as development program with preclinical, clinical, and commercial positioning insights on the potential of how vidofludimus calcium's differentiated approach could reshape the treatment for patients with relapsing MS. Dr. Bar-Or and Dr. Krieger will provide expert perspectives on the MS patient journey, current treatment paradigms, and unmet medical needs. Now, I would like to turn the call over to our CEO, Erik Lundgren, to kick the presentation off. Erik? Great. Thank you, Jessica, and thank you everyone for joining us. Good morning. I am Erik Lundgren, the CEO of Immunic, and I am thrilled to be with all of you here today. Thank you so much for your interest in our story. Jessica, if you could just push onto the next slide. I will be very quick so we can get into the exciting science here this morning. Just to set the stage, we are at an incredibly exciting and important pivot point in the company's history, where we are really moving towards developing a fully integrated MS-focused company. As you will hear throughout the session, we are right on the precipice of unblinding two pivotal phase III studies that we hope will create a path for us to advance our lead asset, vidofludimus calcium, into relapsing MS, so that we can address some significant remaining unmet needs in the MS community, and needs that are faced by people living with MS on a daily basis. As I sort of frame the conversation to follow, we are going to really focus in on that near term inflection and catalyst point in relapsing MS. Keep in the back of your minds, we are not going to spend much time at all today on this, but another huge part of the value proposition for Immunic and for vidofludimus calcium sits in a potential progressive MS population with data to come. In fact, I will tease at the end of this a little bit of opportunities where we are going to have to share that story in a more fulsome way with this community in a few weeks. The other pieces I would love to just stress here is this pivot point of the company itself. We are really poised to build an MS-focused company full of executives and team members who have been in the field, who care deeply about and deeply understand the plight of people living with this disease, and are really committed and passionate about transforming care in MS. That is really where we are focused, and we think we have got the right asset to do it, we have got the right capital structure to support it, and we have got the right momentum in our hiring practices to build that organization to take us into this new era for the company. Finally, you are going to hear a red thread throughout all of these conversations that our principal posture right now, in addition to driving our programs, is listening. Really focusing on listening to the people who treat MS every day, and the people who live with MS every day, so that we are understanding what it is that needs to be developed so that we can take on the remaining unmet needs, which are significant. Next slide, please, Jessica. You can see highlighted in green where we are going to focus a lot of our conversation today. That is on the relapsing program, really anchored by our two phase III studies, the ENSURE-1 and the ENSURE-2 studies. As you will hear throughout, these are fully enrolled, and we are tracking towards reading these out by the end of this year. Well on track there. Much more detail to come. Worth popping down to see the phase II EMPhASIS study as well, which Dr. Panzara will go through some of the highlights of that study to sort of set the stage for what we can hope to see towards the end of the year. Next slide, please, Jessica. Finally, just before we get into the science, just a few words on the market itself. Headline here is that MS is a large and growing market with significant remaining unmet need. From a market perspective, it is large. Globally, it is a $30 billion market, or nearly a $30 billion market. In the U.S., it is about a $17 billion market today, growing at about 7% annually. It is a market that recognizes and rewards innovation, and you can see that in the fact that there has been over 11 blockbuster therapies developed in MS over the last 25 years. Maybe the most important piece to highlight here is it is a large and heterogeneous patient population dealing with a chronic disease. What patients need at various points along their journey changes. What that results in is the need for diverse sets of therapeutic options, unique mechanisms of action, and the potential to address a wide range of needs over time. This is not a winner-take-all market. It is a market where we want to really tap into the needs of people living with MS, be aggressive in our development posture so that we are meeting and exceeding those needs. If we do so, it is a market that will value the innovation that we can deliver. Ultimately, we will see that rewarded in how the company can grow from that. With that, it is my immense pleasure to turn the stage over to the first of our guest speakers. It is Dr. Amit Bar-Or. Amit holds the Melissa and Paul Anderson President's Distinguished Chair at the University of Pennsylvania. There, he directs the Center for Neuroinflammation and Experimental Therapeutics, and serves as the Chief of the division for MS and related disorders. Dr. Bar-Or's research focuses on neuroimmune health and central nervous system inflammatory diseases. He runs a cellular and molecular neuroimmunology lab, directed at understanding general principles of immune regulation and immune neural interactions and their contributions to inflammation, injury, and repair of the human central nervous system. Following an undergraduate degree at McMaster University, Amit earned his medical degree at McGill University in Montreal. Dr. Bar-Or has published over 400 peer-reviewed publications and has led multiple national and international collaborative research initiatives. Thank you, Amit, for joining us, and I'll turn over to you. Thanks, Erik. First, let me just confirm that you can both see the screen with the presentation and hear me. We can. Yes, we can. Perfect. Thanks for the kind introduction, Erik. Hello, everybody. Pleasure to be here and follow on Erik's background presentation to tell you about targeting novel mechanisms to address the unmet needs in terms of the clinical context. This is really going to end up leading to the biological basis by which we think vidofludimus calcium may offer some very unique advantages in relapsing MS with a focus here, but as Erik had already alluded to, in the context of protection and repair throughout the spectrum of MS. To do that, I am going to start by presenting a very simplified model of MS immune pathophysiology. I will try to avoid jargon and really only highlight the key points, so it is not about too much immunology jargon to contend with, but use that as a basis for commenting about some evolution in our concepts of the clinical spectrum of MS. You will hear more about this from Dr. Krieger, but I will introduce these terms of RAW, relapse associated worsening, and PIRA, progression independent of relapse activity, and try to talk about some of the biological underpinnings as a way of then providing the framework for thinking about the mechanism of action of vidofludimus calcium. The unmet needs and the novel promising targets is what we are really going to be segueing into to then deal with the biology, in particular of the Nurr1 pathway, with a focus on trying to protect and support repair from ongoing injury throughout the MS process. In the context of vidofludimus calcium in particular, the attraction of having potential for dual mechanism of action, both activating the Nurr1 pathway, but also selectively inhibiting the DHODH enzyme, where we have a precedent in the MS field of an effective therapy that does so, teriflunomide, limiting relapsing disease activity as well as progression of disability. So we will start with a simplified model, and it is a very simple sort of three-compartment concept that many, if not all of you, I am sure have seen before. The lower right is the central nervous system, the target in MS, separated by barriers from the immune system. We think of immune cells in the periphery outside of the CNS getting activated, upregulating molecules that enable them to more efficiently engage and cross the barrier, and then get reactivated within the central nervous system compartment and bring to bear on the tissue. Historically, for many years, for decades, MS had been thought of as a T cell-mediated disease, very much driven by most commonly used animal modeling in experimental autoimmune encephalomyelitis. But really, our thinking has evolved importantly, particularly with the selective targeting of B cells with anti-CD20 therapies that really has helped us understand that it is not just about T cells, it is about B cells and T cells, and very importantly, interactions between B cells and T cells in the periphery that are thought to drive the relapsing aspect of MS. Within the central nervous system, compartmentalization of processes that include almost certainly both inflammation and degeneration, and the inflammation is thought to be driven by the reaction and the participation of brain cells, glial cells, in particular microglia and astrocytes, and infiltrating immune cells, principally B cells as well as T cells, where the interactions between immune cells and immune cells, as well as immune brain interactions, are almost certainly contributing to the ongoing progressive injury that manifests clinically with progression of disability independent of relapsing activity. Again, highlighting here the involvement of the brain cells, the microglia, and the astrocytes. Also, as a side note, I think all of you will appreciate that there has been a resurgence of interest in Epstein-Barr virus, now recognized clearly as an important necessary, though insufficient element in developing MS, and more and more data interestingly coming out in high-profile papers to suggest that EBV may be involved not just in the initial triggering of the disease, but also potentially in propagation, with strong data suggesting an involvement in relapsing disease, but also the suggestion that within the CNS, there may be propagation of that compartmentalized inflammation and injury. The reason I point that out is because if a drug also has some antiviral properties, that may be an added advantage, and it turns out that this class of medication seems to have at least a component of that. Now, looking a little bit about the clinical spectrum and providing a backdrop for, again, what Dr. Krieger will go into in greater detail. This would be the typical profile if you look at disability or neurological dysfunction on the y-axis and time on the x-axis, most people with MS present with bouts of disability that comes and goes in the context of the relapsing and remitting aspect. But then many, most of whom end up with some aspect of progression independent of relapses. So these events here are considered relapse associated worsening, someone getting worse from a relapse but not remitting completely. This can also happen later in the disease, but eventually abates. PIRA, progression independent of relapse activity, is represented as this little segment that may occur between relapses and then eventually without appreciating any relapses per se. So these are terms, they are not biological constructs. They are concepts that we try to identify people based on their clinical presentation. We are interested in better understanding the underlying biology if we are going to set the stage for thinking of therapeutic targets. A point to make, and again, Dr. Krieger will highlight this, I think, elegantly, the manifestation clinically does not necessarily capture the underlying biologies, which are clearly present largely under the surface. We have come to realize that it is not as though someone with relapsing MS magically one day transitions into secondary progressive MS, rather that these biologies overlap over decades of the MS process. It really is about the clinical threshold. If you had the clinical threshold set there, the shaded area would be subclinical. You would consider this person as having relapsing remitting onset and secondary progressive MS. But if you had an individual whose threshold was here, then clinically they would no longer look like RMS to SPMS, but rather primary progressive MS. This is a very quick way of trying to capture the evolution conceptually in the field that we recognize MS as a spectrum where these different clinical phenotypes represent people who clinically manifest differently, but all of whom harbor under the surface both the biologies of relapsing and progressive type of processes. This