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All right, good morning to everyone on our webinar today and welcome to Immunix Virtual R&D Day, focusing on our relapsing MS development program with Vitofluidimus Calcium. My name is Jessica Brue, Vice President Investor Relations and Communications at Immunic, and I will be the moderator for today's webinar. In the beginning, a few organizational remarks. Please note that all participants will be in listen-only mode and this event is being recorded. After today's presentation, there will be an opportunity to ask questions. The Q&A session will be held at the end of today's presentation. Our two experts will still be available for questions at this point. If you join the webcast via the Zoom platform, there are two ways to submit questions. You can either submit your questions in writing via the Q&H tool of the Zoom portal, or if you would like to speak with us directly, please use the raise hand function of the zoom portal to view your question. Before we begin, I would like to remind you that this presentation may contain forward looking statements. These statements can be identified by words such as may, will, expect, anticipate, estimate, or words with a similar meaning, and such statements involve a number of risks and uncertainties that could cause Immunix's actual results to differ materially from those discussed here. Please note that these forward-looking statements reflect Immunx's opinions only as of the date of this presentation, and it undertakes no obligation to revise or publicly release the result of any revision to these forward looking statements in light of new information or future events. Please refer to Munich's SEC filings for a more detailed description of the risk factors that may affect Munich's results and these forward-looking statements. Now, let's turn to what we will actually focus on today. First of all, I'm very pleased that two internationally renowned MS experts will be speaking during today's event, Dr. Amit Baur from the University of Pennsylvania and Dr. Stephen Krieger from the Mount Sinai Hospital in New York. Moreover, we will have members of the Munich management team presenting, including Eric Landgren, CEO, Dr. Mike Panzara, CMO, Dr.-Hala Kohlhoff, CSO, and Jason Tardio, President and COO. Our event today will focus on the status quo and future potential of our late-stage clinical asset, Vitoflutimus calcium, for the treatment of relapsing MS. Our team will share mode of action, preclinical, clinical, and commercial positioning insights on the potential of how Vito Flutimus Calcium's differentiated approach could reshape the treatment for patients with relapsing MS. Dr. Spar-Oren 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, Eric Lundgren, to kick the presentation off. Eric? Great. Thank you, Jessica, and thank you, everyone, for joining us. Good morning. I'm Eric Lundgren, the CEO of Munich, and I'm thrilled to be with all of you here today. Thank you so much for your interest in our story. So, Jessica, if you could just push onto the next slide. I'll be very quick so we can get into the exciting science here this morning. But just to set the stage, we're at an incredibly exciting and important pivot point in the company's history where we're really moving towards developing a fully integrated MS-focused company. And as you'll hear throughout the session, we're right on the precipice of unblinding two pivotal phase three studies that we hope will create a path for us to advance our lead asset, phytofluidinous 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. And so 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 relapsed MS. Keep in the back of your minds, we're not going to spend much time at all today on this, but another huge part of the value proposition for Immunic and for Vita Flutimus Calcium sits in a potential progressive MS population with data to come. And in fact, I'll tease at the end of this a little bit of opportunities where we're going to have to share that story in a more fulsome way with this community in a few weeks. But the other pieces I'd love to just stress here is this pivot point of the company itself. We're 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 NMS. That's really where we're focused. And we think we've got the right asset to do it. We've got right capital structure to support it, and we've the right momentum in our hiring practices to build that organization to take us into this new era for the company. And finally, you're 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're 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. So you can see highlighted in green where we're going to focus a lot of our conversation today, that is on the relapsing program, really anchored by our two phase three studies, the Insure One and the Insured Two studies. As you'll hear throughout, these are fully enrolled and we are tracking towards reading these out by the end of this year. So well on track there, much more detail to come. Worth popping down to see the phase two emphasis study as well, which Dr. Penzara 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. And finally, just before we get into the science, just a few words on the market itself. The 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's a $30 billion market or nearly a $ 30 billion market. In the U.S., it's about a $17 billion market today, growing at about 7% annually. It's a market that recognizes and rewards innovation. And you can see that in the fact that there's been over 11 blockbuster therapies developed in MS over the last 25 years. And maybe the most important piece to highlight here is it's a large and heterogeneous patient population with dealing with a chronic disease. And so what patients need at various points along their journey changes. And 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. So this is not a winner-take-all market. It's 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're meeting and exceeding those needs. And if we do so, it's a marketplace that will value the innovation that we can deliver. And ultimately, we'll see that rewarded in how the company can grow from that. So with that, it's my immense pleasure to turn the stage over to the first of our guest speakers, Dr. Amit Baror. Amit holds the Melissa and Paul Anderson President's Distinguished Chair at the University of Pennsylvania, and there he directs the Center for Neuroinflammation and Experimental Therapeutics and serves as the chief of the Division for MS and Related Disorders. Dr. Barar'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 systems. Following an undergraduate degree at McMaster University, Amit earned his medical degree at McGill University in Montreal. Dr. Baror has published over 400 peer-reviewed publications and has led multiple national and international collaborative research initiatives. Thank you, Amite, for joining us, and I'll turn over to you. Thanks, Eric. First, let me just confirm that you can both see the screen with the presentation and hear me. We can. Yes, we can. Perfect, perfect. Thanks for the kind introduction, Eric. And hello, everybody. Pleasure to be here and follow on Eric's background presentation to tell you about targeting novel mechanisms to address the unmet needs in terms of the clinical context. And this is really going to end up leading to the biological basis by which we think glutamate of flutamase calcium may offer some very unique advantages in relapsing MS with a focus here, but as Eric had already alluded to, in the context of protection and repair throughout the spectrum of MS. And so to do that, I'm going to start by presenting a very simplified model of MS immune pathophysiology. I'll try to avoid jargon and really only highlight the key points, so it's 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 the mass. You'll 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 evita flutimus calcium. So the unmet needs and the novel promising targets is what we're really going to be segueing into to then deal with the biology in particular of the Nr1 pathway with a focus on trying to protect and support repair from ongoing injury throughout the MS process. And in the context of Vitaflutimus callosum in particular, the attraction of having potential for dual mechanism of action, both activating the Nrr1 