Immunic, Inc. (IMUX) Earnings Call Transcript & Summary

All right. Good morning to everyone on our webinar today, and welcome to Immunic virtual R&D Day focusing on our relapsing and development program with vidofludimus calcium. My name is Jessica Breu, 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. [Operator Instructions] and this event is being recorded. [Operator Instructions] Before we begin, I would like to remind you that this presentation may contain forward-looking statements. statements can be identified by words such as may, will, expect, anticipate, estimate or words with similar meaning, and such statements involve a number of risks and uncertainties that could cause Immunic's actual results to differ materially from those discussed here. Please note that these forward-looking statements reflect Immunic's opinions only as of the date of this presentation, and it undertakes no obligation to revise or publicly release the results of any revision to these forward-looking statements in light of new information or future events. Please refer to Immunic's SEC filings for a more detailed description of the risk factors that may affect Immunic's results and these forward-looking statements. Now let's turn to what we will actually focus on today. First of all, I'm very pleased that 2 internationally renowned MS experts will be speaking during today's event Dr. Amit Bar-Or from the University of Pennsylvania and Dr. Stephen Krieger from the Mount Sinai Hospital in New York. Moreover, we will have members of the Immunic management team presenting, including Erik Lundgren, CEO; Dr. Mike Panzara, CMO; Dr. Hella Kohlhof, 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 with vidofludimus calcium for the treatment of relapsing MS. Our team will share mod of action, preclinical, clinical and commercial positioning insights on the potential of how Vidofludimus Calcium's differentiated approach could reshape the treatment for patients with Relapsing MS. Dr. Bar-Or and Krieger will provide expert perspectives on the MS patient journey, current treatment paradigms and unmet medical needs. Now I would like to turn the call over to our CEO, Erik Lundgren, to take the presentation off, Erik?

Great. Thank you, Jessica, and thank you, everyone, for joining us. Good morning. I'm Erik Lundgren, the CEO of Immunic, 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 on to 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 are 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 2 pivotal Phase III studies that we hope will create a path for us to advance our lead asset, vidofludimus calcium into relapsing MS, so that we can address some significant remaining unmet needs in the MS community and needs that are faced by people living with MS on a daily basis. so as you sort of frame the conversation to follow, we are going to really focus in on that near-term inflection and catalyst point in relapsing MS. Keep in the back of your minds, we're not going to spend much time at all today on this, but another huge part of the value proposition for Immunic and for vidofludimus calcium sits in a potential progressive MS population with data to come. 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 more 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 and deeply understand the plight of people living with this disease and are really committed and passionate about transforming care in MS. That's really where we're focused. And we think we've got the right asset to do it. We've got the right capital structure to support it, and we've got 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 are 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 2 Phase III studies, the ENSURE-1 and the ENSURE-2 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 II EMPhASIS study as well, which Dr. Panzara will go through some of the highlights of that study to, sort of, set the stage for what we can hope to see towards the end of the year. Next slide, please, Jessica. 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., 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. 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 market 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 Bar-Or. Amit holds the Melissa and Paul Anderson president's Distinguished Chair at the University of Pennsylvania. And he -- there he directs the center for neuro-inflammation and experimental therapeutics and serves as the Chief of the division for MS and related disorders. Dr. Bar-Or's research focuses on neuroimmune health and central nervous system inflammatory diseases. He runs a cellular and molecular neuroimmunology lab directed at understanding general principles of immune regulation and immune neural interactions and their contributions to inflammation, injury and repair of the human central nervous system. Following an undergraduate degree at McMaster University, Amit earned his medical degree at McGill University in Montreal, Dr. Bar-Or has published over 400 peer-reviewed publications and has led multiple national and international abortive research initiatives. Thank you, Amit, for joining us, and I'll turn over to you.

Thanks, Erik. First, let me just confirm that you can both see the screen with the presentation and hear me.

We can.

Yes, we can.