is another way of recapitulating the notion of the overlap. In gray, the left-sided triangle focuses on relapse biology and its manifestations, including the imaging. The lower right is CNS compartmentalized inflammation and degeneration, and you can see here that they overlap by decades. The predominant process changes over time, and this, of course, from a clinical expression standpoint, is also going to be influenced by issues of repair capacity, compensatory mechanisms, and the reserve, all of which diminish over time. In parallel to that, along the same timeline, increasing influence of immune senescence, inflammaging, comorbidities, and so on and so forth. In this context of a biological framework, we can think of what we currently have and what remain as unmet clinical needs, and this is just very quickly shown here. We've done a very good job as a field overall in limiting new relapsing disease activity. That's the green check mark here. Although one notes that while we control relapses extremely well with the high efficacy therapies, we're increasingly appreciating that there's a safety signal that will grow over time as more and more people are exposed for longer and longer periods. We have not yet done much in terms of CNS compartmentalized inflammation and degeneration, and we certainly have not really done much at all in terms of supporting repair and protecting. Probably to some extent, we have a grapple on some of the comorbidities and trying to deal with them, but this on the lower right is still a plus/minus area of unmet need. This is the framework of thinking in the clinical spectrum of the various aspects of unmet clinical need, and we're going to transition now to the last part of my presentation, which really hones in on vidofludimus calcium's mode of action, which starts with targeting Nurr1 to address aspects of protection and repair from ongoing injury. This includes, as Erik highlighted, injury that take place in the context of an acute inflammatory event, the relapsing biology. But again, as mentioned, and I think importantly, this is present throughout the spectrum, including subclinically, and the progressive biology also would benefit from neuroprotection and supporting repair. The potential impact then, which will set the stage for some of the discussion of this unique dual mode of action, combining the Nurr1 activation with selective inhibition of DHODH. A few words on Nurr1, also known as NR4A2, as a potential neuroprotective target in multiple sclerosis. It has been known over the years that Nurr1 plays a central role in terms of its signaling in general neuronal health. As a transcription factor of the steroid nuclear hormone receptor family, it regulates a variety of genes that are involved, starting with neural development, but all the way through to function and survival. It provides protection at the level of energy metabolism, the mitochondria, but also neurotrophic signaling, and when activated, also supports resistance to inflammatory types of injury. As a target in MS in particular, one can on one hand identify that reduced peripheral Nurr1 expression correlates with more aggressive relapsing disease, a higher relapse rate, and EDSS change, presumably the RAW, the relapse associated worsening, normalized during pregnancy, which is probably one of the biological reasons as to what happens in terms of limiting the MS activity just by virtue of the pregnant state. Importantly, within the central nervous system, higher levels of Nurr1 expression in pathology samples were associated with preserved density, supporting a potential for neuroprotective roles. When one thinks of Nurr1 activation in the context of neurodegenerative disease processes, which of course extend beyond MS, but are very relevant for MS, it is known biologically when activated to reduce neurotoxic mediator release from activated microglia and astrocytes that I highlighted before are considered now principal players at a chronically activated state in driving CNS compartmentalized processes and progressive disease. It supports mitochondrial and reactive oxygen species related defense mechanisms, particularly relevant in acute relapsing injury, but also progressive injury, and then induces neurotrophic factors like GDNF and BDNF, very important for supporting neurons, and promotes gene expression profiles that are linked to survival and normal function of neurons. In the context more broadly of neurodegenerative diseases, of course, there are pathologic hallmarks that are shared across conditions, MS and otherwise, and that is something I think that will be an exciting prospect moving forward. Segueing now to the DHODH aspect of vidofludimus calcium's mode of action. DHODH is a known metabolic checkpoint and particularly relevant as one of the pathways for pyrimidine synthesis involved in highly activated immune cells. When you inhibit this pathway, you do not limit the capacity of cells to deal with pyrimidine and DNA synthesis entirely, but you kind of cut the edge off the more activated immune cells, which are the ones that would be expected to participate in autoimmune processes, including in MS. It is a key mitochondrial enzyme, and it is highly expressed again in these particularly highly active, rapidly dividing lymphocytes. Resting lymphocytes less depend on it, and therefore inhibiting it is not going to affect the broad immune system capacity to protect us as part of the normal immune response. And we, with colleagues Heinz Wiendl and others, were able to show biologically that teriflunomide as a DHODH inhibitor indeed kind of cuts the edge off the overly activated immune cells involved in disease. This inhibition is particularly targeting cells thought to be pathogenic in the context of MS relapsing disease activity. As I had alluded to earlier on, there is a certain aspect about DHODH inhibition that may limit viral responses, including RNA and protein synthesis, and that this may include EBV, and of course, therefore may be important to consider as an added benefit given EBV's increasing implication. I think overall, this is a really interesting context where neuroprotection meets immune regulation. Nurr1 again, having both direct and indirect neuroprotective effects and DHODH targeting as a way of reducing the immune cell hyperactivation involved in the relapsing disease process. This is just a cartoon that recapitulates the three compartments and the capacity or the potential of vidofludimus calcium to be acting on these different biologies in the different compartments, leading to better support for neuron survival as well as immune modulation, having, in my mind, relevance across the broad spectrum of MS in relapsing and through progressive disease. So I will stop here and I think transition to the next speaker, having set the stage, hopefully, for suggesting that the dual mode of action, combining Nurr1 activation and selective inhibition of DHODH may be very attractive in the context of the MS spectrum. So I am going to unshare here and pass the baton on. Thank you very much, Amit. This is wonderful. This was a wonderful overview. Actually, so on the MS biology and specifically on Nurr1 and the role of Nurr1 and DHODH in MS. I will go on now and fill it with data. So I will talk about vidofludimus calcium dual mode of action on Nurr1 and on DHODH. We know already that vidofludimus calcium has a unique dual mechanism approach to MS. Potentially, it is the only oral MS drug that is really addressing PIRA and RAW simultaneously. So vidofludimus calcium is a direct Nurr1 activator. It modulates the gene expression directly in neurons. It mediates neuroprotection and neuronal survival, and it reduces the neurotoxicity of microglia and astrocytes, which indirectly supports neuronal survival again. Therefore, it targets neural degeneration beyond the focal inflammation. In addition, what we heard already, it is a selective DHODH inhibitor, what is wonderful because it selectively targets metabolically hyperactive T and B cells, and it reduces the focal inflammation, MRI lesions, and relapses. What we heard as well, it prevents reactivation of Epstein-Barr virus. Next one. As we said, it is a selective DHODH inhibitor, and actually, I am pretty proud about this, that it is a DHODH inhibitor in addition to the Nurr1 activation. So it selectively inhibits DHODH. You see here in this table that it has an IC50 of around 240 nanomolar, and I just put in teriflunomide as a comparison. Teriflunomide is most active on rat DHODH, whereas vidofludimus is most active on human DHODH. How does it come? Well, there is a species specificity for DHODH, and this can be explained because these are completely different chemical structures. You see it here on the right. We see the structure of vidofludimus, and you see, just for comparison reason, you see the structure of teriflunomide. In addition to this, we know that vidofludimus does not inhibit kinases. Whereas teriflunomide targets different kinases, PIM, Aurora A, PDGFR, and especially EGFR. EGFR inhibition actually is known or is related to skin diseases, diarrhea, and liver enzyme elevations. Both of them are active on DHODH and on high affinity immune cells. So vidofludimus, you see here just with the abbreviation Vido, and you see teriflunomide. They both reduce hyperactive or high affinity immune cells due to the restriction of the needed pyrimidines. In addition to this, of course, we tested vidofludimus calcium in different animal models. Just an example here that vidofludimus reduces the disease score in an inflammation-driven EAE model. It's a selective DHODH inhibitor, but in addition, that's on the next slide. In addition, it's a potent Nurr1 activator, what is really important and relevant in MS biology and in neuroprotection. So I depicted here the three, I would say, most important cell types in MS. So we have microglia, astrocytes, and neurons, and actually, Nurr1 is expressed in microglia, astrocytes, and in neurons. Nurr1 activation leads in the glial cells to a reduction of pro-inflammatory cytokines, nitrogen oxide, and ROS as well. In neurons, there's a direct effect as well, because when we here activate Nurr1, we see a reduction of oxidative stress, we see an increase of neuronal survival and differentiation of dopaminergic neurotransmission, and of myelination. So that means that Nurr1 activation is believed to be involved in halting neurodegeneration and disability progression. This is also, of course, supported by literature. That's not just my idea, it's really supported by literature. We heard it already very nicely summarized and explained by Amit Bar-Or. Next slide, please. Now we can, of course, just postulate vidofludimus calcium is a Nurr1 activator, but can we prove it? Yes, we can. That's great. You see here in the center, actually, you see the proposed binding model of vidofludimus towards Nurr1 ligand binding domain. This is just a model, but we were able to show by using ITC and DSF that vidofludimus calcium shows direct and measurable binding to a Nurr1 protein. So on the left, you see the ITC, and that demonstrated specific binding signal with an estimated dissociation constant of around 700 nanomolar, which really supports pharmacologically relevant target engagement. On the right-hand side, you see DSF, and that's actually an orthogonal assay, which independently confirmed the interaction through a statistically significant shift in one melting temperature versus DMSO control. So together, these two complementary biophysical data strengthen the evidence that Nurr1 is a direct molecular target of vidofludimus calcium. So now you can say, okay, it binds. Does it matter? Yes, it matters. Nurr1 is a transcription factor, and therefore, we looked into Nurr1-associated gene expression, which is modulated by vidofludimus calcium. You see here we tested in astrocytic cells, in microglia cells, and in neuronal cells, and we looked for TH and VMAT, which are two well-known and described direct target genes of Nurr1. You see here that vidofludimus calcium increased the expression in the selected Nurr1 regulated genes in a dose-dependent manner. So next is, okay, we see gene expression modulation. Is there any impact on function? Yes, of course, there is. Otherwise, I wouldn't show it to you. Vidofludimus calcium improved neuronal survival, and it reduced injury under apoptotic stress conditions. Here, we used TNF alpha cycloheximide model. We incubated viable neurons with TNF alpha cycloheximide. This is an apoptotic and necrotic stress signal here. The cells undergo apoptosis, and in the presence of vidofludimus, you see an improvement of the neuronal survival. This is actually depicted here in the middle, where you see that in the presence of vidofludimus