic infiltration, what you see in the depicted picture here. It showed as well that nuclear Nurr1 expression in layer three correlated with an older age at death, longer disease, and longer time to wheelchair. Therefore, we think that a drug which affects the expression and activity of Nurr1 is a valuable treatment option for progressive MS. Later on in the CALLIPER session, we'll hear more about it. Next slide, please. Yeah.
Here, we come to vidofludimus calcium, which provides a differentiated dual mechanism approach for the treatment of MS. Vidofludimus is a direct Nurr1 activator, which therefore may support neural resilience under inflammatory conditions and oxidative stress conditions. Preclinical findings suggest that vidofludimus has both direct and indirect neuroprotective mechanism. In vitro, in cell culture assays, vidofludimus calcium promoted neural survival and reduced neurotoxic signaling of activated microglia and astrocytes. In vivo, even in an inflammatory EAE model, vidofludimus calcium increased BDNF levels, and expression of Nurr1-regulated target genes were consistently increased with Nurr1 pathway activation. In addition to the direct and potent Nurr1 activation of vidofludimus, which clearly differentiates from other medications used in MS, vidofludimus calcium is a selective DHODH inhibitor, and thereby it contributes to anti-inflammatory effects, but by only targeting highly metabolically active T and B cells with no indication of broad immunosuppression.
Reducing EBV reactivation might be beneficial in addition. How is Nurr1 involved in neuroprotection? As I said, Nurr1 is a nuclear receptor and a transcription factor, and therefore it mediates its effects via gene regulation. This happens directly in neurons, but also indirectly via microglia and astrocytes. In neurons, which are depicted here on the left, you see that neuronal survival and differentiation is addressed via upregulation of BDNF and GDNF, for example, whereas functionality of dopaminergic neurons by better neurotransmission is addressed via the upregulation of direct target genes, like tyrosine hydroxylase and VMAT2. In addition, the reduction of oxidative stress and improvement of cellular energy production is mediated by direct target genes like SOD1 and COX5B, and further supports the neuronal resilience here.
Coming to the glial cells on the right-hand side, we see that activation of Nurr1 in microglia and astrocytes reduces neurotoxic cytokines like IL-1β and TNF-α, as well as reactive oxygen species and nitric oxide. This prevents glial cell-driven neurotoxicity in the brain. The impact and relevance of reduction of microglial activation is broadly discussed and shown for BTK inhibitors, for example. Here, we investigated in vitro the effect of vidofludimus calcium on cytokine production upon LPS-induced activation of human microglia and demonstrated a significant reduction of those cytokines with already low doses of vidofludimus calcium. This shows that vidofludimus is able to reduce microglial activation. What does it mean for neuronal survival? Therefore, we investigated vidofludimus' impact on neuronal survival in a co-culture of activated microglia and neuronal cells.
On the right, in the graph, you see that vidofludimus calcium was associated with increased neuronal viability in inflammatory co-culture. To demonstrate a direct neuronal protection by vidofludimus, which is independent of activated microglia, we used neurotoxic agents like TNF-α, cycloheximide, or what you see on the right-hand side, like six-OHDA, to trigger apoptosis in these neuronal cells. In these test systems, vidofludimus was able to significantly improve the neuronal survival. To further demonstrate the relevance of Nurr1 here for vidofludimus calcium's mediating neuronal survival, Nurr1 was knocked down, and this abolished the neuronal survival benefit of vidofludimus, leading to the conclusion that vidofludimus requires Nurr1 for its direct neuroprotective effects. To further strengthen the neuroprotective properties of vidofludimus and the Nurr1 relevance, we investigated the impact of teriflunomide, which is a DHODH inhibitor approved in RMS, and we used the same in vitro test systems.
Here, you clearly can see that compared to vidofludimus on the left-hand side, teriflunomide on the right-hand side did not significantly improve survival of neuronal cells. This is most likely explained by teriflunomide's lacking binding towards Nurr1 protein, which was tested in two different biophysical methods, namely ITC and DSF. Again, here you see vidofludimus clearly demonstrated binding towards Nurr1 protein, whereas teriflunomide did not. Based on the preclinical data presented here, Nurr1 activation and DHODH inhibition might offer a perfect treatment option for the whole spectrum of MS. Together, they may reduce inflammation, limit harmful microglia activity in the brain, and directly help neurons to survive. Thank you. With this, I would like to hand over again to Jiwon.
Thank you very much, Hella. I am back again, and this time, since we have already set the stage and heard a lot about the neuroprotective effects of vidofludimus, I will just continue on with the discussion about considering patient populations within clinical trials and how we might use both imaging and fluid biomarkers in progressive MS clinical trials and in practice, because clearly the reliance on some of these clinical endpoints is problematic. In the last number of decades, I think it is very clear in the MS field, in part because of the successes of treatment again, and in part because of rapidly changing diagnostic criteria that allow us to diagnose MS, really with the first clinical presentation, but even now in some situations, even before the first typical clinical presentation.
The face of MS that we are seeing now, specifically that we're recruiting in clinical trials, is very different than what we were doing decades ago. When you actually look at the annualized relapse rate that's been observed in clinical trials, specifically in placebo arms over the years, clinical trials that were done back in the early 1990s, up to almost the millennium, reported annualized relapse rates, which, as you know, is the primary endpoint still in relapsing MS clinical trials, between 0.5 and 0.87. When you look at annualized relapse rates that have been reported in more contemporary clinical trials, so within the last six years, as you can see, the ARR has dramatically decreased, sometimes is reported as 0.01 to 0.15.
It's really clear that this primary endpoint that we use and entirely rely on in phase III clinical trials of relapsing MS has decreased dramatically over time because of all of the reasons that we talked about, there really has been a nearly 80%-90% reduction on this measure that we're reliant on. It's very clear, again, in the modern era of MS, specifically MS clinical trials, prior clinical endpoints may no longer be sufficient to use because of the changing face of MS. As we discussed in the prior presentation, it's also very clear, based on contemporary MS clinical trials, that progression is not something that only happens at the end stages of disease or in progressive subtypes of MS, but again, happens across the entire disease spectrum, even in very early relapsing MS.
Based on this, really, the face of MS is changing, based on what we simply observe from clinical trials, so that these clinical endpoints that we still rely on for phase III trials are really not the same and are not as sensitive. We recognize that disability is happening even in early relapsing MS. We recognize that relapsing disease activity, based on MRI findings, is happening even in progressive MS. This raises this really important question. Given all of this, and that everything that we thought is shifting, how do we build these facts into upcoming MS clinical trials so that we may still adequately test drugs that we think have very unique mechanisms of action and can address some of these unmet needs that we still clearly have in clinical practice? Where should we go with clinical trials?
First of all, given all that we discussed, that MS is a disease spectrum, relapsing and progressive disease biologies happen across the entire disease spectrum. We see this. Clinical endpoints that we used are likely no longer adequate. The question that comes up is, when we're thinking about MS clinical trials, do we really need to restrict for specific MS subtypes in clinical trials, given that we know that both disease biologies happen? In a way, with this knowledge, we should be thinking about clinical trial inclusion criteria, and criteria should reflect the underlying disease biology that you think a drug targets, rather than relying on these outdated clinical phenotypes.
This is something that, as a field, we most definitely need to think about, because if we want to test drugs that we know have a very clear mechanism that addresses some aspect of MS disease biology, then we should think about inclusion criteria that go beyond the simple clinical designation and include people that have that biology of interest. In addition, again, based on the mechanism of the drug, we need to thoughtfully come up with inclusion/exclusion criteria, because we need to target appropriate populations for specific drugs.