Perfect. Perfect. Thanks for the kind introduction, Erik. And hello, everybody. Pleasure to be here and follow on Eric's background presentation and 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 vidofludimus calcium may offer some very unique advantages in relapsing MS with a focus here, but as Erik has already alluded to, in the context of protection and repair throughout the spectrum by 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 content with, but use that as a basis for commenting about some evolution in our concept of the clinical spectrum of MS. 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 them providing the framework for thinking about the mechanism of action of vidofludimus calcium. So the unmet needs and the model promising targets is what we're really going to be segueing into to them deal with the biology in particular, of the Nurr1 pathway with a focus on trying to protect and support repair from ongoing injury throughout the MS process. And in the context of vidofludimus calcium in particular, the attraction of having potential for dual mechanism of action, both activating the Nurr1 pathway, but also selectively inhibiting the DHODH enzyme where we have a precedent in the MS field of an effective therapy that does so teriflunomide limiting relapsing disease activity as well as progression of disability. So we'll start with a simplified model, and it's a very simple sort of 3 compartment concept of many, if not all of you, I'm sure have seen before, the lower right is the central nervous system, the target NMS separated by barriers for the immune system. We think of immune cells in the periphery outside of the CNS getting activated, upregulating molecules that enable them to more efficiently engage and cross the barrier and then get reactivated within the central nervous system compartment and bring to bear on the tissue. Historically, for many years, for decades, MS had been thought of as a T-cell mediated disease, very much driven by most commonly used animal modeling in experimental autoimmune encephalomyelitis, but really our thinking has evolved importantly, particularly with the selective targeting of B cells with anti-CD20 therapies that really has helped us understand that it's not just about T-cells, it's about B cells and T-cells and very importantly, interactions between B cells and T cells in the periphery that are thought to drive the relapsing aspect of the 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, glia 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 but insufficient element in developing MS. And more and more data interestingly coming out in high-profile papers to suggest that EBV may involve not just in the initial triggering of the disease, but also potentially in proposition with strong data suggesting involvement in relapsing disease, but also the suggestion that within the 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 the mass present with bouts of disability that comes and goes in the context of the relapsing and remitting aspect, but then many, most of whom, end up with some aspect of progression independent of relapses. So these events here are considered relapse associated were sitting. Some I'm 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're 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 the 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 a mess magically when they transition into secondary progressive MS rather with 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 consider this person as having relapsing-remitting MS onset and secondary progressive MS. But if you had an individual whose threshold was here, then clinically, they would no longer look like RMS to SPMS, but rather primary progressive MS. So this is a very quick way of trying to capture the evolution conceptually in the field that we recognize MSSP 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 side of triangle focuses on relapsed 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 the 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 terms of 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 unmet clinical need, and we'll be transitioned now to the last part of my presentation, which really hones in on vidofludimus calcium's mode of action, which starts with targeting Nurr1 to address aspects of protection and repair from ongoing injury. This includes, as Erik highlighted, injury that take place in the context of an acute inflammatory event or 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 Nurr protection 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 Nurr1 activation with selective inhibition of DHODH. So a few words on Nurr1, also known as NR-482 as a potential neuroprotective target in multiple sclerosis. It has been known over the years that Nurr1 plays a central role in terms of signaling in general neuronal health. As a transcription factor of the steroid nuclear home and receptor family, it regulates a variety of genes that are involved, starting with neuro development but always 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, on one hand, identify that reduced peripheral neuron expression correlates with more aggressive relaxing disease, a higher relapse rate and EDSS change presumably the raw the relapse associated worsening, normalized during pregnancy, which is probably 1 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 Nurr1 expression in pathology samples were associated with preserved density, supporting a potential for neuroprotective roles. And when one thinks of Nurr1 activation in the context of neurodegenerative disease processes, which of course, extend beyond MS, but are very relevant for MS, it's known biologically when activated to reduce neurotoxic mediator release from activated microglia astrocytes that I highlighted before, are considered now principal players in a chronically activated state in driving CNS compartmentalized processes and progressive disease. It supports mitochondrial and reactive oxygen piece related defense mechanisms, particularly relevant in acute relapsing injury but also progressive injury and then induces neurotrophic factors of GDNF and BDNF, very important for supporting neurons and promotes gene expression profiles that are linked survival and normal functional neurals. In the context more broadly in 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 DHODH aspect of vidofludimus calcium's mode of action. DHODH is known metabolic checkpoint and particularly relevant as one of the pathways for permitting synthesis involved in highly activated immune cells. So when you inhibit this pathway, you don't limit the capacity of cells to deal with [indiscernible] DNA synthesis entirely, but you kind of cut the edge off the more activated immune cells, which are the ones that would be expected to participate in autoimmune processes, including in MS. It is a key mitochondrial enzyme and it's highly expressed again in these particularly highly active rapidly dividing lymphocytes and resting lymphocytes, less depend on it, and therefore, inhibiting it is not going to affect the broad immune system capacity to protect us as part of the normal immune response. And with colleagues, [indiscernible] and others were able to show biologically that teriflunomide as a DHODH inhibitor indeed kind of cuts the edge off the overly activated immune cells involved in disease. And this inhibition is particularly targeting cell start to be pathogenic in the context of MS relapsing disease activity. And as I alluded to earlier on, there's a certain aspect about DHODH inhibition that may limit viral responses, including RNA protein synthesis and that this may include EV, of course, therefore, may be important to consider as an add-in benefit given EBV's increasing implication. And so I think overall, this is a really interesting context, where neural protection meets immune regulation. Nurr1 again, having both direct and indirect neuroprotective effects and DHODH targeting as a way of reducing the immune cell hyperactivation involved in the relapsing disease process. This is just a cartoon that recapitulates the 3 compartments and the capacity or the potential of unifies calcium to be acting on these different biologies in the different compartments, leading to better support for neuron survival as well as immune modulation, having, in my mind, relevance across the broad spectrum of MS in relapsing and through progressive disease. So I'll stop here, and I think transition to the next speaker. Having set the stage, hopefully, for suggesting that a dual mode of action combining Neuron activation and selective inhibition of DHODH 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 a wonderful was a wonderful overview. And actually, so on the MS biology and specifically on Nurr1 and the role of Nurr1 and DHODH in MS. And I will go on now and fill it with data. So I want to talk about vidofludimus calcium's mode of action on Nurr1 and on DHODH. And we know already that vidofludimus calcium has a unique dual mechanism approach to MS. Potentially, it's the only oral MS drug that is really addressing PIRA and ROW simultaneously. So vidofludimus calcium is a direct Nurr1 activator. It modulates the gene expression directly in neurons. It mediates neuroprotection and neuron survival, and it reduces the neurotoxicity of microglia astrocytes which indirectly supports neural survival again. Therefore, it targets neurodegeneration beyond the focal inflammation. In addition, what we heard already is the Select DHODH inhibitor, which is wonderful because it selectively targets metabolically hyperactive T and B cells, and it reduces the focal inflammation, MRI lesions and reductions. And what we heard as well, it prevents reactivation of Epstein-Barr virus. Excellent. So as we said, it is a selective DHODH inhibitors. And actually, I'm pretty proud about this that is this with the a inhibitor in addition to the Nurr1 activation. So it selectively inhibits DHODH, you see here in this table that it has a 50 of around 240 nanomolar. And I just put in teriflunomide as a comparison. Teriflunomide is not active on the right, DHODH. Vidofludimus is most active on the [indiscernible] DHODH. How does it come? Well, there is a thesis specificity for DHODH. And this is -- can be explained because these are completely different chemical structures. You see here on the right, we see the structure of vidofludimus and you see just for comparison reason, you see the structure of Teriflunomide. In addition to this, we know by vidofludimus does not inhibit kinases. And where Teriflunomide targets different kinases, PIM or PDGFR especially EGFR and EGF, our inhibition actually is known or is related to skin diseases, diarrhea and liver enzyme elevation. Both of them are active and -- on