To the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Vigil Neuroscience, and it's a pleasure to introduce Ivana Magovčević-Liebisch. It's correct? All right. Good. Good job. And, David Gray, our CSO. So, CEO and CSO. Thank you. Welcome. You know, let's start off with an introduction of yourselves, you know, a description of the company, and why Vigil was founded. Sure. Thank you so much, and thank you, Cantor, for inviting us- Mm to share the Vigil story with you today. So Vigil is a clinical-stage microglia-focused therapeutics company. The goal is to discover and develop novel therapeutics to treat both rare and common neurodegenerative diseases by restoring the vigilance of microglia, which are the sentinel cells of the brain immune system. Actually, microglia are responsible for the health and well-being of the brain, and they control a number of neurological functions to prevent neurodegeneration. So you ask how Vigil was formed. We're a very young company. We've been around only four years. It was formed in 2020 in partnership with Atlas. What happened is actually that Amgen decided to exit neuro at the end of 2019, and they had these two very exciting assets, TREM2, that were high quality. And on the other side, there was a long-standing interest in TREM2 because we know through GWAS analysis that TREM2 is the second highest risk for Alzheimer's disease. Amgen also liked these assets, so they didn't want to just outlicense them, and so we decided to form the company, and that's how we got started. I think there is a couple things that really differentiate us from others in the space. First is we have a precision-based approach to neurodegeneration, and what I mean by that is that we have, we work on indications where there is a very strong genetic, mechanistic, and biochemical association to microglia dysfunction because we strongly believe that that reduces the downstream translational risk and also allows us to get to that proof of concept quickly. The other thing is that we're the only company that has two TREM2 modalities. So we have both a fully human monoclonal antibody and a small molecule, a first-in-class small molecule TREM2 agonist, and what that has allowed us is to be very thoughtful and strategic on how we build our pipeline. So right now, our antibody, which we'll, I'm sure, talk more about, iluzanebart, is in phase II for a rare genetic disease called ALSP. The reason we chose that disease is because it checks a lot of those boxes that we just mentioned, and then we have this first-in-class small molecule TREM2 agonist currently in phase I for Alzheimer's. We had a very busy summer this summer. A lot of things, very good things happened for Vigil. First, we had a very productive meeting with the FDA around our ALSP indication, where the FDA actually opened the door to accelerated approval and potential for MRI to serve as a surrogate endpoint. We'll, I'm sure, talk about that more as well, and then in our phase I trial, we actually released interim data around our small molecule, and everything that we've seen so far supports continued development, and then also, very importantly, we forged a very exciting partnership or strategic relationship with Sanofi, where Sanofi invested $40 million in the company for a right of first negotiation on that small molecule program, so really exciting summer that I think has positioned us well for next year when we'll have the data on phase I from the small molecule. In the first quarter, we'll also have a final data readout for ALSP. And one thing that I didn't mention is that that $40 million from Sanofi also extended our runway into 2026. So we have the opportunity to see these important milestones, and they have sufficient cash beyond that. So I think we're in a very good position right now. I'm very excited for next year. Excellent overview. Thank you. So, you know, let's get into your program. I think you called it IIluzanebart. I was gonna call it lluza, but, Iluza and iluzanebert, yes. I'd just make it iluzanebert. It's easier to pronounce. Yeah. And so you- Yeah, you know how these USAN names are. I know. So it's a TREM2-activating antibody. You're developing it for a rare neurodegenerative disease, ALSP. For those not familiar, could you just give an overview of the disease and, you know, just provide the scientific rationale for TREM2 activation? Sure. So I'll give an overview of the disease, and then I'll let David talk about the scientific rationale. So ALSP stands for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. It's a rare, neurodegenerative disease. It's fatal. It hits in the prime of adulthood, and from symptoms to loss of ambulation is about two years, and from symptoms to death is six to eight years, so very rapidly progressing. No treatments available. The reason we really like this disease, because remember I said we are interested in