pathway, but also selectively inhibiting the DHO-DH enzyme, where you 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'll start with a simplified model. And it's a very simple sort of three compartment concept that many, if not all of you, I'm 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 and 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's not just about T cells, it's about B cells and T cells. And very importantly, interactions between B cells and H cells in the periphery that are thought to drive the relapsing aspect of MS. And then 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's 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 remaining 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. And this can also happen later in the disease but eventually abates. And 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're not biological constructs. They are concepts that we try to identify people based on their clinical presentation. We're interested in better understanding the underlying biology if we're going to set the stage for thinking of therapeutic targets. And a point to make, and again, Dr. Krieger will highlight this, I think, elegantly, the manifestation clinically doesn't necessarily capture the underlying biologies, which are clearly present largely under the surface. And we've come to realize that it's 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. And it really is about the clinical threshold. If you had the clinical Threshold set there, the shaded area would be subclinical. You'd consider this person as having relapsed remitting onset and secondary progressiveMS. 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. So 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. And 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. And in parallel to that, along the same timeline, increasing influence of immune senescence, inflammation, comorbidities, and so on and so forth. In this context of sort 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 checkmark 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 termsof supporting repair and protecting. And probably to some extent, we have a grapple on some of the comorbidities and trying to deal with them. But this sort of on the lower right is still a plus minus area of unmet need. So this is the framework of thinking in the clinical spectrum of the various aspects of unmit clinical need. And we're going to transition now to the last part of my presentation, which really hones in on Vita Flutimus Calcium's mode of action, which starts with targeting NUR1 to address aspects of protection and repair from ongoing injury. This includes, as Eric 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. And the potential impact then, which will set the stage for some of the discussion of this unique dual mode of action, combining the NIR1 activation with selective inhibition of DHO-DH. So a few words on NIR-1, also known as NR482, as a potential neuroprotective target in multiple sclerosis. It has been known over the years that NIR 1 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 neurodevelopment, 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 neuro-1 expression correlates with more aggressive relapsing disease, a higher relapse rate and EDSS chain, 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. But then importantly, within the central nervous system, higher levels of NeurOne expression in pathology samples were associated with preserved density, supporting a potential for neuroprotective roles. And when one thinks of NeuroOne activation in the context of neurodegenerative disease processes, which of course extend beyond MS, but are very relevant for MS. It's 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-space-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's something I think that will be an exciting prospect moving forward. Segueing now to the DHO-DH aspect of Vitaflutamase 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. So when you inhibit this pathway, you don't limit the capacity of cells to deal with pyrimidy 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 NMS. It is a key mitochondrial enzyme, and it's highly expressed, again, in these particularly highly active, rapidly dividing lymphocytes. And resting lymphocites 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 Windel and others, were able to show biologically that teriflunomide as a DHO-DH inhibitor indeed kind of cuts the edge off the overly activated immune cells involved in disease. And this inhibition is particularly targeting cells thought to be pathogenic in the context of MS relapsing disease activity. And as I alluded to earlier on, there's a certain aspect of that DHO DH 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. And so I think overall, this is a really interesting context where neuroprotection meets immune regulation. Neur1, 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 vitiflutimous 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 relapsed and through progressive disease. So I'll stop here and I think transition to the next speaker, having set the stage, hopefully, for suggesting that the dual mode of action combining neuron activation and selective inhibition of DHO-DH may be very attractive in the context of the MS spectrum. So I'm going to unshare here and pass the baton on. Thank you very much, Amit. This is wonderful. This was a wonderful overview. And actually, so on the MS biology and specifically on NO1 and the role of NO1 and DHO-DH in MS. And I will go on now and fill it with data. So I will talk about vitoflutimus calcium dual mode of action on NO2 and on DHODH. And we know already that vitoflitimus calcium has a unique dual mechanism approach to MS. Potentially, it's the only oral MS drug that is really addressing PIRRHA and ROLL simultaneously. So, Vitoflutimus calcium is a direct NO1 activator. It modulates the gene expression directly in neurons. It mediates neural protection 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's a selective DHODH inhibitor, what is wonderful because it selectively targets metabolically hyperactive T and B cells, and it reduces the focal information, MRI lesions, and relapses. And what we've heard as well, it prevents reactivation of Epstein-Barr virus. Next one. So, as we said, it is a selective DHO-DH inhibitor, and actually, I'm pretty proud about this, that it is a DHO inhibitor in addition to the NO-1 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 teraflunomide as a comparison, teriflunomide is most active on red DHO-DH, whereas vitiflutimus is most active on human DHODH. How does it come? Well, there is a species specificity for DHODAH, and this can be explained because these are completely different chemical structures. You see here on the right, you see the structure of vitifrutimus, and you see, just for comparison reason, you See the structure of terifflunomate. In addition to this, we know that Vitoflutimus does not inhibit kinases. And whereas teriflunomide targets different kinases, PIM, RR1, RRA, PDGFR, and especially EGFR. And EGF, our inhibition actually is known or is related to skin diseases, diarrhea, and liver enzyme elevations. and both of them are active and on dhodh and on high affinity immune cells so vitoflutimus you see here just with the abbreviation vito and you see teriflunomide they both reduce hyperactive or high affinityimmune cells due to the restriction of the needed permittance and in addition to this of course we tested vitofludimus calcium in different animal models. Just an example here that Vitoflutimus reduces the disease score in an information-driven EAE model. So it's a selective DHODH inhibitor, but in addition, that's on the next slide, in addition it's potent NO1 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 NO1 is expressed in microglial astrozytes and in neurons. And NO1 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 NO1, 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 no one activation is believed to be involved in halting neurodegeneration and disability progression. And this is also, of course, supported by literature. That's not just my idea. It's really supported by literature and um yeah and we heard it already very nicely summarized and explained by amit so next slide please uh now we can of course just postulate