DHODH and on high affinity immune cells. So vidofludimus you see here just with the abbreviation Vido and you see Teriflunomide, they both reduce hyperactive or high affinity immune cells due to the restriction of the needed permittance. And in addition to base, of course, the tax including calcium in different animal models, just an example here that vidofludimus reduces the disease score in an information-driven EAE model. So it's a select agile inhibitor. But in addition, that's on the next slide. In addition, it's a potent Nurr1 activator. What is really important and relevant in MS biology and in neuroprotection? So I depicted here, the 3, I would say, most important cell types in MS. So we have microglia astrocytes and [indiscernible] and actually, Nurr1 is expressed in microglia and astrocytes and in neurons. And Nurr1 activation leads in the glia cells to a reduction of pro-inflammatory cytokines and nitrogen oxide and [indiscernible] as well. In neurons, there's a direct effect as well because when we hear activate Nurr1, we see a reduction of oxidative stress, we see an increase of neuronal survival and differentiation of dopaminergic neurotransmission and myelination. So that means that Nurr1 activation is believed to be involved in holding neurodegeneration and visibility progression. And this is also, of course, supported by [indiscernible]. That's not just my idea, it's really supported by [indiscernible]. And yes, and we heard it already very nicely summarized and explained by Amit. So next slide, please. Now we can, of course, just populate vidofludimus calcium is Nurr1 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 vidofludimus towards Nurr1 ligand binding domain. This is just a model. But we were able to show by using ITC and DSS, vidofludimus calcium shows direct and leveragable binding 201 protein. So on the left, you see the ITC and the demonstrated specific binding signal with an estimated association content of around 700 nanomer, which really supports from of largely relevant target engagement. On the right-hand side, you'll see GSF and that can also [indiscernible] assay, which independently confirmed the interaction to a statistically significant shift in 1 melting temperature versus DMSO control. So together, these 2 complementary biophysical data strengthened the evidence that Nurr1 is a direct molecule target of the vidofludimus calcium. So now you can say, okay, fine, does it matter? Yes, matters. Nurr1 is a transcription factor and therefore, we looked into Nurr1 associated gene expression, which is modulated by vidofludimus calcium and you see here, we tested in astrocytic cells, in microglial cells and in neuronal cells. And we look for PH and VMAT, which are 2 well-known and described direct target genes of Nurr1. And you see here that vidofludimus calcium increase the expression in the selected non-regulated gene in a dose-dependent manner. So that is, okay, we see gene expression modulation. Is there any impact on function. And yes, of course, there is otherwise I wouldn't talk to you. So vidofludimus calcium improved neural survival and it reduced injury under [indiscernible] condition. So here, we use TNF [indiscernible] model. So we incubated viable neurons with NFL [indiscernible], this is an apoptotic and [indiscernible] and necrotic stress signal year in cells undergo apoptosis. And in the presence of vidofludimus, you see an improvement of the neural survival. This is actually depicted here in the middle where you see that in the presence of vidofludimus calcium in a dose-dependent manner, you see an improved neuronal survival. We did not only count just in neural cells here, but we looked as well for neuronal injury marker. And this is a well-known neuropen light chain, what is measured in clinical studies quite often. And here that, again, in a dose-dependent manner, you see a reduction of neuronal injury marker neurofilament light chain. So vidofludimus calcium was associated with a full serial survival and reduced neurofilament light chain release under these [indiscernible] stress conditions. Next slide, please. Now you can say, okay, that's vidofludimus, because it is Nurr1 important here or is it just because of the DHODH inhibition. And we were able to demonstrate that really Nurr1 is required to mediate this neuronal survival here. So again, [indiscernible] is quite similar to the previous picture, where you're at in about cyclohexane, you see it in red, you have a decrease of the viability or the number of the living cells. And in the presence of vidofludimus, you see again the increase or a higher number of the living cells. That was performed with [indiscernible] cyclohexane, but we use 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 [indiscernible] signal and what you see on the left. So vidofludimus calcium is able to do it. Now is Nurr1 important here or not. And this can be seen now because here, we used crystal-mediated Nurr1 lockout. And you see it that when you have neurons, which unlocks out for Nurr1, then vidofludimus calcium is no longer able to improve the viability and the number of living cells in this model. So vidofludimus associated improved neuro survival really requires Nurr1. Next one, please. Of course, I talked about microglia. Microglia super important because they drive inflammation in the brain as well. So we were interested in the role of vidofludimus calcium on neural viability and the neuroinflammatory condition. And therefore, we performed the neuron microglia co-cultures here. So we co-cultured microglia and neurons then stimulated the microglia to produce pro-inflammatory cytokine and see just on the graph on the left that the neurons are undergoing apoptosis in the presence of vidofludimus, they have a higher -- we see again a higher number of neuron stuff. So in the middle, you see when you add LTS into from [indiscernible], you see a reduction of living cells of the -- in this case, human saline [indiscernible] cells. And when you then add in the presence of vidofludimus, you have an improved survival ability. Of course, we wanted to know is a really mediated by microglia or is it just toxicity that is driven by LTS and [indiscernible] gamma. Therefore, we added the control experiment what you see on the right that no LTS and grammar [indiscernible] don't do any harm to neuron alone. So vidofludimus calcium was associated with increased neural viability in inflammatory coculture. Now it comes to animal models. Does vidofludimus calcium work in animals? Yes, of course, it does. We did several EAE models and we were able to demonstrate that vidofludimus calcium reduced disease severity in EAE model. Now we know in a prophylactic setting and therapeutic setting. And of course, we all know that EAE models are mainly inflammatory driven. So it could be that DHODH inhibitors work there. And indeed, works there. That's fine. Vidofludimus works there. And we use these models because we are interested in investigating the impact of vidofludimus in these models on Nurr1 and we were able to do it. So on the next slide, you see here that vidofludimus calcium model related Nurr1 related gene expression in the CNS of the mice in these EAE model. We investigated the brain and the spinal cord, and we looked into the prophylactic and into the therapeutic tapping of these animal models. And you see here in the brain on the left that in the presence of vidofludimus calcium, we see an increase of Nurr1 itself. So there seem to be an auto regulation. So we have higher levels of Nurr1 in the brain of these animals. And we look as well for Tapityrosine hydroxylase, which is a well-described primary targeting of Nurr1. So in the brain, we saw Nurr1 upregulation and TH upregulation by vidofludimus calcium. And we look as well into the spinal cord. And actually in the spinal cord, we focused more on the detoxiccation of super [indiscernible] radicals by SOD upregulation and we looked into ATP production in principle via the upregulation of [indiscernible]. So vidofludimus calcium treatment was associated with the modulation of Nurr1 regulators related gene expression in CNS tissue in both the prophylactic and the therapeutic inflammation-driven EAE settings. And we look for functions while we were interested in proteins in the plasma, if we can measure it looks for BDNF, which is brain-derived neurotrophic factor, and you see that even in the plus more this, we can demonstrate that we have a higher exposure or a higher production of BDNF and the plasma of these -- vidofludimus calcium treated mice, EAE mice and here, we, again, we looked for neurofilament light levels, which will decrease under the treatment of the vidofludimus calcium. Okay. So now you can say if every DHODH inhibitor and Nurr1 agonist, and I would clearly say no. So there was a publication from [indiscernible] in 2023. They described it already, but I'm pretty sure that you guys are super interested in Teriflunomide because it's approved for MS. So we looked into this. And you see again here, ITC testing, you DFS testing. We were able -- you see again for vidofludimus calcium. There is a binding signal detected, of course, for vidofludimus calcium on Nurr1. And we did under the same conditions we have for Teriflunomide and actually, there's no proper curve, so we don't see any natural binding here in ITC. We did it as well in DSF, being just a different assay system. And again, and the curious calcium in users a temperature shift, melting temperature shift, which indicates the binding here, whereas Teriflunomide does not. So that means, okay, there's -- most likely, there is no binding of Teriflunomide to Nurr1, but it could mean maybe there's an indirect effect towards Nurr1 that can't be measured via the direct interaction. So we looked as well for the function. And I told already about neuronal survival and [indiscernible] stress conditions, and we did the same experiment on the next slide. It's the same experiment in the presence of Teriflunomide. And what you clearly see here is that vidofludimus calcium improves the neuronal survival and apoptotic stress conditions, whereas on the right Teriflunomide did not. So in this test system, Teriflunomide did not significant improve survival of neuronal cells. Another hint that it's really not directing Nurr1, it's not binding, and it's not promoting any survival functions in neuronal cells. So to summarize everything, we can show that vidofludimus calcium activation and selective inhibits DHODH. So with Nurr1 activation, it's improving the survival of neurons and it's reducing neurotoxic microglial activation. DHODH inhibition selectively targets only metabolically active TMB cells and with having DHODH inhibition, vidofludimus calcium is able to inhibit the EBV associated B-cell responses. Thank you.