a precision-based approach, is that this is a monogenic disease. It's caused by mutations in the CSF1R, which is a receptor that sits on microglia, and those mutations have a direct impact on the number and function of microglia. So when there's a direct correlation between the mutations, the loss of function, and the... what we're seeing. So, with that, I will let David tell you. Yeah ... about why we think that TREM2 agonism is the right way to go. ... So as Ivana mentioned, it's very clear that ALSP is caused by microglia dysfunction. They're not, you know, they're compromised in both number and function, and so that's the fundamental goal, is to restore them to activity. But because the mutations are in the CSF1R and compromise that entire protein structure, what we've looked at is how do we get around that, and how do we circumvent that? And it turns out that TREM2 is also expressed on microglia and shares a common downstream signaling element with, with CSF1R, that allows us to compensate for that deficient CSF1R signaling by activating TREM2. And we've been able to demonstrate that through a number of in vivo or in vitro studies, where we've shown that there's a very nice ability to do that compensation across a number of different models. Importantly, also, there's some clinical linkage between these two. So in addition to ALSP, there's a clinical disease known as Nasu-Hakola, which is loss of function in TREM2, and that disease looks very similar in both onset and disease presentation to ALSP. So we have clinical symptomatology that links these two diseases, and then we also have a really robust amount of evidence that indicates that. I'll just briefly mention, and we might get into it later, that you know, we have clinical data now from our phase one- Mm-hmm. and initial look at our phase two and in those studies, we've been able to show changes on a couple important biomarkers. Notably, one that I'll mention is on CSF1R. So we've been able to see an increase in CSF1R, in soluble CSF1R levels in the CSF after dosing with iluzanebart. So all of this is really going to show that this hypothesis of sort of solving this issue by going through TREM2 looks very promising. All right, excellent. So, you know, so I guess part of pioneering drug development in a rare disease, especially neuro, you know, there are many unknowns, you know, and there are many variables that could influence clinical outcomes in terms of a clinical study, and you know, I guess one of the key things is to map out the natural history, you know, which you did. I believe it was called ILLUMINATE. So just, you know, walk us through the data from that and the key takeaways. Yeah. So ILLUMINATE, to your point, is the first natural history study in this patient population. We actually started it now three years ago, so we've been amassing tremendous amount of data around the patient journey, but also how different biomarkers and clinical endpoints behave in this patient population, 'cause obviously, we didn't know that, to your point. So now, three years in, we know that for example, MRI is an excellent biomarker. We've now seen that there is statistically significant correlation between, for example, increase in ventricular volume and a decrease in cognition, which are exactly the kind of things that you know, an agency would wanna see if you're gonna try to use one of these biomarkers as your surrogate endpoint. We have also learned, to David's point, that soluble CSF1R is markedly reduced in this patient population, so it really serves as a biomarker of disease pathology, and then we are also seeing a very significant increase in NfL in this patient population. Again, that's a biomarker, as we all know, of active neurodegeneration, so we learned a lot about that. We know that some of these biomarkers move very quickly. For example, MRI, we can actually see quantifiable changes in, for example, ventricular volume, you know, brain atrophy in as little as six months. Okay. So we can actually see those quantifiable changes. We see them as very... They are objective, very easy to measure, they're consistent, and that's why now MRI is kind of elevated to the biomarker that we think, makes the most sense to continue to follow in this patient as a primary, correlation to the disease progression. The other thing that we've learned from this study, too, is that, soluble TREM2 levels are unchanged between healthy and symptomatic patients. Again, very important when you're gonna use a TREM2 agonist. And as I mentioned, NfL is highly available. On the clinical endpoints, we know that it takes longer for those. It takes at least a year to start seeing a separation on the clinical endpoints, which again, you know, shows why it's so important to use biomarkers in this patient population. Anything else, David? It is. I'm glad you asked about the natural history study