vitoflutimus calcium is a no one activator but can we prove it and yes we can that's great and you see here in the center actually you see the proposed binding model of vito flutimous towards no one ligand binding domain. This is just a model, but we were able to show by using ITC and DSF that vitoflutimose calcium shows direct and measurable binding 201 protein. So on the left, you see the ITC, and that demonstrated specific binding signal with an estimated dissociation constant of around 700 nanomole, 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 NO1 is a direct molecular target of Vitofluidimus calcium. So now you can say, OK, it binds. Does it matter? Yes, it matters. NU1 is a transcription factor, and therefore we looked into NU2-associated gene expression, which is modulated by Vitoflutimus calcium. And you see here we tested in astrocytic cells, in microglia cells, and in urinal cells. And we looked for TH and VMAT, which are two well-known and described direct target genes of NU3. And you see here that Vitoflutimus calcium increased the expression in the selected NU1-regulated genes in a dose-dependent manner. So next is, OK, we see gene expression modulation. Is there any impact on function? And yes, of course there is. Otherwise, I wouldn't show it to you. So Vito Flutimum calcium improved neuronal survival and it reduced injury under apoptotic stress conditions. So here we used TNF-alpha cyclohexamid model. So we incubated viable neurons with TNf-alphacycloheximid. This is an apoptotic and necrotic stress signal here. The cells undergo apoptosis and in the presence of Vitoflutimus you see an improvement of the neural survival. This is actually depicted here in the middle where you see that in the present of Vidoflutinus 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. And this is a well-known neurofilament light chain, what is measured in clinical studies quite often. And you see here that, again, in a dosed-dependant manner, you see a reduction of neuronal-injury marker neurofilamate light chain. So, Vito-Fluidimus calcium was associated with improved neural survival and reduced neurofilament light chain release under these apoptotic stress conditions. Next slide, please. Now, you can say, okay, that's Vito Fluidimum. Is NO1 important here, or is it just because of the DHL-DH inhibition? And we were able to demonstrate that really a new one is required to mediate this neuronal survival here. So again, TNF-alpha cyclohexamid is quite similar to the previous picture where you add TNV-alphacycloheximid. You see here in red, you have a decrease of the viability or the number of the living cells. And in the presence of betaflutimus, you see again an increase or a higher number of the living cells. That was performed with CNF-alpha and cyclohexamid, but we used as well an additional trigger here. So 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. So, beta-fluidimus calcium is able to do it. Now, is NO1 important here or not? And this can be seen now because here we used CRISPR-mediated NO1 knockout. And you see it that when you have neurons which are knocked out for NO1, then Vitoflutimus calcium is no longer able to improve the viability and the number of living cells in this model. So Vito Flutimum associated improved neural survival really requires NO1. Next one, please. Of course, I talked about microglia. Microglia is super important because they drive inflammation in the brain as well. So we were interested in the role of Vitoflutimus calcium on neural viability under neuroinflammatory condition. And therefore, we performed the neuron microglial co-cultures here. So, we co-cultured microglia and neurons, then stimulated the microglial to produce pro-inflammatory cytokines. And you see just on the graph on the left that the neurons are undergoing apoptosis in the presence of Vitoflutimus. They have a higher, we see again a higher number of the neuron cells. So in the middle, you see when you add LPS into from gamma, you see a reduction of living cells of the, in this case, human cell line, SH, SW, 5Y cells. And when you then add in the presence of Vitoflutimus, you have an improved survival of this. Of course, we wanted to know, is it really mediated by microglia or is it just toxicity that is driven by LPS and into from comma? Therefore, we added the control experiment, what you see on the right that no LPS and the defogamma do not don't do any harm to neurons alone. So Vitoflutimus calcium was associated with increased neuronal viability in inflammatory co-culture. Now it comes to animal models. Does Vito Flutimis work in animals? Yes of course it does. We did several EAE models and we were able to demonstrate that VitoFlutimous calcium reduced the disease severity in EAE model. Now we know in a prophylactic setting and in a therapeutic setting. And of course, we all know that EAE models are mainly inflammatory driven. So it could be that DHO-DH inhibitors work there. And indeed, tereflunomid works there. That's fine. Vitoflumibs work there, and we use these models because we were interested in investigating the impact of Vitoflutimus in these models on NUR1 and we were able to do it. So in the next slide you see here that Vito Flutim's calcium modulated NUR 1 related gene expression in the CNS of these 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 and you see here in the brain on the left that in the presence of Vitoflutimus calcium, we see an increase of Nr1 itself. So there seems to be an autoregulation. So we have higher levels of Nr 1 in the brain of these animals. And we looked as well for TH, so tyrosine hydroxylase, which is a well described primary target gene of NR1. So in the brain, we saw Nr-1 upregulation and TH upregelation by Vito- flutimus calcium. And we looked as well into the spinal cord. And actually, in the spinal cord, we focused more on the detoxification of superoxide radicals by SOD upregulation. And we look into ATP production in principle via the upregelation of COX-5B. So, Vito flutumus calcium treatment was associated with a modulation of no one regulated related gene expression in CNS tissue in both the prophylactic and the therapeutic inflammation-driven EAE settings. And we looked for function as well. So we were interested in proteins in the plasma, if we can measure it, look for BDNF, which is brain-derived neurotropic factor. And 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 these of vitofluidimus calcium treated mice, EAE mice. And here, again, we looked for neurofilament light levels, which were decreased under the treatment of vitifluidumus calcium. Okay, so now you can say, is every DHO-DH inhibitor in one agonist? And I would clearly say no. So there was a publication from Vieto et al. in 2023, they described it already, but I'm pretty sure that you guys are super interested in tereflonamide because it's approved for MS. So we looked into this and you see again here, ITC testing, you see DSF testing. We were able, you See again for vitofluidimus calcium, there's a binding signal detected, of course, for vitofludimus on NO1. And we did, 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're just a different assay system. And again, vitofludimus calcium induces a temperature shift, melting temperature shift which indicates the binding here whereas teriflunomide does not so that means okay there's most likely there's no binding of teriflonomide to no one but it could mean maybe there's an indirect effect towards um towards no one what can't be measured by the direct interaction so we looked as well um for the function and um i i told already about neuronal survival under apoptotic stress conditions and we did the same experiment on the next slide it's the same in the presence of teriflunomide and what you clearly see here is that vitoflodimus calcium improved the neuronal survival under apoptotic stress conditions, whereas on the right, teriflunomide did not. So in this test system, teriflonomide didn't significantly improve survival of neuronal cells. Another hint that it's really not addressing no one, it's not binding, and it's NOT promoting any survival functions in neuronal cell. So to summarize everything, we can show that Vitoflutimus calcium activates NU1 and selectively inhibits DHODH. So with the NU-1 activation, it's improving the survival of neurons and it's reducing neurotoxic microglial