If you know that a drug targets a specific aspect of MS pathophysiology, Nurr1, for instance, that might neuroprotect, or a certain aspect of chronic inflammation, then you want to target an appropriate population for a specific drug that you know is enriched in the type of pathophysiology that you think the drug can target, so that you can detect a meaningful effect on that mechanism of disease biology that you want. Essentially, this means that when we're thinking about inclusion and exclusion criteria, rather than relying simply on these clinical phenotypes, we need to think about, what is the drug that you have, what is the mechanism that you're targeting, and what population can we recruit that has enough of that mechanism that we think this drug benefits, so that we can meaningfully show an effect if it's there?
Again, this leads us to the conclusion that with clinical trials, reliance on these clinical endpoints may be outdated, and it's very clear that we need more sensitive ways to detect whether a drug has an effect on the disease biology of interest, and we need clinical or endpoints that are a composite of clinical and other endpoints that reflect what we're trying to measure. Very clearly, we need more sensitive measures, which likely will include, inevitably, clinical measures, but also paraclinical measures, enhanced clinical measures, and these biomarkers, so imaging and blood biomarkers that reflect the outcomes that are of interest to us. In addition, this concept of enrichment is really important.
It's not just the endpoints that we need to figure out how to do better, but again, at the very beginning of the trial, when we're thinking about inclusion criteria, we need to include a trial population that we think has a lot of the disease mechanisms that a certain drug is likely to benefit. We actually already do this in MS clinical trials for relapsing disease, where with most relapsing MS clinical trials, we'll recruit people who have had frequent relapses in the years prior to enrollment or have MRI evidence of relapsing disease activity, which is either gadolinium-enhancing lesions or new T2 lesions.
The question comes up, now that we clearly understand that the unmet treatment need in MS are definitive treatments that target mechanisms underlying progressive disease biology, how are we going to enrich for people who have an abundance of progressive disease biology and the mechanisms that you want to target with specific drugs? This is where some imaging biomarkers may have an important role. In the MS field, there has been a lot of interest in imaging paramagnetic rim lesions, or PRLs. This is simply an imaging measure that we think reflects chronic active lesions, which we know are one important, but not the only component of progressive disease biology. Many studies have been done. We know PRLs are linked to having greater disability.
What is really interesting is that when you look at recent post-hoc analyses from some of the BTKI clinical trials, it turns out having a PRL at baseline greatly increases your risk of developing disability over a trial period of two to three years. As you can see from this diagram here, just focus on the gray bars, when somebody had zero PRLs, the risk of disability progression in the HERCULES trial was 21%. But when an individual had four or more PRLs, the risk of disability progression prospectively over the clinical trial period was nearly twofold. This is a way that potentially in clinical trials moving forward, we can address that issue of enrichment for progressive disease biology, because it maximizes our chances of seeing if a drug has an effect on the biology that we are interested in targeting.
In addition, PRLs are potentially being looked at as measures of treatment response. Very recently in the FENtrepid and FENhance clinical trials, this BTK inhibitor showed a reduction in the percentage of patients who had an increased PRL count at the end of the study. It seems like there is potential for enrichment with this imaging biomarker, as well as potentially as a biomarker of treatment response. In addition, an alternate way that we image chronic active lesions other than PRLs is something called slowly expanding lesions, which is a technique when you have a few MRIs in the same person over time, you can see if a lesion slowly expands. There seems to be quite a bit of potential for use of this measure as a measure of treatment response in progressive MS trials.
From the CALLIPER study, people treated with vidofludimus calcium showed a reduction in the number of new SELs at the end of the study in comparison to those who were treated with placebo. Again, in the fenebrutinib phase III clinical trial, SEL count and SEL volume were reduced in people who were treated with fenebrutinib in comparison to the active comparators. Both of these imaging measures, they are different methods to detect the same thing, which are chronic active lesions, a major driver of progressive disease biology, seem to have potential as an enrichment biomarker, as well as a biomarker that reflects treatment response. In addition, blood biomarkers.
I don't want to go into too much detail about this, but things like NfL and GFAP, it seems when you use them smartly, may be able to reflect not just relapsing disease biology, but also progressive disease biology, particularly when you think about timing as well as combinations. Again, we land on this slide that you've already seen, where ultimately in clinical trials, it's clear that we need to move away from exclusive clinical endpoints to more composite multimodal endpoints. I'm just going to end by saying clearly the face of MS has changed. Previous clinical endpoints that we relied on need to be revisited. When designing future clinical trials, we need to think about inclusion criteria and endpoints. Thank you very much.
Thank you, Jiwon. Thank you so much for diving into progressive MS clinical trials, patient populations, and the different biomarkers and endpoints. We really appreciate your insights. I would like to bridge to our next speaker, Maria Pia Sormani, who will continue diving into these details and more look at clinical and disability endpoints. Maria Pia Sormani, Full Professor of Biostatistics at the University of Genoa in Italy, is an internationally recognized biostatistician with over 25 years of impactful contributions to MS. Her work has fundamentally shaped clinical trial design, surrogate endpoint validation, and data-driven decision-making in MS worldwide. Her contributions bridge methodological innovation and clinical applicability with direct impact on patient care and regulatory strategies. Maria Pia, over to you.
Thank you, Jessica. Thank you very much for this kind introduction. In these 10 minutes, I'll try to show you some issues we have with clinical trial design and endpoints for progressive MS. As Jiwon clearly explained, we are going through a new vision of MS. We are passing from rigid clinical labels to a biological view of MS as a unique disease with shared biological mechanism. However, even if our vision is changing, our approaches are still very rigid. This is the classical standard development of a drug in MS. We have a phase II based on MRI lesions, a phase III based on relapses, usually in the relapsing forms of the disease, and then a separate phase III trial to address some effect of the drug on disability.
This schema has worked for many years because we were testing drugs with very similar mechanism of action, mainly anti-inflammatory drug with a strong effect on acute inflammation. Of course, we are having this approach is less effective if we want to test the effect of a drug on the progressive biology. Here we have the endpoint challenge for progressive MS trials. First of all, we have a few biomarkers, and the biomarkers we are using has a lot of limitation. For designing a phase II in progressive MS is always an issue. The classical, the standard biomarker we have used so far for phase II studies in progressive MS is brain atrophy, but brain atrophy is a very aspecific marker. It's the volume of the brain, so it's not linked to any specific mechanism, and recently it gave inconsistent findings.
We had some positive trials on disability and negative on brain atrophy or vice versa. Jiwon alluded to the MRI markers of chronic inflammation like paramagnetic rim lesions and slowly evolving lesions. I mean, their biology is clear. We are all pretty sure that they are markers of chronic inflammation, but they are still under investigation as endpoint for clinical trials. We still don't have clear quantification of these biomarkers to be used as endpoint in clinical trials. Well, Jiwon also alluded to the limitation of clinical endpoints. The EDSS has a limited sensitivity to change, is heavily weighted towards ambulation, and it does not cover the full spectrum of disability. For this reason, now in progressive trials, but also in relapsing-remitting trials, we use composite endpoints integrating EDSS with other functional endpoints. But this causes some issues with regulatory acceptance and sometimes also in the interpretation.
Why, I mean, we need different endpoints. This is just an example about what happened to confirm disability progression. That's the standard disability endpoint since the first clinical trials in MS. The event rate declined over time, exactly as the relapse rate has declined a lot over time. The same happened for disability progression events, also because we are now forced to use active comparators. While in the early 2000, the rate of event for confirmed disability progression was around 25%, now has dropped incredibly, and in recent trials, it is below 10%. I mean, it's quite impossible to demonstrate the superiority of a drug to such low rate of events. I'm talking here of relapsing MS. In progressive MS, the rate of events is a bit higher, but anyway, it declined over time also for progressive MS. Composite endpoints.