because I think that is sometimes an underappreciated element. When you're in a new disease, you have to understand what really is the right way to measure if we wanna bring this to patients quickly. This, I mean, Ivana hit on all the key points. Basically, we need to know what we can measure in a short enough period of time, where the disease hasn't progressed, you know, too significantly, and I think it's remarkable where we're at right now. Yeah. I mean, it's important, natural history studies. You can see it for FTD, right? GenFI, you know, the consortium or... You know, they mapped out completely- Yeah ... you know, from pre-symptomatic to symptomatic, which is my question here also for you. Do you have like, what's the frame of patients that you have? Are they actually asymptomatic, you know, going through symptomatic, or are you just capturing as they begin?... in terms of the natural history? So the natural history has both prodromal and symptomatic patients. So we are actually looking at both. We know that patients actually don't stay in that prodromal state very quite long. It actually, because I said it's very fast progressing, that changes very quickly. And usually what we see there is that there is a real spike in NfL- Mm-hmm. and there is a meaningful loss in cognition, and from there, then it's all, it's kind of all downhill. Yeah. But in our phase II study, the other importance of the natural history study that I didn't mention is, in our phase II study, we have actually transitioned some of the patients from the natural history study into the phase II, so they can serve as their own controls- Yeah ... because we collected data on them prior to putting them on drug. The other important aspect of the natural history study is we really want to position natural history as a synthetic control arm. So you can think of ILLUMINATE as a cornerstone of our clinical development strategy. So important. Very important. So I guess, moving on, you have a phase II proof of concept, IGNITE. You just mentioned it. Just, you know, provide an overview of, study design and, you know, the outcomes- Sure ... that you assessed. Yes. So it's an open label, phase 2 study. Twenty patients enrolled. These patients are all mild to mildly moderate in their disease progression. We administered the drug monthly, IV, and we're measuring all of the biomarkers that I mentioned, as well as some clinical endpoints. 12 months in duration, and we had our first interim look, which was six patients at six months. The reason we looked at six months is because what I mentioned to you, that we actually can see quantifiable changes in MRI as early as six months. So we were very encouraged by what we saw in those six patients. Obviously, small time duration, small ends, but what we saw in patients who had progressive disease is that there was a slowing of progression across all of the biomarkers, and we're actually starting to see, even at six months, that NFL is starting to go down. We know that NFL is gonna take a bit longer because it's, you know, it's microglia is not on target necessarily. This is a biomarker of neuronal degeneration, so as in some other diseases, it takes a little bit longer, but we're certainly starting to see that change as well. So we were very encouraged by that, and that's actually the data we took to the FDA, as well as our natural history data, when we had the conversations around potential for accelerated approval. Yeah, I mean, time to NfL response definitely does vary across different neurodegenerative diseases. And so when you went to the FDA, what were they most interested in? I guess- So the focus of the conversation is around the MRI. We think- MRI. Because what happens with NfL in this patient population, it spikes, but then it stays high, right? It's not a dynamic biomarker, where MRI is a very dynamic biomarker. It. You know, you can still continue to see a continuous regression, right? The ventricular volume increases, the overall brain atrophy is happening, and it just continues to go down. Where NfL stays, you know, very high, and then once, unfortunately, most of your neurons are gone, it tends to go down. So we think that MRI is the right biomarker in this patient population, and so the focus of the conversations obviously will be a totality of the data, but MRI is what we see as the most important biomarker, the most consistent and most dynamic biomarker. Okay, and you did mention that you had patients in the natural history, and you flipped them over. Mm-hmm. You know, what are the differences that you saw there? So we do see those patients when we look at their curve, and we project how they would continue to progress. We are seeing a slowing of progression in those patients, for example, on ventricular volume and gray matter volume as well. Anything else you wanna add, David? I mean, it's a small data set, and