activation. DHO-DH inhibition selectively targets only metabolically active T and B cells. And with having DHOBH inhibition, Vitoflutimus calcium is able to inhibit the EBV-associated B-cell responses. Thank you. Great. Thank you, Hela. And good afternoon, everybody. I'm Mike Panzera. I am the Chief Medical Officer at BIMINIC. It's a great pleasure to be here with you today to talk about our efforts in relapsing multiple sclerosis, focusing on the NSHER program. Next slide, please. So I think, you know, in the 25 years I've been doing this drug development and academics and MS focus before that as a neurologist seeing these patients, you Know, the way things have changed over that time in the treatment of multiple sclurosis has been just remarkable. And I think Stephen and Amit, my colleagues in the space would agree, it's been quite, what has been accomplished and what is available for patients today, we couldn't have even thought about back then. But if you, you know, that makes you feel pretty good about what we've all accomplished. But if you really don't 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-plus 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're doing great, they're not having relapses, their MRI lesions are not detectable, they just feel like they're getting worse. They just are running out of options because of their age for a variety of reasons, and they're looking for something new. And this was really a remarkable revelation, certainly when I've watched this, and really speaks to why vitiflutimous calcium is so important and has great potential to help many of these patients. Next slide, please. I mean, you've already heard about the biology. You've already read about the about how the dual mechanism of action leads to potential to treat different aspects of the disease. But, you know, these effects would be anticipated to address both these important elements of disease, as Amit 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 has Amit 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. So as we dove into Edemunic using beta-flutamase calcium in relapsing MS, the phase two study here has shown the emphasis study. This was a study I'm looking at a double-blind study focused on relapsing MS, looking, as is often the case in MS development programs, lesion formation, looking at whether Vitaflutamide calcium, when given to patients with early active multiple sclerosis, whether there can be lesion reduction. because this is truly really one of the best predictors of whether a drug has the potential to be successful in phase three using the support and MRI biomarker. And 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. And you can see that both the 30 and the 45 milligram dose were quite effective versus placebo with a very minimal effect of a 10 milligram dose. So with this, this led to the initial decision that there would be great potential of this 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 is, 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. And this is for the 30 milligram dose, there wasn't much difference with the 45 milligram, just similar to the MRI, eye, there was no difference. And you're starting to see an effect in six to eight weeks. So with the gadolinium enhancing lesion results, as well as this result on an approvable endpoint, this led to the design of the NSHER study. But very importantly also, there's a very favorable safety profile, and that's what you're seeing here. There is really no signal in this cohort of lipid injury, no indication of bone marrow suppression or GI side effects. The drug has a very short half-life. And when one looks at this in the context of currently 3,500 patients that have been exposed to Vitaflutamase calcium over six and a half years, with the longest patients now past six and half years in open-label studies, this seems very encouraging in terms of the benefit-risk proceeding into a phase three study. Now, many of these patients ended up going into an open-label extension study, and that's what you're seeing on the next slide. And what's really encouraging there is that the study is currently ongoing. The retention rate is extremely high. And you can see that there's this stable, low progression of patients with continued open-label treatment with a low discontinuation rate. Now, acknowledging it's an open-labels study, but nonetheless, when one sees that patients are remaining in this study and continuing on treatment with favorable safety and tolerability profile, this is extremely encouraging as we head into phase three studies. So now, as was noted earlier, we are approaching the end of our phase three studies. These are the Ensure phase three studies, they've now been going on for several years. And these are the pivotal studies designed to confirm the immunomodulatory effects. So specifically the relapse reduction effect. Now 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. And the way that was done is that these two large phase three 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 vitiflutimous calcium is a meaningful effect at relapse reduction, which is a clinically meaningful endpoint, as well as associated endpoints. But 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. But 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 risk reduction, that would lead paved the way to a U.S. submission. And we're likewise encouraged by the fact there was interim analysis in October of 2024, where it was a utility analysis where the Independent Data Safety Monitoring Committee recommended that the study continue unchanged. So all this is very encouraging as we move forward. Now, 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're 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 left, again, targeting that population that we saw an effect on in our phase two study, in the emphasis study, specifically looking for early active patients that had met the diagnosis of relapsing mass per the McDonald criteria, as well as the Loveland criteria for active disease. And when one looks at the next slide, which is actually the baseline characteristics, you can see this is exactly what we've achieved. We've recruited a very similar population and ensured to the emphasis population. We have patients of similar age and gender, as well as the distribution of BDSS. And 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 receive treatment, how Vitaflutimus does perform in those patients. But 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 Ensured, it certainly does. This is about as close as you can get to confirmatory studies. Now, when we were deciding on endpoints, as I mentioned, time to first relapse as the endpoint for the reasons I've outlined, but we also are included a variety of secondary endpoints that allow us to further understand the effect that the effluent calcium has in patients with MS. And actually, in selecting those endpoints, you can see on the right, again, quotes from the 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. And that's namely focused on the typical things like relapse, as we've 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 two studies, progressive MS, which you'll hear about at another time, where we've seen patients who we just, there are signals about not just slowing disability worsening, but improving. Certain patients improve on treatment. And 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. And so, and 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. So in summary, you know, 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 two study and endpoints in phase three that are comparable with alignment with the regulatory authorities and the precedent behind us on our endpoints. And that gives us a clear path to submission upon a positive outcome later this year. So with that, I want to turn the mic over to Steven 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'll 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's my pleasure to turn it over to Stephen. Thank you, Stephen. Mike, I appreciate it. I hope you can all see my slides now. So this has been a great background about the science of our field and the science that has led to the development of vitiflutamase calcium, what I'm 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. And I titled it The Unmet Need in Relapsing MS Has Changed because