The composite confirmed disability progression is a standard composite that is also accepted by regulators and is made up of three different components. A patient is defined as progressed if he progressed on EDSS or 9-Hole Peg Test , addressing upper limb function, or Timed 25 ft Walk, addressing walking ability. Of course, a combination of endpoints in an or fashion increase the number of events. It is sufficient to be progressed in one of the three components to be defined as progressed. However, more events does not automatically translate in higher sensitivity to detect a treatment effect. Here we have a list of trials. The red trials are those where the confirmed disability progression based on EDSS alone was more sensitive, and the blue are those where the composite was more sensitive.
You can note that even if the higher number of events gives narrower confidence limits, sometimes the disability based on EDSS alone has lower hazard ratio. You must find the balance of higher number of events and more specific outcomes, because if you add noise, you can't have a treatment acting on noise. The noise always dilute the treatment effect. This is why our group of statistician is trying to propose new methods for combining endpoints in composite endpoints. Here, I'm showing you an example coming from oncology, the approach based on the net benefit. The net benefit approach, instead of taking the average effect, the average number of events in both groups and taking the ratio, compare each treated patient with each control patient. You will have a lot of comparison, and for each comparison, you evaluate who is the winner.
If the treated patient is better than the control patient, you will have a win. If the control is better, you will have a loss. Otherwise, the two patients has the same outcome, you will have a tie. The net benefit is the excess of wins over losses, or on a relative scale, you will have the win ratio, that is the ratio between the wins and the losses. In this way, it is possible to combine in a unique way a combination of endpoints. You must create a hierarchy based on the most important outcome, followed by all the other, and you evaluate each pair based on the most important outcomes. If you have a win or a loss, you stop. If you have a tie, you go for the second outcome. Here is a random list.
We put disability as the first, brain volume loss as the second, relapses as the third, and so on. You can include also patient-reported outcomes and other outcomes in the list. You can create a very long list in order to eliminate the ties and keep into a single measure the effect on different endpoints. The interpretation, if you have a net benefit of 15%, this means that over 100 patients, you have 15% more wins than losses. Or on a relative scale, a win ratio of 1.5 means 1.5 x as many wins as losses. This approach, interestingly, can be also applied to EDSS improvement and worsening. Please note that EDSS improvement is a relevant endpoint, especially for drugs showing neuroprotective effect, because this kind of drugs can cause an improvement in the clinical disability.
It is important to take also into consideration the possibility of detecting an improvement. However, regulators, they don't trust improvement if they don't have an effect on worsening first. With this net benefit approach, we can combine in a single measure improvement and worsening. You compare two patients, for example, on improvement first, and then if you don't have a win or a loss on improvement, you can compare them on worsening. Here, it's an example on CALLIPER. CALLIPER was the phase II clinical trials in progressive MS evaluating vidofludimus calcium versus placebo, 200 patients per arm, approximately. A very low number for having the power to see an effect on disability. The study was negative on the primary outcome, that was brain volume, but there was some signal on the 24-week composite disability progression. Interestingly, the drug had also a very strong effect on improvement.
The possibility to improve, the risk of improvement was doubled in patients treated with vidofludimus calcium versus placebo. With the win ratio approach, so combining all the wins over all the losses and comparing each patient to each other in both treatment arms, and comparing if the patients improved or stable or worsened, the win ratio was 1.55 and the p-value was significant. This approach includes improvement and worsening, so it can be accepted by regulators and in a single measure bring all the information we need about the effect of the treatment. This is the interpretability of this measure, but I already talked about that. A conclusion. Jiwon clearly stated that new outcomes must be explored for progressive MS. This is something that we continue to talk about, but we are still very locked in the standard approach.
So, the primary outcome of our clinical trial is still confirmed disability progression. New standard methods can be evaluated for composite endpoints. This is for free because it does not imply collecting new kind of endpoint, but it's just a way for optimizing what we have collected. The net benefit and the win ratio can summarize multiple outcomes according to a pre-specified clinical hierarchy. This is very useful also for incorporating patient-reported outcomes. Other EDSS outcomes, so worsening and improvement, must be evaluated, especially for drugs that are expected to have a neuroprotective effect. Also patient priorities can inform the hierarchy. So, the hierarchy can be different according to different patients' perspective, so creating a very patient-oriented treatment effect measure. That's all on my side.
Great. Thank you. Thank you so much, Maria Pia, and thank you, Jiwon. I'm going to start next, but I'm not going to have a lot to add to those great presentations from Jiwon and Maria Pia, and of course, Hella's introduction, as we go into where we're headed with our progressive MS program. Next slide, please. I think understanding, we don't have to go much into the unmet need. It's been well established now, I think, in this conversation and by others, the unmet need here. This title of potential to change treatment paradigm, I don't say that lightly. I think that it's unusual to be in a situation where you have a compound with a potential mechanism that targets what we believe is the underlying process, part of the underlying progressive process in multiple sclerosis throughout all stages of disease.
At a time when progression is becoming increasingly realized is such a core element from disease onset, that there is that potential to introduce a new approach with novel drug trial design and lead to an understanding and hopefully benefit to people with the disease, again, targeting that core underlying concept. Next slide. That's sort of what's shown here and already has been described. It is increasingly clear that the progression in MS is a continuum of common underlying process from the earliest stages. I think this just summarizes some of what was already highlighted by Jiwon in her presentation. But where we are now with the environment and our understanding of the disease, it's really a perfect time to take into a progressive study a compound with a potential unique mechanism, as well as pulling in some of these learnings to help evaluate a potential benefit.
Next slide. This is the study design of CALLIPER now. So the phase II study, Maria Pia mentioned the study. This is some of the inclusion criteria on the left, the study design on the right. I think a couple things just to point out. First of all, it's a large study. This is a very large phase II study, 467 patients, most of whom are still in the open-label extension study with a follow-up of nearly six years or so in many of these patients.
The other unique aspect, it was a pooled progressive population. This is sort of what the biology and our understanding of the disease is telling us, that these people, if you're going to treat the underlying progressive portion of the disease, whether they're relapsing onset or progressive onset, you should be able to study these populations together, and that's what was done here, and you can see the distribution. On the next slide, you can also see a little bit more of the demographics. This was a very typical progressive population, slightly older than the relapsing study with a higher EDSS score of 5.5 median. No relapses in the two years prior to coming into the study. Nonetheless, some inflammation detected at baseline, 16.3% got a lesion at baseline.
Mostly non-active patients and a very long duration of disease, and again, about nearly 60% of your non-active secondary progressive. Next slide. As was already pointed out, they missed the primary endpoint of brain percent change in brain volume. I think in retrospect, as Maria Pia highlighted of the limitations of this outcome measure, I think are manifest here. I mean, you have now looking back with what we know, we know that this endpoint does not necessarily reflect clinical progression. There are studies that demonstrate clinical progression negative on this endpoint and positive in this endpoint and no effect on clinical progression. So in retrospect, we know now that this is not a great endpoint for a progressive study.
But this study, given its size and the endpoints that were captured, teaches us an enormous amount about vidofludimus, about the disease, and makes us feel really comfortable and excited about proceeding into a follow-on study in progressive MS. Couple of the interesting observations also is we had a nice effect on regional atrophy. Regional atrophy tends to be a little bit better at being reflective of changes in progression, and particularly thalamic changes, as you've shown. These were non-significant, but nonetheless, some meaningful differences. Next slide. The most interesting part of the results, I would say, are related to these clinical outcomes. We missed the primary endpoint, so these things, we can't say these are statistically significant changes, I mean, in any sort of hierarchy, but there's some very interesting trends.