I think that's one of the things. You know, we're still learning some things. Mm-hmm. I'll just give you one example of that. In the study, we enrolled per a certain criteria, which is a clinical criteria of having symptoms and MRI evidence of progression. It turned out that a couple of people we enrolled were, you know, really kind of early in terms of not having substantial levels of NfL and not having, you know, substantial cognitive impairment. Now, they had other symptoms that qualified for them, for the study, and what we noticed is that there are some differences in the way that those patients responded- Mm ... to iluzanebart compared to the ones that were in the more classic, advancing- Mm-hmm ... aggressive ALS stage. And specifically, during the six months, we didn't see changes for on NFL or on MRI for those, you know, within a measurement for those early kind of, you know, early stage of that disease, which is potentially very, very encouraging. So given that we know this disease tends to progress very rapidly and that there isn't a long residence time in this prodromal phase or in this early phase, being able to maintain somebody in that phase would be tremendous for the disease. And so we'll continue to follow them. Now, it's not, you know, most of the patients we have are in the more progressive classic ALSP, but that's an example of something that you don't necessarily know going into the study that you're gonna see that. But, upon looking at the data, we think about those two groups a little bit differently. It's an experiment. Yep. So I guess we'll get a look at those patients in our first one Q twenty-five, I believe, correct? It's the first half of 2025. Yes, we'll do the final analysis. And then, how many patients in each dose group? It's 20 patients. I didn't mention actually, 2 doses, 20 and 40. We haven't actually disclosed the flip, but we have a nice number of them in 20 and then a very nice number as well at 40. We'll be looking at both at both groups at 12 months out. That's the final analysis. What can we expect to see? Like, in terms of, you know, outcomes. Yes. So obviously, the drug I did mention is doing great in terms of safety and tolerability at both doses. So that's been great to see. But what we're also gonna be looking at is do we see to continue that slowing of progression? So that's going to be really important for us on MRI. And then, as you know, for accelerated approval, you also like to see the totality of the data. So obviously, we'll be looking at NfL as well. We'll be looking at, you know, soluble CSF1R. We mentioned that, you know, we get soluble CSF1R to increase in patients on drugs, so that's going to be important. And then we'll be looking at some clinical endpoints as well, but we recognize that that takes longer. Yeah ... and we know that from our natural history data. All right. And, from the healthy volunteer study, is there anything from that study that suggests that you may actually see a different response between the two different doses? So not necessarily from the natural history study, but when we looked in our phase one, and we looked at some of these biomarkers. Sorry. Yeah, it's okay. Did I say natural history? All right. That's all right. No worries. I think I knew where you were going. So in phase 1, when we looked at the doses, we know that both 20 and 40 milligram were pharmacologically active. We didn't really see a big difference in biomarkers. However, in phase 1, there was very slight elevation of soluble CSF1R in healthy, which is to be expected. What we saw in IGNITE, in our phase 2, is that actually we can get that soluble CSF1R, you know, 30% higher with 20 mgs. Mm-hmm. So there is potentially an opportunity to push that further, even though we didn't see a difference in the healthy. Okay. That's why we actually did two doses, and one reason is obviously, we wanted to make sure that we understood what happens in patients, but also we know that, you know, the likes, the dose, you know, those response studies. Yeah. So that's why we included two doses. Okay, and what's gonna enable movement forward? What do you wanna see to say yes? As I said, if we continue to see slowing of the progression and movement on these biomarkers, absolutely, we plan to continue. Okay. So I guess, let's move on to your small molecule 'cause we only have about eight minutes left, so you have a small TREM2 agonist. You know, you're developing it for AD, you know, again, scientific rationale for targeting TREM2 in Alzheimer's. Absolutely. David? Yeah, so I mean, TREM2 is the, you know, just really a focus of a huge amount of data recently that points to microglia as being, and specifically dysfunction, as being implicated in a lot of neurodegenerative diseases, definitely Alzheimer's, and in the case of TREM2, it is the loss-of-function mutations that exist in TREM2 that were