calcium in a dose-dependent manner, you see an improved neuronal survival. We did not only count just the neuronal cells here, but we looked as well for neuronal injury marker. This is a well-known neurofilament light chain, what is measured in clinical studies quite often. You see here that again, in a dose-dependent manner, you see a reduction of a neuronal injury marker, neurofilament light chain. Vidofludimus calcium was associated with improved neuronal survival and reduced neurofilament light chain release under these apoptotic stress conditions. Next slide, please. Now you can say, okay, that's vidofludimus. Is Nurr1 important here, or is it just because of the DHODH inhibition? We were able to demonstrate that really Nurr1 is required to mediate this neuronal survival here. Again, TNF alpha cycloheximide is quite similar to the previous picture where you add TNF alpha cycloheximide, you see here in red, you have a decrease of the viability or the number of the living cells, and in the presence of vidofludimus, you see again an increase or a higher number of the living cells. That was performed with TNF alpha cycloheximide, but we used as well an additional trigger here. We were able to demonstrate it with 6-OHDA, which is a model where it's more about oxidative and mitochondrial injury compared to extrinsic death receptor signaling, what we see on the left. Vidofludimus calcium is able to do it. Now, is Nurr1 important here or not? This can be seen now because here we used CRISPR mediated Nurr1 knockout, and you see it that when you have neurons which are knocked out for Nurr1, then vidofludimus calcium is no longer able to improve the viability and the number of living cells in this model. Vidofludimus-associated improved neuronal survival really requires Nurr1. Next one, please. Of course, I talked about microglia. Microglia are super important because they drive inflammation in the brain as well. We were interested in the role of vidofludimus calcium on neuronal viability under neuroinflammatory condition. Therefore, we performed the neuron microglia co-cultures here. We co-cultured microglia and neurons, then stimulated the microglia to produce pro-inflammatory cytokines. You see just on the graph on the left that the neurons are undergoing apoptosis. In the presence of vidofludimus, we see, again, a higher number of the neuron cells. In the middle, when you add LPS and interferon gamma, you see a reduction of living cells of the, in this case, human cell line SH-SY5Y cells. When you then add in the presence of vidofludimus, you have an improved survival of these. Of course, we wanted to know, is it really mediated by microglia or is it just toxicity that is driven by LPS and interferon gamma? Therefore, we added the control experiment, what you see on the right, that no LPS and interferon gamma don't do any harm to neurons alone. So vidofludimus calcium was associated with increased neuronal viability in inflammatory co-culture. Now it comes to animal models. Does vidofludimus work in animals? Yes, of course it does. We did several EAE models, and we were able to demonstrate that vidofludimus calcium reduced disease severity in EAE model. Now we know in a prophylactic setting and in a therapeutic setting. Of course, we all know that EAE models are mainly inflammatory driven, so it could be that DHODH inhibitors work there. Indeed, teriflunomide works there. That's fine. Vidofludimus works there. We use these models because we were interested in investigating the impact of vidofludimus in these models on Nurr1, and we were able to do it. In the next slide, you see here that vidofludimus calcium modulated Nurr1-related gene expression in the CNS of the mice in these EAE models. We investigated the brain and the spinal cord, and we looked into the prophylactic and into the therapeutic setting of these animal models. You see here in the brain on the left that in the presence of vidofludimus calcium, we see an increase of Nurr1 itself, so there seemed to be an autoregulation. So we had higher levels of Nurr1 in the brain of these animals. We looked as well for TH, so tyrosine hydroxylase, which is a well-described primary target gene of Nurr1. So in the brain, we saw Nurr1 upregulation and TH upregulation by vidofludimus calcium. We looked as well into the spinal cord. Actually, in the spinal cord, we focused more on the detoxification of superoxide radicals by SOD upregulation, and we looked into ATP production in principle via the upregulation of COX5B. So vidofludimus calcium treatment was associated with the modulation of Nurr1-related gene expression in CNS tissue in both the prophylactic and the therapeutic inflammation-driven EAE settings. We look for function as well, so we were interested in proteins in the plasma, if we can measure it. Looked for BDNF, which is brain-derived neurotrophic factor. You see that even in the plasma of this, we can demonstrate that we have a higher exposure or a higher production of BDNF in the plasma of vidofludimus calcium-treated EAE mice. Here, again, we looked for neurofilament light levels, which were decreased under the treatment of vidofludimus calcium. Okay, so now you can say, is every DHODH inhibitor a Nurr1 agonist? I would clearly say no. So there was a publication from Vietto et al. in 2023 that described it already, but I'm pretty sure that you guys are super interested in teriflunomide, because it's approved for MS. So we looked into this, and you see again here, ITC testing, you see DSF testing. You see again, for vidofludimus calcium, there's a binding signal detected, of course, for vidofludimus on Nurr1. Under the same conditions, we tested for teriflunomide, and actually, there's no proper curve, so we don't see any measurable binding here in ITC. We did it as well in DSF. They are just a different assay system. Again, vidofludimus calcium induces a temperature shift, a melting temperature shift, which indicates the binding here, whereas teriflunomide does not. So that means, most likely there is no binding of teriflunomide to Nurr1, but it could mean maybe there is an indirect effect towards Nurr1 what cannot be measured via the direct interaction. We looked as well for the function. I told already about neuronal survival under apoptotic stress conditions, and we did the same experiment on the next slide, did the same experiment in the presence of teriflunomide. What you clearly see here is that vidofludimus calcium improved the neuronal survival under apoptotic stress conditions, whereas on the right, teriflunomide did not. So in this test system, teriflunomide did not significantly improve survival of neuronal cells. Another hint that it is really not addressing Nurr1, it is not binding, and it is not promoting any survival functions in neuronal cells. To summarize everything, we can show that vidofludimus calcium activates Nurr1 and selectively inhibits DHODH. With the Nurr1 activation, it is improving the survival of neurons, and it is reducing neurotoxic microglial activation. DHODH inhibition selectively targets only metabolically active T and B cells, and with having DHODH inhibition, vidofludimus calcium was able to inhibit the EBV-associated B cell responses. Thank you. Great. Thank you, Hella. Good afternoon, everybody. I am Mike Panzara. I am the Chief Medical Officer at Immunic. It is a great pleasure to be here with you today to talk about our efforts in relapsing multiple sclerosis, focusing on the ENSURE program. Next slide, please. I think, in the 25 years I have been doing this drug development and the academics and MS focus before that as a neurologist seeing these patients, the way things have changed over that time in the treatment of multiple sclerosis has been just remarkable. I think Stephen and Amit, my colleagues in the space, would agree it has been quite What has been accomplished and what is available for patients today, we could not have even thought about back then. It makes you feel pretty good about what we have all accomplished. But if you really do not want to feel really good, just listen to this patient-focused drug development meeting that happened at FDA at the end of last year, that despite 20 therapies, 20+ approved DMTs in this space, there are enormous unmet needs that exist. Just listening to the people with MS talk about how while their doctors are telling them they are doing great, they are not having relapses, their MRI lesions are not detectable. They just feel like they are getting worse. They just are running out of options because of their age for a variety of reasons, and they are looking for something new. This was really a remarkable revelation, certainly when I have watched this, and really speaks to why vidofludimus calcium is so important and has great potential to help many of these patients. Next slide, please. You've already heard about the biology, you've already heard about how the dual mechanism of action leads to potential to treat different aspects of the disease. These effects would be anticipated to address both these important elements of disease, as Amit Bar-Or outlined for you, and that's what the next therapies really should be doing. We should be thinking about how do we tackle not just how do we reduce those relapses, but how do we treat this underlying progression of disease, this biology that, as Amit Bar-Or laid out, begins right at the earliest diagnosis of the disease, even if the threshold of visible activity is not there. It's happening, it's moving along, and it needs to be addressed. Next slide, please. As we dove into, at Immunic, using vidofludimus calcium in relapsing MS, the phase II study here is shown, the EMPhASIS study. This was a study looking as double-blind study, focused on relapsing MS, looking, as is often the case in MS development programs, lesion formation. Looking at whether vidofludimus calcium, when given to patients with early active multiple sclerosis, whether there can be lesion reduction. This is truly one of the best predictors of whether a drug has the potential to be successful in phase III using this important MRI biomarker. Next slide. What we saw was very clear, is there was a robust lesion reduction over 24 weeks in this patient population, using cumulative active lesions as well as combined unique active lesions, as well as gadolinium-enhancing lesions. You can see that both the 30 mg and the 45 mg dose were quite effective versus placebo, with a very minimal effect of a 10 mg dose. With this led to the initial decision that there would be great potential of this in relapsing MS. When one looks at relapse outcome, next slide, you can also see that there was an encouraging effect on relapse. What you're looking at here is the time to first relapse, which this is a Kaplan-Meier curve. What you're seeing is that it trended towards significance, a 42% reduction in the risk of relapse, and you can see the proportions relapsing there. This is for the 30 mg dose. There wasn't much difference with the 45 mg. Just similar to the MRI, there was no difference. You're starting to see an effect in six to eight weeks. With the gadolinium-enhancing lesion results, as well as this result on an approvable endpoint, this led to the design of the ENSURE study. Very importantly also, there is a very favorable safety profile, and that's what you're seeing here. There is really no signal in this cohort of liver injury, no indication of bone marrow suppression or GI side effects. The drug has a very short half-life. When one looks at this in the context of currently 3,500 patients that have been exposed to vidofludimus calcium over six and a half years, with the longest patients now past six and a half years in open label studies, this seems very encouraging in terms of the benefit risk, proceeding into a phase III study. Many of these patients ended up going into an open label extension study, and that's what you're seeing on the next slide. What's really encouraging there is that the study is currently ongoing. The retention rate is extremely high, and you can see that there is this stable low progression of patients with continued open label treatment, with low discontinuation rate. Acknowledging it is open to open label study, but nonetheless, when one sees that patients are remaining in this study and continuing on treatment with a favorable safety and tolerability profile, this is extremely encouraging, as we head into phase III studies. As was noted earlier, we are approaching the end of our phase III studies. These are the ENSURE phase III studies. They have now been going on for several years, and these are the pivotal studies designed to confirm the immunomodulatory effects, specifically the relapse reduction effect. To do this study, it was very important to focus on the