First of all, left-hand side, 24-week confirmed disability worsening, right-hand side, 24-week confirmed disability improvement, where worsening is an increase in EDSS that's sustained, and improvement is a decrease in the EDSS that is sustained, each for 24 weeks. What you're seeing on the left is that across these subgroups of non-active secondary progressive and primary progressive, you're seeing a fairly interesting and pretty consistent change that favors vidofludimus calcium. Even more interesting, on the right-hand side, looking at improvement, when one looks at the overall patient population and the effect of vidofludimus on confirmed disability improvement, the trial achieved nominal statistical significance. There was a nominally significant p-value of 0.034, apparent effect on the overall improvement of the pooled population, and very, very consistent changes in that direction through the subgroup. So very encouraging results that made us excited about continuing to explore these effects.
Next slide. This is another result that was encouraging regarding the potential effect on disability. This is your change in volume of new enlarging T2 lesions. Nominally significant effect over time that, as you can see, increased, as you see, accumulation of lesion volume in the placebo group, a reduction in volume in the active group. Next slide. Jiwon already pointed out the effect on SELs. Again, a very encouraging result considering its predictability for chronic inflammation. Next slide. Then we went into the. Now we just looked into the extension study, looking at whether these effects were maintained, and this was just presented at the MSToronto 2026 meeting. You can see pretty clearly that the disability slowing of worsening and disability improvement effects were maintained through the recent cutoff of the open-label extension study with the apparent effect increasing.
All of these signs made us feel comfortable about proceeding into a confirmatory phase III study. Next. Even more interesting, exciting, was deploying the net clinical benefit, as Maria Pia already pointed out, to the CALLIPER study, where the win ratio, 1.5 x more likely to have a win, namely, disability outcome on vidofludimus calcium versus placebo. If this had been the endpoint of the study, we would be having a very different conversation now. Now is the time. Very excited to be able to repeat this, confirm this in a larger pooled population. Next slide. You cannot have a discussion of a clinical study of this size certainly without discussing safety. The safety profile remains favorable. One of our strongest assets as we head into a drug that has the potential to have these meaningful types of benefit with a favorable profile.
Next slide. This is another factor that makes us pleased with the overall profile and the retention, the conversion to the phase from the main treatment period or the double-blind period into the open-label extension period, and how many patients transitioned and remain in that study. All of this, just as I did not point out earlier, all of this is with the 45 mg dose of vidofludimus, which will be the dose that we are taking into the next phase III study. Let me tell you about that study. The name of the study is ProTEct-MS. The name is listed here. Next slide. Inclusion criteria, the ProTEct-MS study population is similar to what we recruited, who we recruited for CALLIPER. We are trying to match the patient population to the greatest extent possible.
You can see washout period there will be required for people coming off an anti-CD20, but there will be other washouts as relevant. We are trying to get the whole spectrum of progressive MS patients. We do not have any exclusion criteria for drug-drug interactions, other things of that nature, and anticoagulants as an example, as we head into this initiation, which is currently underway. Next. This is the study design. The objective is to determine whether vidofludimus impacts disability progression in progressive people with progressive MS, targeting about 1,400 patients, vidofludimus versus placebo. It is a variable end study, so we are going to be stratifying by the subtype of progressive MS, as well as EDSS score, following them over time.
It's a variable ending, meaning it'll be required number of events before we're able to. That allows us to monitor these slow event rates that are now, as described, occurring more and more often. But also, we're including interim analyses to assess the futility along the way, to adapt the sample size as necessary, and potentially enable stopping sometime over the course of the study due to a meaningful effect on efficacy. Next slide. Endpoints. Primary endpoints is time to 24-week confirmed disability worsening or 9-Hole Peg Test. So we're going in the direction of the composite.
But equally as important, some of our secondary endpoints around confirmed disability improvement, net clinical benefit, as currently described, are really featured high in the hierarchy, and as well as these key imaging outcome measures that we believe will help us to best understand the biology of the disease and our impact on the biology of the disease, as well as our impact on people with the disease through a variety of PROs. They're going to tell us how does this profile benefit these people who really, as of now, have no effective treatment. And of course, standard safety assessments would be performed throughout the study. Next slide. Just in summary, we believe there's treatment paradigm-changing potential, both in the mechanism of the drug, as well as how we expect to evaluate this drug.
We have really interesting, strong imaging and exploratory disability signals that we've seen in this large phase II study, CALLIPER, favorable profile at the 45 mg dose. And some of the observations in the non-active patients make us really optimistic about the Nurr1 mechanism. And we are, as I've mentioned, we're initiating studies currently, and we anticipate the first patients to be enrolled in the first half of 2027. So with that, I'm going to turn it over to Jason.
Thank you, Mike. We've spent much of today's presentation discussing the underlying biology of progressive MS, the clinical challenges facing patients, the clinical development challenges facing drug developers, and the potential of vidofludimus calcium. I'd like to shift gears now and spend the next few minutes to discuss what this means from a commercial perspective and why we believe progressive MS represents such a significant opportunity for both Immunic and vidofludimus calcium. Next slide, please. Despite the tremendous progress that's been made in treating relapsing MS over the past three decades, progressive MS remains one of the biggest challenges in neurology. Approximately 25% of diagnosed MS patients have progressive disease. These patients face increasing disability, declining independence, and significant burdens on families and caregivers. Treatment options remain limited, and even where therapies are available, their benefits can be modest, particularly for patients without active inflammatory disease.
What makes this opportunity especially compelling is the convergence of several factors: significant unmet medical need, clear physician demand, an evolving competitive landscape, and a large addressable market. Importantly, we believe there is a real opportunity for a differentiated therapy like vidofludimus calcium to address both non-active secondary progressive MS and primary progressive MS, while potentially offering a favorable long-term safety and tolerability profile. Next slide, please. The burden of progressive MS extends well beyond the clinical manifestations of the disease. As disability accumulates, healthcare costs increase substantially. On the left, you can see data showing that annual healthcare costs for patients with non-relapsing SPMS are approximately 2.4 x higher than for matched individuals without MS. For PPMS, the difference is even more striking, with costs approximately 4.5x higher over a two-year period.
These figures do not fully capture the broader economic burden, including lost productivity, early retirement, home modifications, and informal caregiving. The important takeaway is that disability progression is extraordinarily costly, not only for patients and their families, but for healthcare systems, and therefore, a therapy that meaningfully slows disability progression could therefore deliver substantial value to patients, their families and caregivers, and the broader healthcare ecosystem. Next slide, please. As we heard from Dr. Oh during her presentation today, and further highlighted in this slide, the need for additional therapeutic options in progressive MS is clearly recognized by the physicians who treat these patients. This slide summarizes market research conducted with both general neurologists and MS specialists, showing that new treatments targeting PIRA, or progression independent of relapse activity, as well as new therapies for primary progressive MS and non-active SPMS, rank among their highest priorities.
It is also important to note that while neurologists are eager for new therapies that can meaningfully address disability progression, they also emphasize the importance of safety, tolerability, and convenience, particularly in this older, more vulnerable, and often difficult-to-treat patient population. From a commercial standpoint, these findings demonstrate not only strong physician demand for new treatments, but also the importance of developing therapies with a differentiated overall profile, reinforcing what we believe is a compelling opportunity for vidofludimus calcium. Next slide, please. When we look at current treatment patterns in progressive MS, the dominance of anti-CD20 therapies in the U.S. market is understandable, particularly given that OCREVUS remains the only FDA-approved disease-modifying therapy specifically indicated for primary progressive MS.
As you can see, based on physician-reported data, anti-CD20 therapies account for approximately 80% of disease-modifying therapy-treated patients in PPMS, and about 55% of treated patients in non-relapsing secondary progressive MS.