the whole field of MS has changed. Our approach to relapsing disease is evolving. And even though, you know, in a sense, we have a real plethora of treatments available to us, this is not a solved problem. And Mike alluded to the voice of the patient report from the MS Society. I'm going to allude to it also, but it's honestly facing that voice and those perspectives that we're looking at every day. And I'm gonna try to bring some context to that. In his intro, Mike mentioned the topographical model of MS. It's my life's work, and I'm to summarize it for you in one minute to try to make it as relevant as possible to what we're facing in our practices and what the unmet needs are in our field. So you've heard a little bit about PIRA and RAW, and I'm sure you're familiar with it from looking at trials, but I want to put that in context of the disease course, and that's really what the topographical models intended to do. So when we think about lesions in MS, new T2 lesions, some of our main outcomes, as you heard in our early trials and phase two 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. So 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 spine, the spinal chord 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're 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. But as time passes, that threshold drops, the brain atrophies, and so much of the disease burden gets revealed above the threshold as pura, most of the disability that accumulates is progressive. And even though we're here talking about relapsing forms of MS, this is happening early on in relapsed forms of the disease. And so 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 relapsis almost as an end in themselves. Now we can think of it as treating relapse as a way of shutting down acute inflammatory disease. that is something we've become very good at, as I'm sure all of you know, with the advent of high efficacy therapies and B-cell depleters. And I'm going to talk about that in a moment. But what that has revealed for us, in a sense, is pura. It has revealed to 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's begin at the beginning. Our disability scale is the EDSS. An EDSs of zero has been defined as normal for 40 years in our field. And 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 zero. So we talk about the clinical threshold. I really liked Dr. Baror's way of showing that you place the threshold for different places. You can think of the Disease Course a little differently. I'm pointing out that even at the lowest, earliest level of this disease, we can look below that clinical threshold and find damage. And here's some data to support that. PIRA, this gradual progression, starts out early in the course of relapsing disease. From this project from Ter and colleagues found that 8% of the cohort of relapse MS had PIRA within five years. And 25% of them across the period of follow-up had PIRA. These are not people we're calling secondary progressive MS. This is people who are accumulating disability gradually, even when we don't give it that nomenclature and the sense of futility that that nomanclature has often provided to people living with the disease. The risk of PIRA causes a 26 times higher risk of accumulating significant disability. An EDSS of six is someone needing a cane over the years that follow. And remember, people with MS are in their 20s. They're in their 30s. So needing a pain within years of diagnosis is an unacceptable outcome that we're endeavoring to prevent. Mike Panzara pointed out this NMSS voice of the patient report, which is what we're listening to in practice every day. The patient's 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. And when we look at large data sets, this was work done by my mentor, Fred Loveland, using a massive data set that combines both the real world and clinical trial outcomes. Here's what disability and 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 pure but i want to point out to you that that's happening right from early on in the disease so when we talk about relapsing ms we're talking about both mechanisms that dr bar or talked about talking about Both ways that disability can accumulate how much can we do about this so you know 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. And 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 ocralizumab 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-sociated worsoning is attenuated by a high-efficacy therapy that stops relapses. PIRA, less so. PIRA was less responsive to treatment. Now, 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 notworking to do any sort of restorative technique. And so Pura is going to creep in, even in the setting of keeping, in my language, the disease topography flat, because some of that disease topology is already forged. And 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. I mean, it has been transformative for our field. But what that means is now I face patients every day who've been on B-cel depletors for five years or longer, coming on 10 years. And 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. And so this one study looking at 20,000 patients across an aggregate of studies found 11% of prevalence of hypogamma globulinema on patients on B-cel depleters. This has started to become a concern for us. And 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 five to 10 year plan. And I think that is a way of curtailing some of that cumulative risk. But what that also means is all of the patients with relapsing MS who've been on B-cell depleters for five to 10 years are going to have to look to what happens after that five to ten year plan. We care about low immune globulins because there is emerging data that it does track with an increased risk of infection. It's a predictor. So this was a single site study looking at 238 patients treated with ocrelizumab for six years, up to six years. The drop in immune globulin IgG started to happen on an annualized basis, and it did start to track with infections. So you see here the percentage of patients needing oral antibiotics, still relatively small, but higher in the people who needed or who had rather low immune globulins. Patients who needed IV antibiotics, thankfully, this is a small number, but again, you see the risk is twice as high for people whose immune globilins have already started to drop. And, you know, patients with MS needing IV antibiotics is, 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. So 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 vector here in this project and factored into the regression model. But 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 depletors 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. And when I got started in this field, every day patients taking injectables would say, you know, doc, when are we going to get pills? And then we got pills and things didn't get simpler. All of a sudden they got more complicated. And that's in part because of the legacy of our first oral agents for MS, which was Fingola mode. 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 sort of expecting from having a pill. And I think that as we've now had pills in various forms, fumarates, S1P modulators, teraflutamide, 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 fumarate, there are issues relating to GI tolerability and flushing. Our S1B 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. Teraflutamide has long been associated with alopecia as well as pregnancy and family planning concerns. So that has been an issue for the big cohort of MS patients who are of childbearing age and potential. And 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. So there are issues to contend with with oral agents, and side effects often carry more weight. This was also true in that NMSS 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. So 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 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 and i'm not going to rehash what you've already heard in great detail from the people developing the agent but this is why vitiflutamate 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 Neuro1 modulation. And it is oral. It is simple. It doesn't require infusion centers. And that remains an advantage. So I'll stop there. I'll turn it over to Jason Tardio, who is going