Great. Thank you, Hella. And good afternoon, everybody. I'm Mike Panzara, the Chief Medical Officer. Mike, it's a great pleasure to be here with you today to talk about our efforts in relapsing multiple sclerosis, focusing on the ENSURE program. Next slide, please. So I think in the 25 years, been doing this drug development and academics and MS focus before that as neurologists in these patients. The way things have changed over that time in the treatment of multiple sclerosis has been just remarkable. And I think Steven and meet 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 -- it makes you feel pretty good about what we've all accomplished. But it really don't want to feel really good. Just listening to this patient-focused drug development meeting that happened to FDA at the end of last year that despite therapy, 20-plus approved DMTs in this space, there are enormous unmet need 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. The MRI regions are not detectable. They just feel like they're getting worse. They just running out of options because of their age for a variety of reasons, and they're looking for something new. And this is truly a remarkable revelation certainly, when I watched this and really speaks to why vidofludimus calcium is so important and has great potential to help many of these patients. Next slide, please. I mean you've already heard about the biology. You've already heard about how the dual mechanism of action leads to potential to treat different aspects of the disease. But the effects would be anticipated to address both these important elements of disease as it needs 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 we reduce those relapses, but how do we treat this underlying progression of disease, this biology that is a neat 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 go into Immunic using vidofludimus calcium in relapsing MS. The first -- the Phase II study here is showing the EMPhASIS study. This is a study 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 vidofludimus calcium when given to patients with early active multiple sclerosis, whether there can be leasing reduction because this is truly really one of the best predictors of whether a drug has the potential to be successful in Phase III using this important MRI biomarker. In the next slide, what we saw was very clear. There was a robust lesion reduction over 24 weeks in this patient population using cumulative active lesions as well as combined unique lesions as well as [indiscernible] enhancing lesions. And you can see that both the 30- and 45-milligram dose were quite effective versus placebo with a very minimal effect of a 10-milligram dose. So with -- this led to the -- some of the initial decision that there would be great potential of this from 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, this is a capital 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, so there wasn't much difference 45 milligram, just similar to the MRI, there was no difference. And you're starting to see an effect in 6 to 8 weeks. So with the Garion-enhancing lesion results as well as this result on an approvable end point. This led to the design of the ENSURE study. But very importantly also, there is a very favorable safety profile, and that's what you're seeing here. There is really no signal in this cohort of injury, no indication of bone marrow suppression or GI side effects. The drug is a very short half-life. And when one looks at this in the context of currently 3,500 patients that have been exposed to vidofludimus calcium over 6.5 years with the longest patients now passed 6.5 years in open-label studies, this seems very encouraging in terms of the benefit risk proceeding into a Phase III 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. We've -- the retention rate is extremely high. And you can see that there is this stable low progression of patients with continued open-label treatment with low description rate. Now acknowledging it's open to open-label study. But nonetheless, when 1 sees that patients are remaining in the study and continuing on treatment with a favorable safety and tolerability profile, which is extremely encouraging as we head into Phase III studies. So now [indiscernible] where, as was noted earlier, we are approaching the end of our Phase III studies. We had these are the NSR Phase III studies. They've now been going on for several years. And these are the pivotal studies designed to confirm the immunomodulatory effect. So specifically, the relapse reduction effect. Now to do this study, it was very important to is very important to focus on the safety of patients, and this is 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 2 large Phase III studies allowed patients on placebo or active treatment 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 the vidofludimus calcium is a meaningful effect of relapse reduction, which is a clinically meaningful endpoint as well as associated endpoints. But what it does do 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 that -- but nonetheless, this -- 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 time to relapse or risk reduction, that would pave the way to a U.S. submission. And we're likewise encouraged by the fact there was a interim analysis in October 2024, where it was a futility analysis where the independent data safety monitor 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 about -- more about the study, and this is some new information here, where we really targeted in 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 so you're up with some sites in Western Europe, U.S. and Canada. You can see the inclusion criteria in the right -- left, excuse me, again, targeting that population that we saw an effect on in our Phase II study in the EMPhASIS study, specifically looking for early active patients that had met the diagnosis of relapsing MS for the [indiscernible] criteria as well as the leveling 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 ENSURE to the EMPhASIS population. We have patients with similar age and gender as well as the distribution of [indiscernible]. And interestingly, about 50% of the patients have received a prior treatment. So we'll be able to see very nicely whether those who are naive to treatment versus those who received treatment, how vidofludimus does perform in those patients. But importantly, when one looks at the EMPhASIS study, the patient population there and the patient population and ENSURE and one figure does what we've seen an EMPhASIS encourage us about what we're going to see in ENSURE, it certainly does. This is about as close as you can get to confirmatory studies. Now when we are deciding on endpoints, as I mentioned, time to first relapse is the endpoint for the reasons I've outlined, but we also include a variety of secondary endpoints that allow us to further understand the effect that the plus 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 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 mainly 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 a 12-week confirmed disability improvement. We've been very encouraged in our phase 2 studies on progressive MS, which you'll hear about it 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 are -- 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, we are on track for 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 derisked as it can be with a robust Phase II study and endpoints in Phase III that are comparable with alignment with the regulatory authorities and the precedent behind us on our endpoints. And that really 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 Stephen Krieger. Dr. Krieger, who's a Professor of Neurology [indiscernible] School of Medicine at Mount Sinai Hospital in New York. He graduated from Columbia College and received his medical degree from [indiscernible] 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, which you'll hear more about today. Dr. Krieger is best known for proposing a topographical model of MS and novel visualization of the MS clinical course. And it's my pleasure to turn it over to Stephen. Thank you.