safety of patients, and this was a placebo-controlled study, and one of the key elements of this study was to, even though we were doing a placebo-controlled study, we need to make sure patients were kept safe. The way that was done is that these two large phase III studies allowed patients on placebo or active treatment to, in the setting of a relapse, receive active treatment as a rescue. That allows us to measure the relapse effect, which was the whole purpose of this study, to be able to detect whether vidofludimus calcium is a meaningful effect at relapse reduction, which is a clinically meaningful endpoint as well as associated endpoints. What it does do is it could cloud our ability to see an effect on disability progression, namely the time or the slowing of 12 or 24 weeks sustained, confirmed disability worsening. Nonetheless, we anticipate that the endpoint here, and we are aligned with the endpoints, with the regulatory authorities as we proceed, such that if we saw an effect on a time to relapse or a risk reduction, that would lead, pave the way to a U.S. submission. We are likewise encouraged by the fact there was interim analysis in October of 2024, where it was a futility analysis, where the independent data safety monitoring committee recommended that the study continue unchanged. All this is very encouraging as we move forward. The next slide shows you a bit more about the study, and this is some new information here, where we really targeted an early active population, and we went to places in the world where we could find an early active patient population for placebo-controlled trials. On the right-hand side, you are seeing the distribution of clinical trial sites. Most of them were in Central and Eastern Europe, with some sites in Western Europe, U.S. and Canada. You can see the inclusion criteria in the right, at left, excuse me, again, targeting that population that we saw an effect on in our phase II study, in the EMPhASIS study, specifically looking for early active patients, that had met the diagnosis of relapsing MS per the McDonald criteria as well as the Lublin criteria for active disease. When one looks at the next slide, which is actually the baseline characteristics, you can see this is exactly what we've achieved. We recruited a very similar population in ENSURE to the EMPhASIS population. We have patients of similar age and gender, as well as the distribution of EDSS. Interestingly, about 50% of the patients had received a prior treatment, so we'll be able to see very nicely whether those who are naive to treatment versus those who received treatment, how vidofludimus does perform in those patients. Importantly, when one looks at the EMPhASIS study, the patient population there and the patient population in ENSURE, and one figures, does what we've seen in EMPhASIS encourage us about what we're going to see in ENSURE? It certainly does. This is about as close as you can get to confirmatory studies. When we were deciding on endpoints, as I mentioned, time to first relapse is the endpoint for the reasons I've outlined. But we also included a variety of secondary endpoints that allow us to further understand the effect that vidofludimus calcium has in patients with MS. Actually, in selecting those endpoints, you can see on the right, again, quotes from that patient-focused drug development meeting, where the endpoints we've selected are the endpoints that we believe, based on this feedback, will be meaningful for people living with MS, should we show an effect. That's namely focused on the typical things like relapse, as we'd expected, including the ARR, but very importantly, novel endpoints such as net clinical benefit and looking at time to disability, 12-week confirmed disability improvement. We've been very encouraged in our phase II studies in progressive MS, which you'll hear about at another time, where we've seen patients who there are signals about not just slowing disability worsening, but improving. Certain patients improve on treatment. We put that in our secondary endpoints at a high level to really confirm that this effect, which would suggest some aspect of the biology that you heard about, and then endpoints looking at whether patients are overall feeling better on treatment. You can see here, we've outlined that for you, so you can understand that the commitment here is not just to look at those endpoints that are so critical, like relapse and disability, but other endpoints that can tell us, are we addressing the needs that patients are telling us we need to address? Next slide. In summary, we are on track for our pivotal readouts this year, before year-end, and focused on delivering NDA following those readouts. We have a program that, in relapsing disease, is about as de-risked as it can be, with a robust phase II study and endpoints in phase III that are comparable with alignment with the regulatory authorities and the precedent behind us on our endpoints. That gives us a clear path to submission, upon a positive outcome, later this year. With that, I want to turn the mic over to Stephen Krieger. Dr. Krieger is a Professor of Neurology at Icahn School of Medicine at Mount Sinai Hospital in New York. He graduated from Columbia College and received his medical degree from Yale and completed his residency and fellowship at Mount Sinai. Dr. Krieger has participated in numerous MS clinical trials and lectures internationally about MS, with an emphasis on emerging therapies in MS disease course, of which you will hear more about today. Dr. Krieger is best known for proposing the topographical model of MS, a novel visualization of the MS clinical course, and it is my pleasure to turn it over to Stephen. Thank you, Stephen. Mike, I appreciate it. I hope you can all see my slides now. This has been a great background about the science of our field and the science that has led to the development of vidofludimus calcium. What I am going to do is step back a little bit and speak from the perspective of a clinician, people in the field treating these patients and facing some of these unmet needs and thinking about what our goals of care are now moving forward. I titled this, "The unmet need in relapsing MS has changed," because the whole field of MS has changed. Our approach to relapsing disease is evolving. Even though, in a sense, we have a real plethora of treatments available to us, this is not a solved problem. Mike alluded to the Voice of the Patient report from the National MS Society. I am going to allude to it also, but it is honestly facing that voice and those perspectives that we are looking at every day, and I am going to try to bring some context to that. In his intro, Mike mentioned the topographical model of MS. It is my life's work, and I am going to summarize it for you in one minute to try to make it as relevant as possible to what we are facing in our practices and what the unmet needs are in our field. You have heard a little bit about PIRA and RAW, and I am sure you are familiar with it from looking at trials. I want to put that in context of the disease course, and that is really what the topographical model is intended to do. When we think about lesions in MS, new T2 lesions, some of our main outcomes, as you heard in our early trials and phase II trials, lesions are often in the cord, the infratentorial compartment, or the hemispheres of the brain. We compensate for lesions, but our ability to compensate is different depending on where those lesions are. Lesions in the spinal cord and the optic nerve cause symptoms. Lesions like these in the hemispheres are often subclinical, below the clinical threshold, a useful measure in our trials for disease activity. But when lesions form in the spinal cord or the optic nerve, that causes a clinical event above the threshold there, CIS first attack. Here, another one causing a relapse with recovery. But what you are seeing happening is the threshold that Dr. Bar-Or mentioned is declining, and as it does, it emerges above the threshold as PIRA, progression independent of new relapses, sometimes with relapse-associated worsening superimposed. As time passes, that threshold drops, the brain atrophies, and so much of the disease burden gets revealed above the threshold as PIRA. Most of the disability that accumulates is progressive. Even though we are here talking about relapsing forms of MS, this is happening early on in relapsing forms of the disease. The issue of treating MS early and trying to quiet down the disease topography, stop new lesions and relapses from forming is important, but it ultimately is trying to change the trajectory of disability as it forms. In that way, controlling relapses is part of our treatment goal, but not the whole one. The perspective on our field began with treating relapses almost as an end in themselves. Now we can think of it as treating relapses as a way of shutting down acute inflammatory disease. That is something we have become very good at, as I am sure all of you know, with the advent of high-efficacy therapies and B cell depleters, and I am going to talk about that in a moment. What that has revealed for us, in a sense, is PIRA. It has revealed for us that even though we can prevent relapses and lesions, declining reserve Neuroaxonal injury is contributing to that dropping threshold and the risk of disease accumulation. That is not something that happens only late in the disease. Talking about relapsing MS, let us begin at the beginning. Our disability scale is the EDSS. An EDSS of 0 has been defined as normal for 40 years in our field. When we did a study here at Mount Sinai looking at that a couple of years ago, we challenged our patients with more difficult physical tasks, harder than what we do on a conventional neuro exam, and found there are signs of weakness, imbalance, incoordination, fall risk, right from the beginning of the disease, right from EDSS of 0. We talk about the clinical threshold. I really like Dr. Bar-Or's way of showing that you place the threshold in different places, you can think of the disease course a little differently. I am pointing out that even at the lowest, earliest level of this disease, we can look below that clinical threshold and find damage. Here is some data to support that. PIRA, this gradual progression, starts out early in the course of relapsing disease. From this project from Terr and colleagues found that 8% of the cohort of relapsing MS had PIRA within five years, and 25% of them across the period of follow-up had PIRA. These are not people we are calling secondary progressive MS. This is people who are accumulating disability gradually, even when we do not give it that nomenclature, and the sense of futility that that nomenclature has often provided to people living with the disease. The risk of PIRA causes a 26 x higher risk of accumulating significant disability. An EDSS of six is someone needing a cane over the years that follow. Remember, people with MS are in their 20s, they are in their 30s. Needing a cane within years of diagnosis is an unacceptable outcome that we are endeavoring to prevent. Mike Panzara pointed out this National MS Society Voice of the Patient Report, which is what we're listening to in practice every day. Patients telling us that they're worsening even when we don't see new relapses or lesions, that they've stopped or changed their disease-modifying therapy because in one way or another, they're unsatisfied with it. Either their disease is worsening or they're having side effects. That's the message we're being told. When we look at large data sets, this was work done by my mentor, Fred Lublin, using a massive data set that combines both real-world and clinical trial outcomes. Here's what disability in MS looks like. This was published in Brain a couple of years ago. In blue is PIRA progression. In teal are relapse-associated worsening. In relapsing MS, there's both. In forms of MS that we conceptualize as progressive, SPMS and PPMS, it's all PIRA. I want to point out to you that that's happening right from early on in the disease. When we talk about relapsing MS, we're talking about both mechanisms that Dr. Bar-Or talked about. We're talking about both ways that disability can accumulate. How much can we do about this? It is easy to look at our field and think with the advent of high-efficacy therapies in general, and B cell depleters in particular, that this whole problem has been solved. In fact, the use of high-efficacy therapies shows us the problem that was, in a sense, hiding in plain sight, that PIRA continues to occur. So in OPERA, which is the ocrelizumab versus interferon pivotal trials from a decade ago, disability accumulated, of course, more in folks on interferon than on ocrelizumab. Most of that disability