to take it from here. And thanks so much for having me join you today. Excellent. Thank you so much, Dr. Krieger. and good afternoon. My name is Jason Tardy. I'm the President and Chief Operating Officer here at Immunic. And what I'd like to do is take all the information we've 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 Vita Flumis calcium in relapsing MS. The main takeaway that I want to establish, and Eric 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 Vita-Fumus calcium during the course of a patient's overall journey. Next slide, please. As we've heard today, despite having more than 20 approved therapies, significant unmet needs remain. We see three in particular, right? PIRA, progression independent relapse activity. We know it begins early. It becomes increasingly important as the driver of disability over time. And I think most importantly, there's no medicines today directly influencing and impacting the neurodegenerative component of the disease that drives PIRA. We believe that Vitaflumib's calcium, given its neuron activation, could do just that. The second on Benita's safety. We know DMTs carry meaningful safety trade-offs. This includes serious infections like progressive multifocal leukoencephalopathy, increased risk of malignancies, increased risk that have paddle or liver toxicity. And these safety considerations become increasingly important as patients age and accumulate comorbidities. And the third unmet need is tolerability. We just heard this from Dr. Krieger. Side effects remain a significant reason why patients discontinue therapy. And if a patient discontinues the therapy or is unable to take the therapy, they're 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 patience on Tecfidera discontinued therapy due to tolerability issues. This is a real issue, and we'll talk about the importance of that to patients in just a moment. So 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. And that opportunity exists with 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 into the 2030s. The anti-CD20 therapies have clearly become the largest class, representing about half the treated patients today. But it's important to note that the oral therapies continue to represent close to 30% of the market by patient share. So 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. And on top of that, even with 20 plus available therapies, there's approximately 125,000 diagnosed relapsing MS patients who are currently untreated. And switching isn't a failure of the market. It's a fundamental feature of just MS journey and MS care. Patients initiate treatment. They switch treatment because of breakthrough disease. They switch treatment because they're having tolerability issues. And treatment strategies evolve as patients get older, as Dr. Krieger, again, just alluded to. Importantly, there's not a single disease-modifying therapy that optimizes every attribute for every patient at every stage of disease that can span decades. So beta-futamase 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. And that's 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's appropriate. At the same time, the prescribing community itself is highly heterogeneous. We heard from two KOL academic clinicians today. But 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. And of course, prescribing behavior can differ between general neurologist, 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. And differentiated therapy needs to offer a clear value proposition across identical patient segments and physician types. And we believe Vitaflumib's calcium has the potential to do just that. Next slide, please. One assumption that's 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. And that is why we believe the totality of the Vita flumis calcium profile could be so important. Next slide. And it shouldn't be surprised 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 a therapy that makes them, how the therapy makes them feel, the risks that they're 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. And this brings us where we believe VitaFloam as calcium will offer a compelling value proposition. We're not trying to build the value proposition around one single attribute. We're 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 neuroinactivation combined with potent anti-inflammatory effects through selective DHODH inhibition. Second, safety. Based on the clinical experience to date, we believe Vita Flumis 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 lipopenia. 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. And finally, once a day oral convenience, which reduces treatment burden for patients, for physicians, and for their offices. Ultimately, we believe the differentiation of Vitofulimus calcium will come from the totality of its profile, the mechanism of action, the efficacy, the safety, the tolerability, and the convenience. And given all of this, we believe Vitoflumus could potentially offer the best benefit risk profile of any disease modifying therapy. Next slide. So 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's 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 colorability concerns or patients continuing to have progression largely linked to PIRA. Over 60,000 patients fall into this bucket. And third, the large and growing population of older relapsing MS patients. Approximately 185,000 currently treated patients with relapsed 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're not mutually exclusive. An older patient sequences away from a CD20 might also prefer an oral therapy. So let's spend a minute just diving a little bit deeper to each of these respective opportunities. Next slide, please. Starting with patients before oral therapies, about 25% of patients starting a treatment today will choose an oral disease-modifying therapies. And as I've mentioned, about 100,000 patients are currently treated today with an oral-disease-modify therapies. There's practical reasons why patients choose an oil. 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. But despite the continued preference for oral therapies, there's still a meaningful unmet need within this class. Every currently approved oral disease modified 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. And 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. So we think there's a meaningful opportunity for oral therapy that can provide effective disease control while offering a favorable safety and tolerability profile and an overall low treatment burden. If Vitaformis 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 orcalizumab-treated patients, about one-third develop low levels of IgG antibodies, and these antibodies are important to fight infection. Consistent with that, recent data has also showed 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 reoccurring infections, low IgG levels, or other safety concerns, still require an effective follow-on treatment that can preserve disease control without compromising immune defense. And 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's 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's because of serious infection, declining IgG levels, or other safety concerns, the question remains, what comes next? And today, there is not a clear answer. And that is where we believe Vitoflumous 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'd like to highlight are the aging relapsing MS population. Approximately 47% of patients diagnosed with relapsed MS today in the United States are age 55 or older. This equates to about 185,000 currently treated patients. So this is not a niche population. It represents a very significant portion of the relapsing market. And 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 Vitaformis calcium that is an immunomodulator. Older age is associated with less complete recovery from a relapse. So even if the relapses become less frequent in these older patients, the consequences of that relapse may become more significant. So 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. And we believe that answer may be Vita-Fluidomus calcium. It could potentially offer a differentiated approach in oral. Again, that's 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. So 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. And 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 ages. 