Mike, I appreciate it. I hope I 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 vidofludimus calcium. What I'm going to do is step back a little bit and speak from the perspective of 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 this 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 -- 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 in those perspectives that we're looking at every day, and I'm going to try to bring some context to that. And in intro, Mike mentioned the topographical model of MS. It's my life's work, and I'm going to summarize it for you in 1 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. 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 model intended to do. So when we think about lesions and MS, new T2 lesions, some of our main outcomes as you heard in our early trials in Phase II trials, lesions are often in the cord, the infratentorial compartment or the hemispheres of the brain. We compensate for lesions, but our ability to compensate is different depending on where those lesions are. So lesions in the spinal cord in the optic nerve cause symptoms lesions like these in the hemispheres are often subclinical below the clinical threshold a useful measure in our trials for disease activity. But when lesions form in the spinal cord of 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 just toehold 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 super imposed. But as time passes, that threshold drops the brain atrophies and so much of the disease burden gets revealed above the threshold as PIRA, most of the disability that accumulates is progressive. And even though we're here talking about relapsing forms of MS, this is happening early on in relapsing 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 relapses almost as an end in themselves. Now we can think of it as treating relapses as a way of shutting down acute inflammatory disease. That is something we've become very good at. as I'm sure all of you know, with the advent of high efficacy therapies in 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 PIRA. It is revealed for us that even though we can prevent relapses in 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. The EDSS of 0 has been defined as normal for 40 years in our field. And when we did a study here in Mount Sinai looking at that a couple of years ago, we challenged our patients with more difficult physical paths harder than what we do on a conventional nerve them and found there are signs of weakness imbalance incoordination, fall risk right from the beginning of this disease, right, from EDSS 0. So we talk about the clinical threshold. I really like Dr. Bar-Or's way of showing that you place the thresholds 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 is some data to support that. PIRA, this gradual progression starts out early in the course of relapsing disease from this project from [indiscernible] and colleagues found that 8% of the cohort of relapsing MS had PIRA within 5 years. And 25% of them across the period of follow-up at PIRA. These are not people who are 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 nomenclature has often provided to people living with the disease. The risk of PIRA causes a 26x higher risk of accumulating significant visibility and EDSS 6 is someone needing a came over the years that follow. And remember, people during their 30s. So meeting a [indiscernible] within years of diagnosis, is an unacceptable outcome that we're endeavoring to prevent. Mike Panzara pointed out this [indiscernible] Voice of the Patient report, which is what we're listening to in practice every day. Patients telling us that they're worsening even when we don't see new relapses or lesions, but 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 Lublin using a massive data set that combines both the real world and clinical trial outcomes. Here's what disability in MS looks like. This was published in brand a couple of years ago. In blue is PIRA progression, in teal are relapses associated worsening. In relapsing MS, there's both. In forms of MS that we conceptualize as progressive SPMS and PPMS it's all PIRA. 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 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 OPRA, which is the oprolizumab versus INTERFERON pivotal trial from a decade ago, disability accumulated, of course, more in folks on INTERFERON and on ocrelizumab, most of that disability was PIRA in both groups, relapse associated worsening with small, even for the interferon-treated patients, Nonetheless, relapse associated worsening is attenuated by a high efficacy therapy that stops or 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, do not working in the central nervous system, and they're not working to do any sort of restorative technique. And so PIRA is going to creep in even in the setting of keeping in my language, the disease topography flat because some of that disease topography is already forged. 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 on to 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-cell depleters for 5 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 these 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 study found 11% of prevalence of hypogammaglobulinemia on patients on B-cell 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 think that they're going to be honest to the rest of their lows. I say, think of this as a 5- 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 have been on B-cell depleters for 5 to 10 years, are going to have to look to what happened after that 5- to 10-year plan. We care about low immunoglobulins because there is emerging data that it does track with an increased risk of infection. It's a predictor. So this is a single looking at 238 patients treated with ocrelizumab for 6 years -- up to 6 years. the drop in immunoglobulin 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, so relatively small but higher in the people who needed -- who had rather low immune module. Patients who needed [indiscernible] antibiotics, thankfully, this is a small number. But again, you see the risk is twice as high for people whose immune globulins have already started to drop. And 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 factor here in this project and factored into the regression model. But the other thing that's happening to our MS population is their 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 and people were 60, 70 and 80 years old. I'll take a step out of the B cell of leaders 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 had say, 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 agent for MS, which was fingolimod. And the S1P modulators brought with them a lot of potential side effects and adverse events and monitoring that had to happen upfront. It wasn't what the MS community was sort of expecting from having a pill. And I think that as we've now had pilled in various forms, prorates, S1P modulators, Teriflunomide and also oral cladribine over the last 15 years, we've gotten a sense of that complexity of some of our oral agents. With the fumarates, there are issues relating to GI tolerability and flexing. Our S1P modulators, now it's a whole class of them, still require a thoughtful consideration of cardiac comorbidities concern from macular edema, concern for infection, concern for liver issues. Taraflutamide has long been associated with alopecia as well as pregnancy and family planning concerns that, that has been an issue for the big cohort of MS patients or of child-bearing age and potential. And oral cladribine, which has now been out for about 5 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 is also true in that NMS asset 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 perspective, 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 Eflux that people are going to come off set 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 to think beyond the immune system itself. We've had great success with the peripheral immune system. But MS is a disease of the central nervous system. We need things that act within the central nervous system to try to address some of those unmet needs. 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 vidofludimus calcium has a niche that it could fill because it works on both a strategy that can address active inflammation and relapses. It works on a strategy at this point, untapped through NEURON 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 joining today.