was PIRA in both groups. Relapse-associated worsening was small, even for the interferon-treated patients. Nonetheless, relapse-associated worsening is attenuated by a high-efficacy therapy that stops relapses. PIRA, less so. PIRA was less responsive to treatment. Partly, that's because of how our high-efficacy therapies work. They work on inflammatory biology. They're not working in the central nervous system, and they're not working to do any sort of restorative technique. PIRA is going to creep in, even in the setting of keeping, in my language, the disease topography flat, because some of that disease topography is already forged. If reserve is being lost and the threshold is dropping, simply preventing new relapses and lesions isn't going to stop it. We have had a huge influx of patients onto B cell therapies over the past decade. It has been transformative for our field. What that means is now I face patients every day who've been on B cell depleters for five years or longer, coming on 10 years. What we're starting to appreciate is the cumulative consequence on the immune system of B cell depletion. When you knock out the emergence of new B cells and the maturation of B cells into plasma cells over years, circulating antibody levels drop and hypogammaglobulinemia kicks in. This one study looking at 20,000 patients across an aggregate of studies found 11% of prevalence of hypogammaglobulinemia on patients on B cell depleters. This has started to become a concern for us. Now, when I talk to patients starting a B cell depleter, I don't say that they're going to be on this for the rest of their lives. I say, "Think of this as a 5 - 10 years plan." I think that is a way of curtailing some of that cumulative risk. What that also means is all of the patients with relapsing MS who've been on B cell depleters for 5 - 10 years are going to have to look to what happens after that 5- 10 years plan. We care about low immunoglobulins because there is emerging data that it does track with an increased risk of infection. It's a predictor. This was a single site study looking at 238 patients treated with ocrelizumab for up to six years. The drop in immunoglobulin IgG started to happen on an annualized basis, and it did start to track with infections. You see here the percentage of patients needing oral antibiotics, still relatively small, but higher in the people who had low immunoglobulin. Patients who needed IV antibiotics, thankfully, this is a small number, but again, you see the risk is twice as high for people whose immunoglobulins have already started to drop. Patients with MS needing IV antibiotics in a clinical trial, we would consider that a serious adverse event. I'm not admitting patients routinely for this. This is not something that we tolerate. If our treatments are starting to cause increased incidence of serious infections, requiring things like IV antibiotics, this is a problem, and we're going to need to adapt as a field to that changing landscape. I'll point out here that age is a risk factor for increasing infections, and it was a risk factor here in this project and factored into the regression model. The other thing that's happening to our MS population is they're aging. We've done a great job with MS, and that means our population is going to live longer and longer into late adulthood and into their geriatric years. Our strategies have to evolve, because we're not going to continue suppressing cell lines in people who are 60 and 70 and 80 years old. I'll take a step out of the B cell depleters for a moment, even though that has really been a huge deal for our field, and say that the first real transformation that happened now 15 years ago in MS was the advent of oral therapies. When I got started in this field, every day, patients taking injectables would say, "Doc, when are we going to get pills?" Then we got pills, and things didn't get simpler all of a sudden. They got more complicated. That's in part because of the legacy of our first oral agents for MS, which was fingolimod, and the S1P modulators brought with them a lot of potential side effects and adverse events and monitoring that had to happen upfront. It wasn't what the MS community was expecting from having a pill. I think that as we've now had pills in various forms, fumarates, S1P modulators, teriflunomide, and also oral cladribine over the last 15 years, we've gotten a sense of that complexity of some of our oral agents. With the fumarates, there are issues relating to GI tolerability and flushing. Our S1P modulators, now it's a whole class of them, still require thoughtful consideration of cardiac comorbidities, concern for macular edema, concern for infection, concern for liver issues. Teriflunomide has long been associated with alopecia, as well as pregnancy and family planning concerns. That has been an issue for the big cohort of MS patients who are of childbearing age and potential. Oral cladribine, which has now been out for about five years, inherited the concern for malignancies from its clinical trial campaign, and that has, in many ways, seriously curtailed its use here and abroad. There are issues to contend with oral agents, and side effects often carry more weight. This was also true in that National MS Society Voice of the Patient Report, which I come back to here because it tells us something about why patients are happy or unhappy with their treatment. When you take into account the sort of MS community perspectives, concerns that people have that the fundamentals of their disease aren't being addressed, repair mechanisms and protection, stopping progression, these are not things that we can comfortably offer to patients now, and they know it, and they're telling us. I think Mike's point that it's quite humbling listening to that Voice of the Patient Report, I think that's good for industry to hear. We, on the clinician side, are hearing it every day, so we know that these unmet needs really exist. The aging MS population, and again, this post-B cell population. We had the B cell influx, now we're facing a B cell efflux, as people are going to come off that strategy need new treatment approaches. Thinking about the unmet needs in the disease and how they've changed, I'll wrap up here to say we need to continue to control visible disease, the above threshold manifestations, new lesions. We need to better control progression, and we need to think beyond the immune system itself. We've had great success with the peripheral immune system, but MS is a disease of the central nervous system. We need things that act within the central nervous system to try to address some of those unmet needs. I'm not going to rehash what you've already heard in great detail from the people developing the agent, but this is why vidofludimus calcium has a niche that it could fill, because it works on both a strategy that can address active inflammation and relapses. It works on a strategy, at this point, untapped in MS through Nurr1 modulation. It is oral, it is simple, it doesn't require infusion centers, and that remains an advantage. I'll stop there. I'll turn it over to Jason Tardio, who's going to take it from here, and thanks so much for having me join you today. Excellent. Thank you so much, Dr. Krieger. Good afternoon. My name is Jason Tardio, I am the President and Chief Operating Officer here at Immunic. What I would like to do is take all the information we have heard today, the science, the biology, the preclinical data, the clinical data, the overview of unmet needs, and translate that into what we believe can be a compelling commercial opportunity for vidofludimus calcium in relapsing MS. The main takeaway that I want to establish, and Erik alluded to this earlier, is that the relapsing MS market is a large, dynamic market where treatment decisions are highly individualized, and patients frequently move between therapies over the course of their disease and over the course of decades treated with disease-modifying therapies. We believe that this creates multiple opportunities for differentiated therapy like vidofludimus calcium during the course of a patient's overall journey. Next slide, please. As we have heard today, despite having more than 20 approved therapies, significant unmet needs remain. We see three in particular. PIRA, progression independent of relapse activity. We know it begins early. It becomes increasingly important as the driver of disability over time. I think most importantly, there are no medicines today directly influencing and impacting the neurodegenerative component of the disease that drives PIRA. We believe that vidofludimus calcium, given its neuro-inactivation, could do just that. The second unmet need is safety. We know DMTs carry meaningful safety trade-offs. This includes serious infections like progressive multifocal leukoencephalopathy, increased risk of malignancies, increased risk of hepatoliver toxicity. These safety considerations become increasingly important as patients age and accumulate comorbidities. The third unmet need is tolerability. We just heard this from Dr. Krieger. Side effects remain a significant reason why patients discontinue therapy. If patient discontinues the therapy or is unable to take the therapy, they are not going to benefit from the potential efficacy of that respective therapy. In fact, in one real-world study, upwards of 50% of patients on Gilenya and close to 70% of patients on TECFIDERA discontinued therapy due to tolerability issues. This is a real issue, and we will talk about the importance of that to patients in just a moment. Despite tremendous innovation in MS, there remains an opportunity for therapies that can deliver a better overall balance of disease control, of safety, and of tolerability. Next slide, please. That opportunity exists within a very large and growing market. The U.S. relapsing MS market is approximately $17 billion today and is projected to grow to over $25 billion by the time we get to the 2030s. The anti-CD20 therapies have clearly become the largest class, representing about half the treated patients today. It is important to note that the oral therapies continue to represent close to 30% of the market by patient share. Despite the success of the anti-CD20 class, there remains a substantial and durable preference for oral treatment, and we believe this creates a significant opportunity for innovation, specifically within the oral disease-modifying therapy class. Next slide, please. If you only remember one slide from my presentation today, please remember this slide. The relapsing MS market is not a winner-take-all market, but rather is a dynamic market in which approximately 45,000 patients initiate therapy each year. Another 45,000 prescriptions are associated with patients switching off of therapy. On top of that, even with 20 + available therapies, there is approximately 125,000 diagnosed relapsing MS patients who are currently untreated. Switching is not a failure of the market. It is a fundamental feature of MS journey and MS care. Patients initiate treatment, they switch treatment because of breakthrough disease. They switch treatment because of safety concerns. They switch treatment because they are having tolerability issues. Treatment strategy evolve as patients get older, as Dr. Krieger again just alluded to. Importantly, there is not a single disease-modifying therapy that optimizes every attribute for every patient at every stage of disease that can span decades. So vidofludimus calcium does not need to be the answer for every patient, but rather it needs to be a compelling answer for the right patient at multiple points along their journey. Next slide, please. That is particularly important because MS treatment is highly personalized. This is not a one-size-fits-all market. Physicians constantly balance disease severity, age, immune status, preferred route of administration, and each patient's individual tolerance for risk when considering a therapy that is appropriate. At the same time, the prescribing community itself is highly heterogeneous. We heard from two KOL academic clinicians today. MS specialists may approach treatment different than general neurologists. Some physicians, about 40%, favor an escalation approach, while about the other 60% favor earlier use of high-efficacy therapies. Of course, prescribing behavior can differ between general neurologists, academic KOLs, and individuals treating within a community setting. Commercially, that means there is not one single relapsing MS patient or one single prescribing algorithm. A differentiated therapy needs to offer a clear value proposition across identical patient segments and physician types, and we believe vidofludimus calcium has the potential to do just that. Next slide, please. One