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, and this is where we believe Vitaflumib's calcium could be differentiated. Vitafilumib will deliver strong efficacy by combining its dual NIR1 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 Vita-Futimus 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. So 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 Vita Fulimus Calcium has the 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 clothes 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. And 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 the clinical data that we have. You heard a lot on unmet needs and where we think Vitaflutimus has the potential to fit in. I'll just close with near term catalysts and relapsing two large phase three 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 in 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 three study in progressive MS by the end of the year. And the team is really focused on that deliverable as well. And 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 makes sure that everyone's aware we will be having another one of these days on November 5th to really focus on Progressive. So Progressive is a hugely exciting and important part of the Immunic and Vitaplutimus calcium story, and so important we thought it was worth breaking out into a separate session. So 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. So that, I want to flip back over to Jessica to take us through some Q&A. Yeah, thank you, Eric. And thank you to all our speakers for these wonderful and interesting presentations. As Eric 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. And I actually see a lot of questions here. So I will start with Paul Matisse over at Stiefel, 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 Vidoca versus how they think about the positioning for oral BTK drugs? Who's the right patient or patients for each? And Amit or Stephen, please. I'm happy to take a first stab. It's Amit. Hi. I mean, I think Jason covered this very, 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 three data, and both relapsing and hopefully progressive to really know. But that said, we have high efficacy therapy for relapsed MS. We want to control relapses very, very well. That said, just controlling relapses very, 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 relapsis 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 newMS, 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 and 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 and 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 for ever 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. And a therapy that has anywhere between a modest to a moderate effect at controlling relapsis, 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, oh, sorry. David, I think, was going to add. Oh, I'm sorry. I was too quick. No, that was a wonderful answer. 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 BTKA agents was to accomplish, in essence, what we're talking about here. But the data didn't take us there. So the data for evobrutinib didn't show superiority for relapses. The data for the Gemini trials in tolibrinib also didn't show superiority for relapses. So the story to use for relapse control is not there across the board, and the progressive data is really mixed. And so, you know, we're not talking about non-relapsing progressive disease in this program. That's the only thing that we have a successful trial for tolbrinib, and that didn't garner approval here. So I think that the, if anything, the complexity of the data, particularly the safety data with the BTK inhibitors, doesn't get in the way of the benefit analysis that you've heard here today for Vitoflutimus. Thank you, Stephen. Thank you. We have another one for our two experts. Actually, a similar question from two attendees here from Paul Matisse at Stifa and Sam Slutsky at LifeSci. What is the bar for a clearly positive outcome in NSHO 1 and 2? Is it important to hit Static on EDSS? Do we need a certain effect size on time to first relapse? And then Sam has a similar question. What do you see as a win in the upcoming phase 3 RMS readout as you consider the current unmet needs? do you want to uh do you want to kick it off again yeah i can i can certainly give it a shot i mean i think that um i i would not necessarily insist on seeing an impact on disability progression to be able to conclude that there's an important effect on targeting relapses although of course one would like to see that and especially when we're 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 three 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've come to realize that impacting disability progression is something that we'd very much like to see, but would not necessarily insist on seeing. And I think, you know, 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 vitiflutimous calcium, to me, would be pretty compelling. Yeah, I think that's quite right. And, you know. 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. And 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 end point 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. And 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 and RMS trial prove that a drug is beneficial on PIRA? Well, I'll pop in there and say, you know, that's where this determination of whether disability occurred consequent of relapses or independent of relapse helps to make that determination. The EDSS is what the regulators require. We all in our field recognize that it's a crude scale, but our regulatory agencies require it. And in that sense, it's okay, because if we can achieve the endpoint on a crude skill, then we can also expect that we'll 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 mean, I think that showing an impact on disability progression in the patient population that has potential relapse contribution, doesn't 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. I would simply add to that, that, you know, this will be the, to Amit's point, the insure readouts will be the next big piece of evidence in a learning journey that will continue around this question. I don't think we'll have a definitive answer out of this, regardless of the magnitude of the clinical effect, which is why we're committed to running a progressive MS study in a clearly progressing population with, you know, correct powering for progression-related endpoints that will yield more evidence over time. You've heard here today a bit of why we are so excited to pursue the science into the clinic around these questions, and the insurer's studies will be a meaningful advance in our understanding of the clinical impact of Vita flutimus calcium on progression, but it won't answer all of the questions, and that's why we're prepared to sort of pursue them even further and beyond, and sure wanted to. Yeah, I also see a lot of raised hands here, and I would like to start with the first live question here. Miles Minter at William Blair. Maltz, please unmute yourself and go ahead. Yeah, have you got me? Hey, yes. Beautiful. Thanks. Yeah. Just for Dr. Kruger and Barora 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 So, you know, against interferon, against teraflunomide. If you go back to the original terafunamide trials, I think on that end point, it was about a 24 to 28 percent benefit over placebo. And then others are obviously looking on top of active drug. Just could you kind of put a number on the on the risk reduction for time to first relapse that you would expect here to to have a clear win for success? That's the first one. And then secondly, just all this focus on confirmed disability worsening at the three-month end point. 