These therapies, specifically anti-CD20s, have fundamentally changed the MS treatment landscape, mainly through their ability to effectively suppress inflammatory disease activity. However, while controlling inflammation is critically important in relapsing disease, it does not necessarily address all of the underlying biological processes driving disability accumulation in progressive MS. That helps explain what we are seeing in the next slide. Next slide, please, Jessica. While disease-modifying therapies, particularly the anti-CD20s, are widely used in progressive MS, many patients continue to experience disability accumulation. Although a significant portion of progressive MS patients are receiving treatment, physicians report that only 37% of patients on a disease-modifying therapy are responding well. The remaining patients are either experiencing suboptimal responses, have tried or failed treatment, or have never received a disease-modifying therapy.
The issue isn't simply whether patients are receiving treatment, it's whether those treatments are adequately addressing the underlying disease process responsible for disability progression. To better understand why this remains such a challenge, it's important to look at how disability actually accumulates in progressive MS. Next slide, Jessica. As we've discussed throughout today's presentation, much of the disability accumulation in progressive MS occurs independent of relapses, or PIRA. In an important paper published by Fred Lublin et al. in 2022, the investigators found that approximately 80% of confirmed disability worsening events in both secondary progressive MS and primary progressive MS were attributed to sustained PIRA. In other words, the vast majority of disability worsening in these populations occurred independent of inflammatory activity.
Because the current therapies are highly effective at controlling acute inflammation disease, they may not adequately address the chronic inflammatory or compartmentalized inflammation within the central nervous system, that contribute to PIRA. This is precisely where we believe vidofludimus calcium could offer a differentiated approach. Next slide, Jessica. What we believe truly differentiates vidofludimus calcium is its ability to directly activate Nurr1, a mechanism associated with neuroprotection and neuronal survival. As Hella discussed earlier, Nurr1 plays an important role in maintaining neuronal health and protecting neurons from an inflammatory and oxidative stress. That is particularly relevant in progressive MS, where neurodegeneration is a major contributor to disability accumulation and remains inadequately addressed by currently available therapies.
Beyond its mechanism of action, we believe the overall product profile could be particularly compelling in progressive MS, especially given the importance of long-term safety, tolerability, and convenience in this older and, again, more vulnerable patient population. Based on the clinical experience generated to date, vidofludimus has demonstrated not only encouraged efficacy in progressive MS patients, as Mike just highlighted, but a safety and tolerability profile that could be highly differentiating. If we're successful in demonstrating a clinically meaningful benefit on disability progression in phase III study, we believe vidofludimus calcium could offer physicians something particularly compelling, an oral therapy with a differentiated, potentially neuroprotective mechanism, and a profile well-suited to the long-term management of progressive MS. Next slide, please. Of course, we're not alone in recognizing the significant opportunity in progressive MS. The development landscape is becoming increasingly active with several late-stage programs pursuing new therapeutic approaches.
As you can see in this slide, BTK inhibitors represent a significant portion of the emerging pipeline, alongside Sanofi's program targeting CD40 ligand. What we believe truly differentiates vidofludimus calcium from these other programs is its potential for direct neuroprotective activity through Nurr1 activation, a mechanism, again, that can be particularly relevant at addressing PIRA. Importantly, unlike most of the programs shown here, we're also pursuing a development program that will collectively go after both primary progressive MS and non-active SPMS, the two MS populations with a particularly substantial unmet medical need. Next slide, please. When we look more closely at the near-term competitive landscape, it's clear that significant opportunities remain for therapies that can meaningfully address disability progression while offering a favorable benefit-risk profile.
I think starting with OCREVUS, the only FDA-approved disease-modifying therapy for PPMS, it established itself as an important treatment option, but its efficacy has been relatively modest, particularly in older patients with less inflammatory disease activity. Long-term B-cell depletion raises important considerations around infection risk and declining IgG levels, especially, again, in an older, more vulnerable patient population. Turning to fenebrutinib, a BTK inhibitor currently under regulatory review by Roche, the drug demonstrated non-inferiority to OCREVUS in a phase III study in PPMS. However, its development program has raised safety considerations, including liver enzyme elevations and a numerical imbalance in deaths. Finally, tolebrutinib, another BTK inhibitor developed by Sanofi, demonstrated a benefit on disability progression in non-relapsing SPMS. However, serious safety considerations specific to liver and regulatory challenges have complicated its path to market.
The FDA issued a complete response letter late last year, and its European approval is restricted to adults with non-relapsing SPMS who have not experienced a relapse in the preceding two years. I want to be clear, OCREVUS will undoubtedly continue to play an important role in progressive MS, and BTK inhibitors, if approved, could provide physicians with a much-needed additional mechanism of action. But the introduction of new treatment options doesn't eliminate the need for continued innovation, again, particularly in a disease where disability progression and safety remain such a significant challenge. This is where we believe vidofludimus calcium can win. Next slide, please. Let's translate into the size of the commercial opportunity. This is a large and white-spaced market today.
We estimate there are approximately 175,000 diagnosed patients with secondary progressive MS and PPMS in the United States, of whom approximately 115,000 are currently receiving disease-modifying therapies, including many who are currently being treated off-label. Based on our current net pricing assumptions, that represents an estimated annual commercial opportunity of up to $13 billion in the United States. In Europe and the U.K., we estimate another 165,000 diagnosed patients, with approximately 60,000 currently receiving therapy. This translates into an additional estimated annual opportunity of up to $5 billion. Taken together, we're looking at an enormous market opportunity of up to $18 billion annually across these major markets. Importantly, we believe this market has potential to expand further as new therapies become available, diagnosis improves, and more patients receive treatment. Next slide, please, Jessica.
But there's another dimension to the commercial opportunity that I think is particularly exciting. Today, most disease-modifying therapies for MS are approved for specific patient populations, whether it's relapsing forms of MS or PPMS, et cetera. As you've heard throughout today's presentation, our development strategy is designed to go beyond these traditional boundaries. With our ongoing ENSURE phase III trials in relapsing MS and our planned phase III ProTEct-MS program in progressive disease, we're pursuing the potential to treat patients across the full spectrum of the disease. If successful, vidofludimus calcium could potentially become the only disease-modifying therapy with indications spanning across all of the MS subtypes shown here, and we believe this could represent a particularly compelling commercial proposition.
Not only could it provide physicians with a differentiated treatment option across the multiple stages of MS, but it could also strengthen their familiarity and confidence in vidofludimus calcium, potentially supporting its use throughout the course of a patient's disease. Next slide. I will close with what I think this could mean for vidofludimus' long-term commercial potential. We believe that vidofludimus calcium, in the near term, has the potential to become a blockbuster product in relapsing MS alone, and we are now just a few weeks away from the phase III ENSURE readouts. What makes the progressive opportunity particularly exciting is the potential to build significantly upon that foundation. Given the substantial unmet medical need, the large addressable patient population, and the limited treatment options available today, we believe success in progressive MS could add multiple billions of dollars in incremental peak annual sales.
Importantly, the opportunity could extend well beyond those incremental revenues. If vidofludimus calcium demonstrates a meaningful benefit on disability progression, we believe it could create a powerful halo effect in relapsing MS, further strengthening physician confidence, supporting earlier use, and potentially expanding its commercial opportunity across the broader MS market. Taken together, we believe success in both relapsing and progressive MS could position vidofludimus calcium as one of, if not the most important therapies in the treatment of multiple sclerosis. Ultimately, that is our ambition, not simply to bring another MS therapy to market, but to build a differentiated multi-billion dollar MS franchise with the potential to address patients across the full spectrum of the disease. With that, I will turn it back to Erik.