assumption that is worth challenging is that MS treatment selection is simply an efficacy hierarchy. It is not. When physicians were asked directly about attributes that matter most when selecting a disease-modifying therapy in MS, safety actually ranked number one, slightly ahead of relapse reduction and reduction in disability progression. Of course, efficacy remains critically important, but physicians ultimately make a benefit-risk decision, not an efficacy decision in isolation. That is why we believe the totality of the vidofludimus calcium profile could be so important. Next slide. It should not be a surprise, when you ask patients, the message becomes even more pronounced. Side effects were by far the largest driver of treatment preference, accounting for more than half the relative importance patients assigned to attributes evaluated. It is important to remember that patients will live with MS for decades, and therefore will be treated for decades with disease-modifying therapies. They obviously want disease control, but they also care deeply about how the therapy makes them feel, the risks that they are accepting, how it affects their daily lives, and how much burden the treatment places on them. So safety, tolerability, and convenience are not secondary attributes. They can be central to long-term treatment success in relapsing multiple sclerosis. Next slide. This brings us where we believe vidofludimus calcium will offer a compelling value proposition. We are not trying to build the value proposition around one single attribute. We are targeting the optimal balance across attributes that matter to both treating physicians and HCPs, and to patients. First, the dual mechanism of action. Potential neuroprotective effects through neuron activation, combined with potent anti-inflammatory effects through selective DHODH inhibition. Second, safety. Based on the clinical experience to date, we believe vidofludimus calcium has the potential to reduce some of the important safety concerns associated with currently marketed and potentially future DMTs, including hepatotoxicity, serious infections, and hypogammaglobulinemia. Third, tolerability. We have observed a favorable tolerability profile to date, with low rates of discontinuation due to adverse events, and without many of the prominent tolerability and side effects that cause patients to discontinue currently marketed products, including GI flushing, alopecia-related tolerability, and others on some of the marketed products. Finally, once-a-day oral convenience, which reduces treatment burden for patients, for physicians, and for their offices. Ultimately, we believe the differentiation for vidofludimus calcium will come from the totality of its profile, the mechanism of action, the efficacy, the safety, the tolerability, and the convenience. Given all of this, we believe vidofludimus could potentially offer the best benefit risk profile of any disease-modifying therapy. Next slide. Where could that profile translate into commercial adoption? We see three particularly attractive segments that are underserved today. First, patients who prefer oral disease-modifying therapies. There is approximately 100,000 relapsing patients today currently treated with oral therapies. Second, patients who need to sequence away from anti-CD20 therapies. This includes patients facing cumulative safety or tolerability concerns, or patients continuing to have progression largely linked to PIRA. Over 60,000 patients fall into this bucket. Third, the large and growing population of older relapsing MS patients. Approximately 185,000 currently treated patients with relapsing disease are age 55 or older, where the benefit-risk equation can change meaningfully as patients get older. These are large, clinically recognizable patient populations, and importantly, they are not mutually exclusive. An older patient sequences away from a CD20 might also prefer an oral therapy. Let's spend a minute just diving a little bit deeper to each of these respective opportunities. Next slide, please. Starting with patients who prefer oral therapies. About 25% of patients starting a treatment today will choose an oral disease-modifying therapy. As I have mentioned, about 100,000 patients are currently treated today with an oral disease-modifying therapy. There are practical reasons why patients choose an oral. Many are looking for convenience and flexibility or simply prefer oral treatment over injections or infusions. This may include patients that have needle aversion, that have busy lifestyles, or have limited access to infusion centers. Despite the continued preference for oral therapies, there is still a meaningful unmet need within this class. Every currently approved oral disease-modifying therapy carries meaningful trade-offs across some combination of either efficacy, safety, tolerability, monitoring burden, immunosuppression, or suitability for that patient, especially as they get older. We see some of that unmet need reflected in persistence. Approximately 30% of patients starting an oral disease-modifying therapy today will discontinue their treatment and are completely off therapy within a year. We think there is a meaningful opportunity for an oral therapy that can provide effective disease control while offering a favorable safety and tolerability profile and an overall low treatment burden. If vidofludimus calcium can deliver that balance, we believe it can become attractive option within the oral disease-modifying therapy class. Next slide. The second opportunity is sequencing away from CD20 therapies. We know that CD20s are highly effective and have transformed the treatment of MS, but not every patient can or should remain on chronic broad B cell depleting therapies indefinitely. As Dr. Krieger alluded to, with longer anti-CD20 treatment, the immune system can become increasingly weakened over time. We know that in a real-world study of ocrelizumab-treated patients, about one-third developed low levels of IgG antibodies, and these antibodies are important to fight infection. Consistent with that, recent data has also shown that patients treated with an anti-CD20 have a meaningfully higher risk of infection compared to patients treating on platform therapies. These cumulative immune consequences matter because patients discontinuing CD20 therapies, often because of recurrent infections, low IgG levels, or other safety concerns, still require an effective follow-on treatment that can preserve disease control without compromising immune defense. We see a meaningful population potentially needing that next option. Our claims analysis shows approximately 18% of anti-CD20 patients switch away from the class. Another 15% will discontinue therapy completely within one year, and approximately 15% use extended interval dosing, potentially reflecting efforts to manage infection risk and treatment burden. There is also another important consideration. Profound relapse suppression does not eliminate disability progression. Approximately 20% of OCREVUS-treated patients may experience PIRA within two to four years, despite strong suppression of relapses. So when a patient needs to move away from an anti-CD20 therapy, whether it is because of serious infection, declining IgG levels, or other safety concerns, the question remains, what comes next? Today there is not a clear answer. That is where we believe vidofludimus calcium could potentially play an extremely important role as a non-immunosuppressant, oral follow-on option designed to preserve disease control while reducing immune burden associated with continued B cell depletion. Next slide, please. The third and last opportunity I would like to highlight are the aging relapsing MS population. Approximately 47% of patients diagnosed with relapsing MS today in the U.S. are age 55 or older. This equates to about 185,000 currently treated patients. This is not a niche population. It represents a very significant portion of the relapsing market. As patients move into their 50s and 60s, the biology, and therefore the benefit-risk discussion, begins to change. Inflammatory MS activity diminishes with age, while immunosenescence, infection susceptibility, and comorbidities increase importantly. For some patients, that shifts the benefit with equation away from indefinite use of immunosuppressant therapies, and more importantly, to a medicine like vidofludimus calcium that is an immunomodulator. Older age is associated with less complete recovery from a relapse. Even if the relapses become less frequent in these older patients, the consequences of that relapse may become more significant. This creates a real therapeutic need. How do we continue to protect older individuals living with MS from disease activity without exposing them to unnecessary levels of broad immunosuppression as they age? We believe that answer may be vidofludimus calcium. It could potentially offer a differentiated approach in oral. Again, that is an immunomodulator, not an immunosuppressant, as an option for older, clinically stable relapsing MS patients who still require relapse protection, but whose benefit-risk priorities have evolved with age. Next slide, please. Let me close and summarize the commercial thesis. First, we are pursuing a large and growing market, $17 billion today, growing to over $25 billion by 2032, with oral disease-modifying therapies continuing to represent a significant portion of the treatment class. Second, this is not a winner-take-all market. Patients will initiate therapy. They're going to switch therapies multiple times. Of course, the benefit-risk evolution changes as patients get older with age. Third, despite more than 20 approved therapies, meaningful unmet needs remains, particularly around PIRA, around disability progression, around the need for safer and more tolerable agents. Fourth, treatment decisions are not solely based on efficacy. Physicians and patients make treatment decisions based upon the overall benefit-risk profile of a medicine. This is where we believe vidofludimus calcium could be differentiated. Vidofludimus will deliver strong efficacy by combining its dual Nurr1 and DHODH mechanism with oral convenience and a potentially very favorable safety and tolerability profile. We see multiple underserved large populations that we think will be very appropriate for vidofludimus calcium. This includes patients who prefer oral therapies, patients that need to sequence or switch away from the anti-CD20 class, and the large and growing population of older individuals with MS. Taken together, if we deliver a medicine and can replicate the data we've seen to date, a medicine that will have an impact on clinical relapses, a medicine that will have significant impact on MRI, and the reduction of MRI lesions, a medicine that we think offers a best-in-disease safety and tolerability profile, we believe that that medicine, in vidofludimus calcium, has a potential to capture meaningful sales in what is a large and growing U.S. relapsing market today. Thank you. I'll conclude with that. Perfect. Thank you, Jason. In the interest of time, and the fact that these slides are available, I'm going to zip through my close so that we can take advantage of the panel and take some questions. Jessica, if you could just flip, there's a slide here on our IP. We have good IP coverage through 2044. You can take a look at the slide later. I'm going to just go to the close here. The main thesis here, you've heard a lot on the science, you've heard a lot on the clinical data that we have, you've heard a lot on the unmet needs and where we think vidofludimus has the potential to fit in. I'll just close with near-term catalysts in relapsing, two large phase III studies reading out at the end of the year. We're tracking to that deliverable, focused on a readout, and should the data support it, an NDA filing in the middle of next year. We did not talk at all about the progressive opportunity, but we will be initiating a phase III study in progressive MS by the end of the year, and the team is really focused on that deliverable as well. That will lead me to flip actually two more slides, just the last slide, because I want to make sure. One more, Jessica, please. I just want to make sure that everyone's aware, we will be having another one of these days on November 5th to really focus on progressive. Progressive is a hugely exciting and important part of the Immunic and vidofludimus calcium story. So important, we thought it was worth breaking out into a separate session. Please join us on November 5th, to learn more about the specifics of our plan, how we plan to design that study, and the supporting evidence we have to date for that, as well as the market potential. I want to flip