Excellent. Thank you so much, Dr. Krieger, and good afternoon. My name is Jason Tardio, the President and Chief Operating Officer here at Immunic. 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 vidofludimus calcium in relapsing MS. The main takeaway that I want to establish, and Erik alluded to this earlier, is that the relapsing MS market is a large dynamic market where treatment decisions are highly individualized and patients frequently move between therapies over the course of their disease and over the course of decades treated with disease-modifying therapies. We believe that this creates multiple opportunities for differentiated therapy like beta plumes calcium during the course of a patient's overall journey. Next slide, please. As we heard today, despite having more than 20 proof of therapies, significant unmet needs remain. We see 3 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 the vidofludimus calcium given its Nurr1 activation could do just that. The second unmet need is safety. We know DMC's carry meaningful safety trade-offs. This includes serious infections like progressive multifocal leukoencephalopathy, increased risk malignancies, increased risk of pad and liver toxicity. And the safety considerations become increasingly important as patients age and accumulate comorbidities. And the third unmet need is tolerability. We just heard this for better premium. Side effects remain a significant reason why patients discontinue therapy. And if patients discontinue therapy or is unable to take the therapy, they're not going to benefit for the potential efficacy of that respective therapy. In fact, in one real world study, upwards of 50% of patients on Gilenya and close to 70% of patients on TECFIDERA discontinued therapy due to tolerability issues. This is a real issue, and we'll talk about the importance of that to patients in just a moment. So despite tremendous innovation in MS and, 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 in a very large and growing market. The U.S. relapsing MS market is approximately $17 billion a day 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 all remember 1 slide from my presentation today, please remember this slide, the relapsing at this market is not a winner-take-all market, but rather as 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 in terms of safety concerns, they switch treatment because they're having tolerability issues. And treatment strategy has evolved as patients get older, Dr. Krieger, again, just alluded to. Importantly, there's not a single disease-modifying therapy that optimizes every attribute for every patient and every stage of disease that can stand decades. So vidofludimus calcium does not need to be the answer for every patient, but rather it needs to be a compelling answer for the right patient at multiple points along their journey. Next slide, please. 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 2 KOL academic clinicians today. But MS specialist 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, prescriber can differ between general urologist, academic KOLs and individuals treating within a community setting. Commercially, that means there is not one single relapsing MS patient or 1 single prescribing algorithm, and differentiated therapy needs to offer a clear value proposition across identical patient segments and physician types, and we believe vidofludimus calcium has the potential to do just that. Next slide, please. One assumption that's worth challenging is that MS treatment selection is simply an efficacy haerarchy. It is not -- when physicians were asked directly about attributes that matter most with selecting a disease modified therapy and MS, safety actually rank #1, 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 vidofludimus 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 EMS for decades and therefore, will be treated for decades with disease-modifying therapies. They obviously want disease control. But they also care to believe that a therapy that makes the therapy makes so 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 vidofludimus 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 Nurr1 activation combined with [indiscernible] anti-inflammatory effects through selective DHODH inhibition. Second, safety. Based on the clinical experience to date, we believe telephones Houten has the potential to reduce some of the important safety concerns associated with currently marketed and potentially future DOTs, including hepatotoxicity, serious infections and lymphopenia. 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 for beautiful discounting will come from the totality of its profile, the mechanism of action, the efficacy, the safety, the tolerability and the convenience. And given all this, we believe vidofludimus 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 3 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 all therapies. Second, patients who need to sequence away from anti-CD20 therapies. This includes patients facing cumulative safety or tolerability concerns where 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 relapsing disease are age 55 or older, where the benefit-risk equation can change meaningfully as patients get older, these are large clinically recognizable patient populations. And importantly, they're not mutually exclusive. And older patients sequences away from a CD20, but 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 prefer 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-modifying therapies. And there's practical reasons why patients choose an oral. Many are looking for convenience and flexibility or simply prefer oral treatment over injections or infusions. This may include patients that have needle inversion 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 in oral disease-modifying therapy today will just continue the 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 vidofludimus calcium can deliver that balance, we believe it can become attractive option within the oral disease-modifying therapy class. Next slide. The second opportunity is sequencing away from CD20 therapies. We know that CD20s are highly effective and have transformed the treatment of MS, but not every patient can or should remain on chronic broad, B-cell depleting therapies indefinitely. As Dr. Krieger alluded to with longer anti-CD treatment -- the CD20 treatment, the immune system can become increasingly weakened over time. We know that in a real-world study of arcolizmab treated patients, about 1/3 developed 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. This cumulative immune consequences matter because patients discontinuing CD20 therapies often because reoccurring affections, low IgG levels or other safety concerns still require an effective follow-on treatment that can preserve disease control without compromising new 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 1 year and approximately 15% use extended interval dosing, potentially reflecting efforts to manage infection risk and treatment burden. There is also another important consideration profound relapse suppression does not eliminate disability progression. Approximately 20% of OCREVUS treated patients may experience PIRA within 2 to 4 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 vidofludimus calcium could potentially play an extremely important role. As a non-immunosuppressant oral follow-on option designed to preserve disease control while reducing the new 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 a lasting MS today in the United States are aged 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 the 50s and 60s, the biology and therefore, the benefit risk discussion begins to change inflammatory activity diminishes with age, while immuno senescence infection susceptibility and comorbidities increase importantly. For some patients that shifts the benefit with equation away from indefinite use of immunosuppressive therapies and more importantly to a medicine like vidofludimus calcium that is an immunomodulator. Older ages 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 vidofludimus calcium. They 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 continue 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 dip over with age. Third, despite more than 20 approved therapies, meaningful unmet need remains, particularly around PIRA, around disability progression around the need for safer and more tolerable agents. Fourth, treatment decisions are not solely based on efficacy. Physicians and patients make treatment decisions based upon the overall benefit risk profile of a medicine. And this is where we believe vidofludimus calcium could be differentiated. Vidofludimus will deliver strong efficacy by combining its dual Nurr1 and DHODH mechanism with oral convenience and a potentially very favorable safety and tolerability profile. We see multiple underserved large populations that we think will be very appropriate for vidofludimus calcium. This includes patients who prefer oral therapies, patients that need to sequence or switch away from the anti-CD20 class and the large and growing population of older individuals with MS. 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 in medicine that will have significant impact on and the reduction of MRI regions in medicine that we think offers the best in disease safety and tolerability profile. We believe that, that medicine in vidofludimus calcium has a potential capture of meaningful sales in what is a large and growing U.S. relapsing market today. Thank you. I'll conclude with that.