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, you know, would that be something that would get you excited? Thanks very much. I'll let Steve maybe take this one initially. Yeah. So I don't have a specific answer to what the bar would be for success. I really don't accept it. Of course, statistical significance would be awfully nice to start with. But I think you're right that the annualized reabsorptive reduction of teraflunomide back in its pivotal trials from the 2012 era was in that 20% to 30% range. And so 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. And so, you know, we sort of look at the actual annualized relapse rate numbers. We've gotten accustomed to seeing numbers that are remarkably low. And 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. Baror said earlier. But 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. because that's the highest bar we kind of have now for what constitutes efficacy in the emerging therapeutic landscape. And so if we saw that here in these trials, I think that would be successful. Yeah. And I would agree completely. I think as Stephen pointed out, it's tough to try to get a number that would 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. But 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 two, 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. But again, I can 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 will emerge as, 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, Miles. The next one I have in the queue here is Zatin Yunea at Guggenheim. Yeah, Zatin, please unmute yourself. Hey, guys, can you hear me? Yes, 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 sort of articulating the buckets of patients, whether these are new patients, switching patients or patients who are not treated or patients who are on CD20. So the question for both the physicians is that, look, I think when this therapy becomes available, you're also going to have remybrutinib, right? Because that is maybe a little bit of a different type of a VTK inhibitor. How would you adopt VEDO in each of these buckets of patients that the company highlights? If you can just talk a little bit about the market adoption, that will be helpful, assuming that the study meets the bar that you sort of 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. So of course, tolobrutinib's principal safety issue has been the liver concern, which limited its FDA approval. With phenobrutinib, 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 Remy, 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. So 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 seeing that yet, with the exception of perhaps the tolibrutinib 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 Vito in terms of safety and the aging population. So I still think that this role, this mechanism has a real role in those buckets in ways that I'm not convinced that the BTK inhibitors are best aligned for. and i might add that especially sort of the longer term lens in the sense that i personally hope i'm sure steven as well and others that we will see at least one or two btks come to the market but that said i think that with btk eyes over time we're going to see more and more individuals running into trouble in terms of immune response defense you know there's still an impact on the immune system that is not that subtle and it's again one of those things where we have very limited experience in terms of long-term exposure. And I suspect that the profile of the flumous 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 that the themes you've 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. And the sort of underlying thrust of the question, I would suggest that, A, first on remabrutinib, specifically, we need to wait and see data. Right now we have a top line press release, no details. So it's a little bit premature and we don't have our own phase three data even read out yet. So, it's little bit pre-mature to talk about positioning. What I'm highly confident in is that both approaches are needed and both approaches have space and both approach can create value for people living with the disease. That is undoubtedly true um and uh and i i i for one uh very much look forward to to seeing their data in toronto in a few weeks um and um and we'll we'll have more to say about it after we've we've seen the results oh we may have lost yatin i will just continue with the next uh question that came in in writing here for Dr. Baor and or Krieger. Does Dr. Baor or Kriege feel that we will have or do have good measures of progression versus relapse for regular clinical practice decision making? Yeah, that's 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 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. And 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. So 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 injury under the service. That one I concur with completely. I couldn't, couldn't add a thing. That's perfect. Thank you both. The next one in the queue here I see is Mark Goodman over at Lyrinc. Mark, please unmute yourself and welcome to the call. Yeah. Hi, Jessica. Thank you. Question for the, 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? Okay. 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, you know, looking to see whether we can use B-cell depletors only briefly and then stop it after a shorter period of time. So you're actually moving that field, 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. So certainly when somebody reaches age 60, for instance, I'm not taking all of them off of a B-cell depletor, 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-cel reconstitution. So rather than doing it at any fixed time scale, waiting for B-cels to come back, which for older patients can sometimes be quite prolonged. And then the third group is those that you take off all together. At this point, I'll be honest, being somewhat reactive still, I take people off of a B-cell depletor when it is starting to cause things that I don't like. What I haven't yet adopted in my own practice is a proactive taking people off the B-cel depletors because I don't think we can perfectly risk stratify who is vulnerable to infections and other consequences. That's where that hypogammaglobulinemia data that I showed is starting to be more and more instructive for our field. So I put that in there because I think that's 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. But what I did say in in my presentation is I'm telling people now, this is a five to 10 year plan. And so I don't imagine we're going to keep a lot of people on B cell depletion for more than 10 years moving forward. Maybe that prediction's wrong. So I think it's more of a duration of therapy rather than a particular age, but we'll see if that prediction is borne out. Dr. Barwer, do you have additional thoughts on that? As I anticipated, I agree completely, Stephen. I think, you know, the study that you're alluding to that we're 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 is relevant or relevant to disease activity. Although it's very clear that not everybody will have sustained durable remission from relapsing disease after the discontinuation, But some probably will. And for us, it's an opportunity to understand the biology of who's different and why and whether that could be predicted from early samples. So it's 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. And by the way, numerically, more people will run into a 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. And so we stay vigilant throughout the course, regardless of the duration of treatment, but increasingly vigilant with increased exposure and age. And there's no single treatment switch that we would consider. We've considered a variety of treatments. It's almost like thinking of a person coming anew and what might you consider that would be sufficient to control their MS. 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. So it's a fresh discussion. That's a good point. Thanks. Great. 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. So please feel free to reach out to me after the webcast. I will hand it back over to Eric 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 science and our session and advancing the science behind Vito, 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 hardwork you do every day to advance Vita Flutimus 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 there's a lot of things you can be doing with your time. We really, really appreciate your interest in learning more about Vitaflutimus calcium and Immunic. And 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. And 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're thrilled and excited to bring butyflutamate calcium into that arena as well. So with that, I'll 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, Eric. 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.