back over to Jessica to take us through some Q&A. Yeah. Thank you, Erik. And thank you to all our speakers for these wonderful and interesting presentations. As Erik said already, I would like to open the session now for questions. In the interest of time, we're a little bit over already. We will prioritize the questions for our two experts here and take those questions first. I actually see a lot of questions here, so I will start with Paul Matteis over at Stifel, who submitted a couple of questions in writing. I know he's in transit right now. For our two KOLs, can the KOLs comment on how they would position vidofludimus calcium versus how they think about the positioning for oral BTK drugs? Who's the right patient or patients for each? Amit or Stephen, please- I'm happy to take a first stab. It's Amit. Hi. I think Jason covered this very well, and I generally agree with the scope. I think that I'd make a couple of brief comments, really just trying to add to that, my perspective. First, of course, we need to wait for the pivotal trial, the phase III data in both relapsing and hopefully progressive to really know. But that said, we have high-efficacy therapy for relapsing MS. We want to control relapses very well. That said, just controlling relapses very well does not address the very important unmet needs that you've heard of. And any drug that has the capacity to limit progression and protect, I think would be viewed as extremely exciting. You've heard that the biology starts from the very beginning, so across the whole range, if you had a sufficiently safe therapy, and if relapses could also be well-controlled. What strikes me as very important is the high retention, the unusually high retention with what you've seen in the open label extension. There are two reasons for people not to be retained. One is tolerability, but the other is a sense that their disease is not sufficiently well-controlled, whether it's relapses or progression. So yet to be proven, but I think promising. And I would make the point that when we introduce people to a new diagnosis, I refer to it now as the new MS, one of the things that makes it the new MS, of course, is that we now should be able to control relapsing disease extremely well. But the other is that the notion of what treatment to start is not a decision as it used to be thought of as this is for life. As was pointed out already, we don't need to think of any given treatment decision as the treatment that a person will be on forever. I would make the point that the high-efficacy therapy that may be increasingly the way people start to control their MS, is not something that needs to be on forever, and not only in the context of being on it for too long to subject people at risk later in the disease course, but that you, after several years, two, three years or so of high-efficacy therapy, you may not need that to control the relapses. A therapy that has anywhere between a modest to a moderate effect at controlling relapses, but has the added value of impacting the progressive biology and supporting protection and repair, could be introduced at that point and as a well-tolerated safe therapy for a long time thereafter. So I agree with Jason in terms of the breadth. I would just add that additional layer to it, and we very much look forward to seeing the data emerge. Thank you, Amit. We have another one here from- It was- Oh, sorry. It was Stephen, I think, who's going to add. Oh, I'm sorry. I was too quick. No, that was a wonderful answer. I would add only, well, I'll add that I'm supposed to give a talk at ECTRIMS about where to use the BTK inhibitors in the current therapeutic landscape, and I haven't figured out what I'm going to say yet, so I'm working on that. But one of the challenges is the promise of the BTK agents was to accomplish in essence what we're talking about here, but the data didn't take us there. The data for evobrutinib didn't show superiority for relapses. The data for the GEMINI trials and tolebrutinib also didn't show superiority for relapses. The story to use for relapse control is not there across the board, and the progressive data is really mixed. We're not talking about non-relapsing progressive disease in this program. That is the only thing that we have a successful trial for tolebrutinib, and that did not garner approval here. I think that if anything, the complexity of the data, particularly the safety data with the BTK inhibitors, does not get in the way of the benefit analysis that you have heard here today for vidofludimus. Thank you, Stephen. Thank you. We have another one for our two experts. Actually, a similar question from two attendees here, from Paul Matteis at Stifel and Sam Slutsky at LifeSci Capital. What is the bar for a clearly positive outcome in ENSURE-1 and ENSURE-2? Is it important to hit stat sig on EDSS? Do we need a certain effect size on time to first relapse? Sam has a similar question: What do you see as a win in the upcoming phase III RMS readout as you consider the current unmet needs? Amit, do you want to kick it off again? Yeah, I can certainly give it a shot. I think that I would not necessarily insist on seeing an impact on disability progression to be able to conclude that there is an important effect on targeting relapses. Although, of course, one would like to see that, and especially when we are talking about a drug that might be doing more than just limiting the relapse-associated worsening of disability. That said, I think as Stephen had pointed out, when we look at the totality of the data emerging from the BTKi phase III trials to date, including in progressive MS and relapsing MS, and the notion that we are still struggling as a field finding the best outcome measures to capture that, the populations, et cetera. We have come to realize that impacting disability progression is something that we would very much like to see but would not necessarily insist on seeing. I think the extent of benefit on relapsing disease activity, even a moderate effect from a drug that looks to be safe and has the additional promise as vidofludimus calcium to me would be pretty compelling. Yeah, I think that's quite right. At the end of the day, the goal is to prevent disability accumulation in all of its forms, either relapse directly associated or this more delayed insidious development of disability. We know that we're not targeting all the mechanisms that can accomplish that yet. So I really would like to see a disability endpoint here. It's not the primary endpoint in the relapsing trials. We have to hit that, of course. But if we saw a disability endpoint and could point out the extent to which this mechanism attenuates disability even beyond or in the absence of relapses, that could really give us a clue as to what the long-term consequence of this strategy could be. It's true, you can't see 10, 15-year outcomes in a two-year trial, but you can see the change in trajectory, and that glimpse is very, very beneficial for our field. Thank you, Stephen and Amit. I have one more for you, or actually I have a couple of more, but I want to be mindful of your schedule, so in case you need to drop, please feel free to drop. One more I have here is, does success on the EDSS in an RMS trial prove that the drug is beneficial on PIRA? Well, I will pop in there and say that is where this determination of whether disability occurred consequent of relapses or independent of relapses helps to make that determination. The EDSS is what the regulators require. We all in our field recognize that it is a crude scale, but our regulatory agencies require it, and in that sense, it is okay. Because if we can achieve the endpoint on a crude scale, then we can also expect that we will be able to achieve it in more nuanced ways, like what I was talking about at the EDSS of zero. So I do think that it will tell us if disability accumulation is being attenuated, and I think we can then do subsequent analyses to see how much of that attenuation is attenuating PIRA specifically. That would be helpful. Yeah, I would agree with that. I think that showing an impact on disability progression in a patient population that has potential relapse contribution does not allow you to conclude that that impact on disability was just because of PIRA. It could be a combination of both. But it really is something that we would want to try to dissect in terms of both clinically evidence, subclinical evidence of focal inflammatory disease, which is the relapse biology. So obviously impacting disability would be great in any context, including in a relapsing trial. But how much of that would reflect non-relapsing biology is a separate question. Right. I would simply add to that, to Amit's point, the ENSURE readouts will be the next big piece of evidence in the learning journey that will continue around this question. I do not think we will have a definitive answer out of this, regardless of the magnitude of the clinical effect, which is why we are committed to running a progressive MS study in a clearly progressing population with correct powering for progression-related endpoints that will yield more evidence over time. You have heard here today a bit of why we are so excited to pursue the science into the clinic around these questions. The ENSURE studies will be a meaningful advance in our understanding of the clinical impact of vidofludimus calcium on progression. But it will not answer all of the questions, and that is why we are prepared to sort of pursue them even further and beyond ENSURE-1 and 2. Yeah, I also see a lot of raised hands here, and I would like to start with the first live question here. Myles Minter at William Blair. Myles, please unmute yourself and go ahead. Yeah. Have you got me? Hey. Yes. Beautiful. Thanks. Yeah, just for Dr. Krieger and Bar-Or again, just on, again, the bar for success in the ENSURE trials and sort of the magnitude of benefit you'd expect on that time to first relapse endpoint. This is against placebo, and a bunch of other trials that you look at are either against interferon or against teriflunomide. If you go back to the original teriflunomide trials, I think on that endpoint, it was about a 24%-28% benefit over placebo, and then others are obviously looking on top of active drug. Just could you kind of put a number on the risk reduction for time to first relapse that you would expect here to have a clear win for success? That's the first one. Then secondly, just all this focus on confirmed disability worsening at the three-month endpoint. If you saw a trend that was similar to some of the BTK inhibitor data that we're seeing, which I think is in the mid-teens percentages, if I remember, would that be something that would get you excited? Thanks very much. I'll let Steve maybe take this one initially. Yeah. I don't have a specific answer to what the bar would be for success. I really don't, except of course, statistical significance would be awfully nice to start with. I think you're right that the annualized relapse rate reduction of teriflunomide back in its pivotal trials from the 2012 era was in that 20%-30% range. I expect we could achieve that here, and in general, relapse numbers now, the raw number, as opposed to the percent difference, are much lower than they were in that era. We sort of look at the actual annualized relapse rate numbers. We've gotten accustomed to seeing numbers that are remarkably low. I think we want to see something that's similarly in that range here, so that we know that we're playing in the same ballpark in modern MS, new MS, as Dr. Bar-Or said earlier. I don't have a specific number that we look to. I really don't. You asked also if there's a progressive signal akin to what we see with the BTK inhibitors in this relapsing population. Would that be useful? Absolutely. That's the highest bar we kind of have now for what constitutes efficacy in the emerging therapeutic landscape. If we saw that here in these trials, I think that would be successful. Yeah. I would agree completely. I think, as Stephen pointed out, it's tough to try to get a number that would be sort of a fair comparison with what we had seen many years ago when the natural history, so to speak, or at least the relapse frequency of people has changed so much over the last years. I think an effect size that is in the range of what you might expect for teriflunomide, with the added concept that there's another biology that's critically important that is being targeted in a way that distinguishes the two, I think would be extremely important. Of course, very much hope, and I think based on the phase II, there's a very good chance of hitting those endpoints at a level that we would be happy with in terms of the relapsing trials. I would, again, make the point