Perfect. Jason. In the interest of time and the fact that these slides are available, I'm going to zip through my close so that we can take advantage of the panel and take some questions. Jessica, if you could just slip, 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 mean I just go to the close here. The main thesis here you've heard a lot on the science, you've heard a lot on the clinical data that we have. You've heard a lot on the unmet needs and where we think vidofludimus has the potential to fit in. I'll just close with near-term catalysts that are lapsing 2 large Phase III studies reading out at the end of the year. We're tracking to that deliverable, focused on a readout and should the data support it 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 III study and 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 put actually 2 more slides, just the the last slide, because I want to make sure -- one more, Jessica, please. I just want to make sure that everyone is aware, we will be having another one of these days on November 5, to really focus on Progressive. So Progressive is a hugely exciting and important part of the Immunic and vidofludimus calcium story. And so importantly, we thought it was worth breaking out into a separate session. So please join us on November 5 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 with that, I want to flip back over to Jessica to take us through some Q&A.

Yes. Thank you, Erik, and thank you for all our speakers for these wonderful and interesting presentation. As Erik said already, I would like to open the session now for your questions. In the interest of time, we are a little bit over already. We will prioritize the questions for our 2 experts here and take those questions first. And I actually see a lot of questions here. So I will start with Paul Matteis over Stifel, who submitted a couple of questions in writing. I know he's in transit right now. For our 2 KOLs, can the KOLs comment on how they would position video [indiscernible] versus how they think about the positioning for oral BTK drugs. Who's the right patient or patients for each. And Amit or Stephen.