Thank you so much, Jason. Thank you to all of our speakers. I will be very quick because I want to get us over to Q and A. Just one slide from me, just the last sort of value creation roadmap for the company. As I started with, we have the ENSURE-1 and ENSURE-2 phase III studies in relapsing MS reading out in December, targeting an NDA submission next year and commercialization in 2028. That sets the frame, the foundation, and the baseline for the company. In the midst of that, we are actively initiating the ProTEct-MS phase III study in progressive MS that Mike outlined just a few moments ago, expecting the first patient to be enrolled in that study in the first half of next year. Then, pending the success of that study, of course, we have the opportunity to expand and address into the progressive MS market.
As Jason just articulated beautifully, our vision here is really that vidofludimus calcium has the potential to affect people living with MS regardless of where they fall on the spectrum, really being the first modern development program in MS that acknowledges these trends that Jiwon articulated, that MS is a spectrum disease. We believe vidofludimus calcium, based on its underlying mechanisms, has the potential to address all people living with MS. What you have heard about here today is our commitment to that vision and our plan to achieve it. With that, I am going to ask Jessica to moderate a Q and A session here for us. Jessica, the floor is yours.
Yeah. Thank you, Erik. I actually see a lot of raised hands here, so I am happy to start the Q and A session. Given we are almost up on time, I would suggest we prioritize questions for our two experts first to be mindful of their schedules. Jiwon, Maria Pia, if you need to drop at the hour, feel free to do so. Our management team will be happy to stay a few minutes longer and take additional questions. Let's jump into it. The first one I see here is Matthew Tan over at Stifel. Matthew, please unmute yourself, and welcome to the show.
Hi. Can you hear me okay?
Yes. Hi.
Hey, this is Matthew on for Paul. Thank you so much for taking our question, and this was a very helpful event. Maybe a question for Dr. Oh. Given your experience with MRI markers and research, maybe could you talk about whole brain atrophy, and were you surprised at all that there was no difference between drug and placebo in phase II CALLIPER? Then maybe a follow-up for management. Could you talk about the choice of confirmed disability worsening plus 9-Hole Peg Tests for the ProTEct-MS study? I think in phase II, you had a hazard ratio of about 0.86 for the three component, including the Timed 25 ft Walk test. How would that look like if you were to exclude that and just do the composite with the two? Thank you so much.
So maybe I can start with the brain atrophy question. The answer is no, I am not that surprised, just because brain atrophy is an okay measure, but it has been problematic. Part of the reason is, brain atrophy is not specific. It basically is shrinkage of the entire brain. That is a delayed measure reflecting all of these different pathological processes that happen in a disease like MS. So, there is a time lag issue, there is a lack of specificity issue, and in many contemporary MS clinical trials, we have seen this discordance many times. Say in the HERCULES tolebrutinib trial, there was a clear clinical effect. The brain atrophy effect was not seen. Similarly, in ORATORIO-HAND, this was the case as well. The clinical effect was not seen, the brain atrophy effect was not seen, and these are all phase III clinical trials.
On the other hand, when you look at the MS-STAT trial, that in the phase II trial showed a clear effect on brain atrophy, but the phase III trial was a dismal failure. This kind of illustrates to us that in certain settings, brain atrophy is useful, but because of the limitations that I described earlier, it probably is not an excellent measure of progression in MS. So, the short answer is no, it does not surprise me, and I do not think, especially given the trends that are seen with the clinical data, overall kind of clinical trends really trump all, especially when it comes to somewhat problematic MRI measures.
Why do not I jump in real quick on the endpoint? Regarding the use of the 24-week CDW or 9-Hole Peg, I think, as you heard from Maria Pia, this seems to add to the sensitivity. We have seen that. So, if you were to just look at the 9-Hole Peg with the EDSS, the numbers that we already showed you with the EDSS alone, you get a bit more out of it than that, but it is around the same. It is similar to what you are seeing in the just the EDSS alone in this particular study, but we pick up a few extra events, which is, again, the purpose of going to a composite.
If I can add something, we recently published a study comparing across many clinical trials, the composite, and with all the single components and all the possible combination, and the combination of EDSS with 9-Hole Peg Test was the only combination adding something more sensitive than EDSS alone in the progressive MS group. So, this analysis underlies that, I mean, it is always a bet which component to combine, but in this case, the 9-Hole Peg Test and the EDSS in progressive MS seems to be the more evidence-based and more sensitive.
Thank you. That is super helpful.
Thanks, Matthew.
Thank you.
The next one I see here is Sam Slutsky over at LifeSci. Sam, please unmute yourself.
Hey, thanks for taking the questions. For the physicians, if both RMS and PMS do receive approval, how would this play in the first-line space? I know Dr. Giovannoni previously indicated that we know progression starts early, so would approval on both make doctors consider vidofludimus calcium in the first line in younger patients? Just curious on that play. Then, just on enrollment in PMS separately, obviously you touched on baselines or inclusion criteria, but obviously prior studies have had certain biases on who they are enrolling between age or disease activity. Just curious on how you think that could play on the control arm and just how you might stratify for that in your study. Thanks.
I can start. In terms of use, should both endpoints be met in the phase III clinical trials, in terms of first-line use, yes, it would be likely very commonly used first line for a few reasons. First of all, we all use teriflunomide, which is a DHODH inhibitor, somewhat commonly as a first-line agent in people with relapsing MS. But as you saw from my slides, in people with relapsing MS, even at the beginning of disease, you often see evidence of PIRA. This would be a very natural choice for people who have some relapsing activity, which technically with today's framework, we would still categorize as having relapsing MS.
But because of if there is this effect in progression and especially neuroprotection, it would be a very attractive first-line agent because we know both disease biologies happen in most people at the very beginning of disease. It would make a lot of sense to try to address that from the beginning.
I can answer about the patient populations. What we anticipate is very similar to what we saw in the CALLIPER study. We believe that progression is progression, and these patients are progressing whether they have been phenotypically called primary progressive or phenotypically called secondary progressive, meaning progressive onset or relapsing onset. We would anticipate that, or in our feasibility tells us, that if we were to just recruit, we would likely get a very similar scenario to what we saw in CALLIPER. But actually, I would say that our ambitions is to have more of the non-active secondary progressive, quite frankly, because that truly is the need.
Okay, maybe we lost Sam. Thank you, Sam.
Give me a second. I'm thinking on my end for that.
Yep, thank you.
Seriously.
All right. Next one in the queue here is Myles Minter over at William Blair. Hello, Myles.
Hey. Thanks for taking the questions. Maybe the first for Dr. Oh, Dr. Sormani. The company's measuring net clinical benefit in the ENSURE trials in RMS, and it's pretty high up in the stats hierarchy. You explained that endpoint really well today. If you did see benefit in an RMS population, does that tell you anything about potential efficacy in a PPMS population? That's the first one. The second one, maybe for the company, what's the rationale for running one study with primary progressive and non-active secondary progressive against placebo rather than running them separately and doing a trial against placebo instead of a non-inferiority study like we saw in FENtrepid? Thanks very much.
Yeah, very good question. Regarding the first question, the net benefit can be tested both in relapsing and in progressive MS. It's a very crucial point, is how to select the hierarchy of the endpoints, because this can affect, of course, the measure, and it must be based on clinical reasoning. Regarding the why running a single trial, I think that Mike alluded already to that. Patients progressing are progressing. Taking all together, facilitate recruitment and also changes the focus of the aim of the clinical trials. The aim is to target progression. If the drug is targeting progression, it must be useful in both the subtypes. The subtypes are somehow artificial. I think it is a very modern approach to include both the phenotype population in the study.
If I could just— Sorry, go ahead, Maria Pia.
I don't remember the third question that was embedded in the—
It was just a question on why run a placebo-controlled study instead of a non-inferiority.