that even if we had a medicine that did nothing against relapses but did something meaningful against the unmet need of the protection and supportive repair, that to me would have a huge place in the MS market. I know we're not talking today in detail beyond the relapsing aspect, but that's something for us just to keep in mind, which is part of my interest in this molecule, and I think it has a good chance of emerging as having a benefit on the two different biologies of importance. Makes sense. Thanks for the great presentation. Thank you, Myles. The next one I have in the queue here is Yatin Suneja at Guggenheim. Yep. Yatin, please unmute yourself. Hey, guys. Can you hear me? Yes. Yep. Hi there. Very good. Thank you for taking my questions and great presentation, both physicians and the company. Just a question on the market dynamics. I think the company has done a good job articulating the buckets of patient, whether these are new patients, switching patients, or patients who are not treated, or patients who are on CD20. The question for both the physicians is that, look, I think when this therapy becomes available, you're also going to have remibrutinib, right? Because that is maybe a little bit of a different type of a BTK inhibitor. How would you adopt vidofludimus in each of these buckets of patient that the company highlights? If you can just talk about a little bit about the market adoption, that will be helpful, assuming that the study meets the bar that you all have in your mind. Thanks. Well, I can start here and say that the safety profile for the BTK inhibitors as a class, and I sort of question whether we should think of them as a class, but the safety margins have not been very reassuring. Of course, tolebrutinib's principal safety issue has been the liver concern, which limited its FDA approval. With fenebrutinib, there is just a real significant imbalance in mortalities and fatalities that we don't yet fully understand, and I don't know what the regulators will do with it. And remibrutinib, of course, we've all seen the same top-line stuff, but I haven't seen anything beyond that yet to really dig into the safety and, of course, the efficacy. When we think about post B cell depleter patients, where we're trying to emphasize safe transitions and a safer modulation of the immune system, I'm not sure yet what we've seen with the BTK inhibitors for which we have data serves that purpose. When we talk about the aging population, where again, we're trying to be gentler to the immune system and target perhaps progressive mechanisms, I'm not sure we've seen that yet, with the exception of perhaps the tolebrutinib SPMS data, but the FDA hasn't brought that to market here. So there are real pressures against the use case that you're hearing about for vidofludimus in terms of safety and the aging population. So I still think that this mechanism has a real role in those buckets in ways that I'm not convinced that the BTK inhibitors are best aligned for. I might add that, especially with a longer-term lens, in the sense that I personally hope, I am sure Stephen as well, and others, that we will see at least one or two BTKis come to the market. That said, I think that with BTKis, over time, we are going to see more and more individuals running into trouble in terms of immune response defense. There is still an impact on the immune system that is not that subtle, and it is again, one of those things where we have very limited experience in terms of long-term exposure. I suspect that the profile of vidofludimus calcium is one that will be tolerated in more people over a more extended period of time. If I could just add on this one really briefly. I think the themes you have heard throughout this talk from all of our presentations today is that MS is a highly heterogeneous disease, chronic treatment, more treatment options are needed, and different types of mechanistic approaches are needed. So I would say, as someone who cares a lot about MS and MS drug development, we welcome the success of BTKis. The underlying thrust of the question, I would suggest that, A, first on remibrutinib, specifically, we need to wait and see data. Right now, we have a top-line press release and no details, so it is a little bit premature, and we do not have our own phase III data even read out yet, so it is a little bit premature to talk about positioning. What I am highly confident in is that both approaches are needed, and both approaches have space, and both approaches can create value for people living with the disease. That is undoubtedly true. I, for one, very much look forward to seeing their data in Toronto in a few weeks. We will have more to say about it after we have seen the results. We may have lost Yatin. I will just continue with the next question that came in in writing here for Dr. Bar-Or and/or Dr. Krieger. Does Dr. Bar-Or and/or Dr. Krieger feel that we will have or do have good measures of progression versus relapse for regular clinical practice decision-making? Yeah. I think the simple answer is we are not where we would like to be. We are increasingly recognizing that there are much more subtle ways in which people can get worse, that we are not able to pick up with a typical follow-up. All sorts of efforts to try to get more sensitive measures, more accurate measures that can, in an individual, over time, inform. Of course, the whole aspect of biomarkers that ideally would capture what's happening under the surface because we think the biology is eating away at the reserve when that reserve is not treated to be protected. So it's not a matter of having a more sensitive clinical measure, it's a matter of recognizing and being able to identify what's under the surface. As of today, we know we need to do better, and people are working hard, including our groups, on trying to be able to establish some additional measures. There's some early traction with some of the fluid biomarkers, but of course, as you know, still looking for ones that are particularly informing on the non-relapsing progressive biology and the injury under the surface. That one I concur with completely. I couldn't add a thing. That's perfect. Thank you both. The next one in the queue here I see is Marc Goodman over at Leerink. Mark, please unmute yourself and welcome to the call. Yeah. Hi, Jessica. Thank you. Yeah. Question for the physicians is what percent of the patients have you switched from anti-CD20 therapies already, basically, and what agent are you switching to today? Steve, why don't you start, and I'll fully agree with you. Okay, perfect. Well, listen, part of my strategy is informed by your trial, looking to see whether we can use B cell depleters only briefly and then stop it after a shorter period of time. So you're actually moving this aspect of our field forward. So there's, as you heard, with the heterogeneity of the disease, there's not a one-size-fits-all answer to this. Certainly when somebody reaches age 60, for instance, I'm not taking all of them off of a B cell depleter. But we are having mitigating strategies, so either extended interval dosing as a bridge to having people come off of a B cell depleter, sometimes treating to B cell reconstitution. So rather than doing it at any fixed time scale, waiting for B cells to come back, which for older patients can sometimes be quite prolonged. And then the third group is those that you take off altogether. I am at this point, I will be honest, being somewhat reactive still. I take people off of a B cell depleter when it is starting to cause things that I do not like. What I have not yet adopted in my own practice is a proactive taking people off of the B cell depleters, because I do not think we can perfectly risk stratify who is vulnerable to infections and other consequences. That is where that hypogammaglobulinemia data that I showed is starting to be more and more instructive for our field. I put that in there because I think that is where our field is going, looking for biomarkers of risk, not just biomarkers of benefit, to help determine who and when to take people off these agents. What I did say in my presentation is I am telling people now this is a 5 - 10 years plan. I do not imagine we are going to keep a lot of people on B cell depletion for more than 10 years moving forward. Maybe that prediction is wrong. I think it is more of a duration of therapy rather than a particular age, but we will see if that prediction is borne out. Dr. Bar-Or, do you have additional thoughts on that? As I anticipated, I agree completely, Stephen. I think the study that you are alluding to that we are pursuing is an early in the course of MS randomized discontinuation trial from anti-CD20 that is based on the biological insight that if you allow B cells to come back, they come back differently and in ways that one thinks are relevant to disease activity. Although it is very clear that not everybody will have sustained, durable remission from relapsing disease after the discontinuation. But some probably will, and for us, it is an opportunity to understand the biology of who is different and why, and whether that could be predicted from early samples. It is really a biologically based hypothesis that we hope to learn a lot about in terms of MS mechanisms and beyond. But I think that the notion of people coming off high-efficacy therapy is being entertained across quite a broad age range. Still, in particular, in people who get older or, as Stephen said, in anybody who, regardless of age, is having problems. By the way, numerically, more people will run into serious infection even with their immunoglobulins perfectly fine than those who, the relatively low frequency who go very low and have an increased risk of serious infections. We stay vigilant throughout the course, regardless of the duration of treatment, but increasingly vigilant with increased exposure and age. There is no single treatment switch that we would consider. We have considered a variety of treatments. It is almost like thinking of a person coming in new and what might you consider that would be sufficient to control their MS. Yeah, thanks for adding that. I didn't mention that. It really depends on what they were on before and then what we're going to start them on. It's a fresh discussion. That's a good point. Thanks. Right. I know we have tons of more questions here, both in writing, and I also see a lot of raised hands. Unfortunately, we are well over time here, so we would like to close the webcast for today. If you have more questions, we are more than happy to address these one-on-one. We are also happy to forward any questions to our two experts here and get back to you guys. Please feel free to reach out to me after the webcast. I will hand it back over to Erik to wrap it up and to summarize today. Gosh, I'm not sure I can summarize. It's been such a full session. But I really just want to first say thank you, especially to Dr. Krieger and Dr. Bar-Or for your expertise, your passion, your care for patients, and lending your voices to our session in advancing the science behind vidofludimus, as well as MS care more broadly. Just so value your collaborations and participation today. So thank you very much. Thank you as well, of course, to my colleagues for all the hard work going into today, but more importantly, the hard work you do every day to advance vidofludimus calcium in the clinic. And for all of the folks on the line, for your interest and your time. This is a huge time investment. We know that there's a lot of things you can be doing with your time. We really, really appreciate your interest in learning more about vidofludimus calcium and Immunic. As I said in the very beginning, this is an unbelievably exciting time for us as we prepare to read these studies out at the end of the year. We continue to be on track for that as we continue to prepare beyond these studies with a progressive MS pivotal trial in the works coming. As Jessica said, we are very committed to addressing any questions that were left unanswered here today. We'll find the right venues to do that. We thank you for your engagement. Please do come back and join us on November 5th. I'm sure if you have a lot of questions about RMS, you'll have even more about progressive MS, because we are thrilled and excited to bring vidofludimus calcium into that arena as well. With that, I will close the session again and just say thank you again to everyone for participating in the great session, and we look forward to engaging with you all at various forums in the very near future. Thanks, everyone. Thank you, Erik. This concludes our event today. Thank you so much for joining. The webinar has now concluded. You may now disconnect. Bye-bye. Thank you. Bye-bye. Bye. Bye.