I'm happy to take a first stab. It's Amit. 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 III data in both relapsing and hopefully progressive to really know. But that said, we have high efficacy therapy for relapsing MS. We want to control relapses very, 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 at the very beginning. So across the whole range, if you had a sufficiently safe therapy and if relapses could also be well controlled. What strikes me as very important is the high retention, the unusually high retention with what you've seen in the open-label extension. There are 2 reasons for people not to be retained. One is tolerability. But the other is a sense that their disease is not sufficiently well controlled, whether it's relapses or progression. So yet to be proven, but I think promising. And I would make the point that when we introduce people to a new diagnosis, I refer to it now as the new MS. One of the things that makes it the new MS, of course, is that we now should be able to control relapsing disease extremely well. But the other is that the notion of what treatment to start is not a decision as it used to be part of [indiscernible] this is for life. And as was pointed out already, we don't need to think of any given treatment decision as retreatment 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 forever and not only in the context of being on it for too long to subject people at risk later in the disease course, but that you -- after several years, 2, 3 years or so of high efficacy therapy, you may not need that to control the relapses and the therapy that has anywhere between a modest or a moderate effect of controlling relapses but has the added value of impacting 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.

Stephen, I think he's going to add.

Oh, I'm sorry. I was too quick.

No, that was a wonderful answer. I would add only well, but I'm supposed to give a talk at ECTRIMS about where to use the BTK inhibitors in the current therapeutic landscape, and I haven't figured out what I'm going to say yet. So I'm working on that. But one of the challenges is the promise of the BTK agents was to accomplish in essence, what we're talking about here, but the data didn't take us there. So the data for evobrutinib didn't show superiority for relapses, the data for the GEMINI trials and tolabrunib also didn't show superiority for relapses. So the story to use for relapsed control is not there across the board and the progressive data is really mixed and so we're not talking about nonrelapsing progressive disease in this program. That's the only thing that we have a successful trial for tolebrutinib and and that didn't garner approval here. So I think that if anything, the complexity of the data, particularly the safety data with the BTK inhibitors, doesn't get in the way of the the benefit analysis that you've heard here today for one.

Thank you, Stephen. Thank you. We have another one for our 2 experts, Actually, a similar question from 2 attendees here from [indiscernible] Life, what is the bar for a clearly positive outcome in ENSURE-1 and 2? Is it important to hit that take on EDSS? Do we need a certain effect size on plan to pursue that. And then Sam has a similar question. What do you see as a win in the upcoming Phase III RMS readout as you consider the current unmet need.

Do you want you want to kick it off?

Yes, if I can certainly give it a shot. I mean I think that 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 Phase III trials to date, including in progressive MS and relapsing MS and the notion that we are still struggling as a field, finding the best outcome measures to capture that, the populations, et cetera. we've come to realize that impacting the stability progression is something that we very much like to see but would not necessarily insist on saying. And I think the extent of benefit on relapsing disease activity even a moderate effect from a drug that looks to be safe and has the additional promise as vidofludimus calcium to be would be pretty compelling.

I think that's quite right. And at the end of the day, the goal is to prevent disability accumulation in all of its forms, either relapsed directly associated or there's more delayed in serious 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, they have to hit that, of course. But if we saw a disability endpoint and could point out the extent to which this mechanism attenuates disability even beyond or in the absence of relapses, that could really give us a clue as to what the long-term consequence of this strategy could be and make sure you can't see 10-year, 15-year outcomes in a 2-year trial, but you can see the change in trajectory. And that glimpse is very, very beneficial for our field.

Thank you, Stephen. Amit. I have one more for you -- or actually I have a couple of more, but I want to be mindful of your schedules. 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 proved that a drug is beneficial on PIRA?"

Well, I'll pop in there and so that's where this determination of whether disability occurred consequent of relapses or independent of relapses helps to make that determination. The EDSS is what the regulators require we all in our field, recognize that it'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 scale, -- and 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 0. 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. Yes, I would agree with that.

I mean I think that showing an impact on disability progression and the patient population that has potentially relapsed contribution, it 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 evident, subclinical evidence of focal intimate disease, which is the relapsed 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 this will be the -- to Amit's point, the ENSURE 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 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 insurers studies will be a meaningful advance in our understanding of the clinical impact of vidofludimus calcium on progression. But it will answer all of the questions, and that's why we're prepared to sort of pursue them even further and beyond ENSURE only to.