Okay. Well, yeah. That's a very good question. I would say that a placebo-controlled study is easier. If it's possible to run such a study, it is much easier. A non-inferiority study is a very challenging study. Also, someone could argue that non-inferiority to ocrelizumab is not satisfying anyway, because we know that the effect of ocrelizumab in progressive MS is significant, but it's not so relevant. Assessing non-inferiority to ocrelizumab, I think that new drug are more ambitious. They want to really cause an improvement in progression, a delay in progression. I think that the answer is because they are more easier and maybe the interpretation is cleaner.
I think the second and third questions are related. There simply is not a standard of care to compare with or use as a control arm, Myles. There is nothing that is approved across the spectrum. This is really truly a skate to where the puck is going kind of mentality in terms of this trial. Why would we include both? Because we fundamentally believe, and the field is with us on this, Jiwon showed some of those papers at the top, that progression is progression. This sort of old world of sort of falsely stratifying across secondary or non-active secondary and primary progressive is reflective of the view of MS 15 to 20 years ago. As Maria Pia said, we do really truly want this to be the first modern MS pivotal trial. We're aligning ourselves with the field.
We think in doing so, we're being true to the biology, the science, and ultimately the patient community. At the end of it, we end up with a data set that is extraordinarily unique in MS and broad in its potential applicability.
I just wanted to chime in from a clinician standpoint. We really don't think that there is any meaningful difference between SPMS and PPMS, so it makes sense in this modern clinical trial to group them together. This trial is actually recruiting for non-active PPMS and SPMS, which we really don't have any treatments for, because most clinicians use ocrelizumab and siponimod for active SPMS and PPMS. So, it makes sense to do a placebo-controlled trial because, as Maria Pia said, it's the purest study design that allows you to look for a clear benefit. There is also no standard of care right now for non-active SPMS or PPMS.
Makes a ton of sense. Thanks very much.
Thank you, Myles. Maybe a follow-up question here probably for Mike on the split for SPMS and PPMS from Martin Fan at Wedbush. "For ProTEct-MS, are we expecting a similar ratio of non-active SPMS and PPMS patients as in CALLIPER, or will enrollment be weighted towards patients with PPMS?"
I think as I've already said, I think we would anticipate something similar based on our early feasibility. Our goal is treating progression, we're going to get both.
Thank you. The next one here is Matt Caufield at H.C. Wainwright. Hello, Matt.
Hi. Can you hear me okay?
Yes. Hi there.
Excellent. Thank you to the team and Drs. Oh and Sormani for the insights today. How much of the clinical effects observed and discussed from CALLIPER do you believe can be attributed to direct neuroprotection through Nurr1 activation rather than conventional anti-inflammatory effects? Thanks for any thoughts or specific points there.
Well, I will start, then I will ask Jiwon to see if she has any thoughts on this. I think that it is always that challenge of what is due to one versus the other. I think if you look at some of these effects on, first of all, you look at lesion formation and that kind of stuff, we can tell there is an anti-inflammatory effect. But if you also look on these other outcome measures where people are improving, that seem to be disproportionately improving relative to other outcome measures, we would anticipate that some of that is due to its neuroprotective effect. But sometimes hard to tease that out. I do not know. I will turn it over to Jiwon if she has anything to add about that.
Agree with what Mike said. It is really hard to disentangle these effects, and in a way, we need to rely on some of these exploratory endpoints to get a better idea, and then, of course, the phase III clinical trial data. First of all, the trial population of CALLIPER was a pretty inactive, progressive MS older population. We know that relapsing disease biology does not play a major role, although it plays a little bit of a role, as I showed in my presentations. So, yes, probably relapsing-associated biology and the fact that we know vidofludimus does attenuate relapsing disease biology plays a portion of the effect we see on disability.
Yet, the fact that it is already a population enriched for mainly progressive disease biology suggests that probably at least a large portion of this effect is related to an effect on progressive disease biology or neuroprotection in this case. The other thing is, this was an exploratory analysis, but when you look at the SEL counts, which again, is not a perfect, but one measure of a big component of progressive disease biology, there was an effect. All of these things together, we never will know for sure, and it is very difficult to disentangle, but there is a good kind of underlying story there suggesting that at least a good proportion of that effect is related to a beneficial effect on progressive disease biology.
Understood. Thank you. I appreciate it.
Thanks, Matt. Next one in the queue here is Eddie Hickman at Guggenheim. Eddie, please unmute yourself. Welcome. That doesn't seem to work, so I jump to the next one while we wait, which is William Wood at B. Riley. Hi, William.
Hi. Yes, thank you for taking our questions, and I appreciate the extra color here today. Just thinking, maybe directed towards both the management team and the KOLs on the call, when thinking about the upcoming ENSURE readout with the discussion surrounding how progressive is essentially underlaid below the relapsing disease states, what might the KOLs be looking for from the ENSURE readouts that would really sort of support or point to this progressive disease benefit? Then maybe could the management team just remind us what potentially progressive endpoints you might be looking at during the ENSURE, whether that's SELs or PRLs, might be looking at within that could give us sort of a better idea on the dual relapsing and progressive benefit here? Thank you.
I'll start. Jiwon, do you want to start, and then I'll jump in?
Sorry. Yes. I think it's kind of similar to what we just discussed with the CALLIPER study. It will be difficult to clearly disentangle these effects, and this gets to kind of one of the points I made in the slides that it's actually really difficult to measure definitively some of these effects on specific disease processes. Having said that, though, if there is a clear effect on relapses and other measures reflecting relapsing disease activity, and then progression as well as other measures, this tells us a story. We may look at things like relative effect on relapsing-associated biology, and if there is a greater effect than we would expect on progressive disease biology measures, that would be one piece that would suggest that there is an additional neuroprotective effect. But then again, using some of these paraclinical biomarkers will be really important.
And yes, they are exploratory measures, but together they would be able to tell us this convincing story of what we are seeing. So, it would include things like looking at PRLs, SELs, as well as combinations of some of these fluid biomarkers.
I have nothing to add to that. That's great. Thank you, Jiwon.
William, does it address all your questions?
Yes. Thank you very much.
Thank you. Great. I have two questions here that came in in writing from Boobalan Pachaiyappan and Aaron Welch over at Roth. First one, "Where is the largest clinical actionable gap today? Patients progressing despite ocrelizumab, patients unsuitable for immunosuppression, or patients with non-active disease? Which group would you prioritize for vidofludimus, and would you envision it replacing existing treatment or being added to it?"
If I can just make a comment. Patients with non-active disease are a subgroup of ocrelizumab-treated patients who progress. Because, I mean, now we have a lot of The treatment with anti-CD20 created a lot of non-active progressive MS. I leave to Jiwon answering this question.
It is number one. Like Maria Pia said, the non-active patients are within that number one category, but it is people who are progressing independent of relapsing activity. It is a huge proportion of people with MS when you look closely enough.
All right. The second question is, with fenebrutinib having demonstrated non-inferiority to ocrelizumab in FENtrepid, what would make a neurologist choose vidofludimus if both were available? Better disability outcomes, a differentiated safety profile, or benefit in a population competitors do not adequately serve? Sorry.
I can say all of the above. Jason actually pointed this out in his slides, but one of the criticisms of the FENtrepid study is that fenebrutinib was tested in a non-inferiority way to ocrelizumab. Many clinicians think the benefit of ocrelizumab in PPMS is entirely related to its extreme benefit on relapsing-associated activity. In the field, there clearly is this need for a treatment that more definitively addresses progression in really non-active people with progressive MS. In this trial, if the benefit is showed, that would be unique. It would be a bit of a unique niche in comparison to what fenebrutinib has shown, partly because of the trial design that was used with fenebrutinib and this notion in the field that ocrelizumab is probably not that effective on any components of progressive disease biology.
It just really helps to shut down relapsing disease activity, and people think the benefit in PPMS of ocrelizumab is really people who have ongoing relapsing disease biology. Should vidofludimus show a benefit in non-active SPMS and PPMS, this is a unique niche. That would be a differentiating efficacy point, and then safety will be key as well. There were some safety signals that have emerged with fenebrutinib, including this imbalance in deaths and this question about suicide. So far, the safety data look good here, and obviously will need to be controlled in phase III clinical trials. Safety would be a big differentiating piece as well, particularly again, in non-active progressive patients that tend to be older, have more comorbidities, and therefore, we have more concerns about safety.
Yeah, the last point I would just make from a general commercial perspective, similar to the relapsing-remitting market, we have to remember that progressive disease won't be a one-size-fits-all. It won't be a one winner-take-all market, right? This is a large market of very little approved therapies today. There's approximately over 300,000 diagnosed patients collectively with SPMS and PPMS across both the U.S. and Europe. As I've highlighted in my slides, we believe if you just extrapolate current net pricing today, that this is upwards of a $15 billion-plus market. Just carving out a significant, say, 25% of that market would be meaningful upside in terms of peak sales for vidofludimus calcium. Again, I think Dr. Oh was very eloquent in her answer about the clear differentiation around the patient population and how that may play out in a commercial setting.
I just wanted to remind people again that this is a huge market. If we can show continued success with vidofludimus calcium in this population and replicate some of the data we've generated to date, specifically on safety and tolerability, my belief has always been that this product will become the cornerstone of care in progressive disease.
Thank you, everyone. Next one in the queue here is Fozia Ahmed at Brookline. Welcome, Fozia.
Hi. Thank you for taking my question, and thank you for the wonderful event. My question is, if you could share, Dr. Oh, your thoughts on the SELs and PRLs. What would it take for either to move from a mechanistic biomarker to something regulatory accept as supportive evidence of neuroprotection? How reliably can each be quantified across sites in a multicenter trial? Additionally, do we have automated detection methods mature enough and in place for our pivotal studies?
Thanks for the question. I wish I knew the answer to that, how to convince regulators that we should use imaging measures as endpoints in clinical trials. I think the safe answer is that it probably will need validation in a number of contemporary trials, showing a clear link to the disability endpoints that we are focused on. However, I know Maria Pia, for many, many, many years, has been trying to get regulators to accept even Gd lesions as a measure of relapsing disease biology, and it has been a really tough kind of obstacle to get over.
However, on a positive note, again, given that the International Advisory Committee on Clinical Trials in MS is aware of this and really pushing and getting regulators on board in these early discussions, and that's what that roadmap paper that I referred to was talking about, I'm confident in the coming years that there will be a change where there will be an acceptance of multimodal composite endpoints. But it has been a challenging game to date and extremely frustrating, I have to say, from a clinician and scientist standpoint, just because we are very convinced that these measures are reflecting biologies we think they are, but the regulators seem to have a different mindset about that. But I think hopefully things will change.
Yeah, if I can add something, it will be easier in the future because modern clinical trials are including these measures. It will be possible to run some post-hoc analysis to try to better understand their link with clinical measure and to convince regulators to accept them.
Then, Fozia, getting to your other point about automated methods. SEL detection is automated, and it's mainly done by NeuroRx. This seems very reliable and uses just conventional clinical sequences that are actually obtained even in clinical routines. You just need T1 and T2-weighted MRI sequences that are reliably obtained on the same patient. With PRLs, there's much more of a consensus emerging about what sequences can be used to detect them. Again, in clinical trial settings, they're done by NeuroRx, and it is by visual inspection by people who have been trained, and there's these consensus statements in the imaging field that guide the detection of PRLs. Overall, it seems relatively reliable. We've done some internal studies about this, and inter-rater agreement tends to be very high.
Especially when you're using an organization like NeuroRx that's very experienced with this is likely something that's a pretty reliable measure to detect, similar to Gd lesions.
Thank you so much. Appreciate it.
Thank you. I would take one last question here, and then I think we close the call to be mindful of everyone's schedules. We have Yanni and Imogen over from the Cantor team asking in the chat, "Thanks for all the insights and highlighting the needs of this very underserved group of patients. CALLIPER's effect size was similar to HERCULES, ORATORIO, and EXPAND, relapses excluded. Given that CALLIPER's a phase II study, could you walk through key differences in baseline characteristic that may have made the selected patient populations more difficult to treat versus other studies, in addition to inactive older population that Dr. Oh mentioned? Could you share how you are thinking about phase II to phase III translatability?
If I can start answering this question. CALLIPER was a phase II study, so it was not powered to see an effect on disability. The primary outcome was disability. 200 patients per arm are a very small number, so it was quite the miracle that we saw this effect on clinical endpoints. This is also a plus of the CALLIPER study to have highlighted some effect on clinical endpoints while the sample size was so small. This is very reassuring, and the characteristic of phase III study is to be powered on a clinical endpoint. Basically, to be much larger and with much more power to see such an effect as significant.
Yeah. I think that captures it in terms of translatability. If you're seeing effects on the same clinical endpoints you're using in your phase III study, that's pretty encouraging translatability. We're just going to power them appropriately and be able to assess them in a way that should allow us to see a statistically significant effect at a meaningful threshold.
Great. Thank you so much for all the questions. This concludes our Q and A session. Erik, back to you for closing remarks.
Great. Thank you. I think in conclusion, when I think about whether or not to invest resources in a big question, I think about, is there value to be created across kind of three pillars? One is there value in the science? Are we able to advance our understanding of the basic scientific questions at play? Second, is there value to the patient community? Meaning, is there an unmet need? Third, is there value capture potential for the company to recoup its investments in that? I think that's my frame that I use to evaluate these types of questions, because these are ultimately quite expensive things to embark upon.
But as I've thought about looking at various questions of that nature across my career, when I look at ProTEct-MS and this study, it is extraordinarily clear that there's tremendous value across all of those ways of thinking about it. To be able to further our understanding of the biological underpinnings of progressive disease through this study and the role of Nurr1 in having an impact, that is a massive opportunity to advance our understanding of progressive MS and Nurr1. For the value to patients, we've heard a lot about that today, but this is the largest unmet need in the MS patient community, and such an opportunity for us to really raise the bar of what's possible in the care of people living with this disease. Jason outlined, this is a large and probably the fastest-growing market segment within MS.
Conservatively, this market is worth about $10 billion in the U.S. alone. When I think about this from, do we have the possibility, if we succeed, to recoup the significant investments that we'll make here, I think I feel very comfortable about that and our ability to advance and create value for ourselves and our shareholders. Across that spectrum, I could not be more excited to be initiating the ProTEct-MS study, to be advancing care, to be running the first truly modern progressive MS study, and to really be doing it hand-in-hand with such great collaborators in the community, such as Maria Pia and Jiwon, who've joined us on this call. With that, I'm going to wrap this, but before I do, I want to really extend a heartfelt thank you to Maria Pia and Jiwon.
Thank you so much for joining us and lending your expertise and your voice, not only on this call, but behind the scenes in terms of really shaping our thinking and the approach to this study. Of course, I'd like to thank my colleagues, Hella, Mike, Jason, and Jessica as well, for all of your extraordinary work to prepare for this. Maybe most importantly, thank you for those who've tuned in and your interest in what we're doing here, because it's really important work. Thank you. If there's any further questions, please don't hesitate to reach out. We'll get back to you via writing, and we look forward to getting this study off the ground as soon as we can, reading out those ENSURE studies, let's not forget about those, right around the corner, and ultimately getting vidofludimus calcium to the patients who can benefit from it.
Thank you so much.
Thanks so much again. This concludes our event today. Thank you for joining, and you may now disconnect. Bye-bye.