first identified in Nasu-Hakola disease, and since then, we've had additional biomarker data that also links increased levels of TREM2 to being protective, and so on, so we have a lot of data that points to the fact that you want to increase TREM2, and the question is, well, why would you want to do that, and that's because microglia, remember, they're the brain's immune system, kind of in a single cell. They are both the surveillance cell, but also the responder, the first responder, and kind of the workhorse. And so what TREM2 does is it senses damage and then signals to those microglia to convert into a more neuroprotective state. And through our work and others, we've shown that that neuroprotective state has a broad number of effects, which are beneficial in a neurodegenerative setting, and that includes effects we've shown in vitro on astrocytes, markers of degeneration, like GFAP, for example, decreases in NfL and in tau that are relevant to neurons, and then also broad anti-inflammatory profile across a number of inflammatory cytokines that can be also associated with damage. So microglia in this neuroprotective state also interestingly, the approved immunotherapies that we have, it's the microglia that clear the plaques. They are the ones that are doing the phagocytosis of these plaques. And so, you know, to really answer your question, the rationale here is that we know that decreased TREM2 is bad, increased TREM2 is good in the context of Alzheimer's. And so through a TREM2 agonist, we aim to convert more of those microglia into a neuroprotective state and help the immune system to combat the neurodegeneration. Okay. You know, you did announce, I think it was this week or last week, that you had a clinical hold lift. So just give the story behind that, partial hold? Yeah. Just the story behind that. Yeah, we're very obviously very excited about that because now we can, you know, explore the full pharmacology of the molecule. Even with the hold, that didn't slow us down in any way. As you saw, we released really exciting interim data from that phase one study. But David, anything else you wanna add? ... No, it didn't actually slow development. So the partial clinical hold that we were sort of working on with the FDA, we ultimately submitted clinical and preclinical data, and we're able to fully align on where we are at with exposure count. But it didn't have to do with toxicology. It had to do with- Exposure ... exposures we could achieve in different studies. Okay. All right, I guess, you're in the middle of a phase I healthy volunteer study. You know, you recently presented the interim data from the SAD portion, I think, at AAIC. Mm-hmm. You know, just walk us through that data? Yeah, why don't you go ahead? Yeah. So in brief, you know, we shared some we continue to really kind of understand our profile. And one of the things that we shared, the high-level safety, tolerability, PK, all continue to support development of the molecule as a once-daily oral therapy. We projected it to have excellent brain penetration, which we've been able to confirm. We projected it to have, you know, all these rest of these properties, which so far we've been able to confirm. And then importantly, we have access to this really wonderful biomarker in soluble TREM2, which gives us, within the brain, by measuring in CSF, we're able to look at not just target engagement, but also a functional target engagement. Because the mechanism by which TREM2 goes down is part and parcel to the function of TREM2 agonism. What we showed was, as we got into the middle of our dose escalation range in the SAD, we started to see a decrease in soluble TREM2, which is. And then that maintained out through the rest of our dose escalation. The magnitude of that effect was as much as what we saw with the antibody across those maximum doses, giving us, you know, just a lot of confidence that our small molecule is behaving as an agonist, is engaging the target in the brain, and that all of the projections that we had going into it are playing out really nicely. All right. So one question that I have. So there have been longitudinal studies, right, where they show that increasing levels of soluble TREM2 are protective, you know, and slow down movement from MCI into dementia. So the question is, does soluble TREM2 have any pharmacological activity, or is it just a by-product, or? Yeah, no, so that's an interesting connection. The data that you're referring to, soluble TREM2 levels are directly reflective of cellular expression of TREM2. So when in those biomarker studies an increase in soluble TREM2 by correlation means more TREM2 at the surface of cells, that's the source of the soluble TREM2. As of right now, there isn't an established specific biological target for soluble TREM2. You know, some people have talked about it as potentially being helping like kind of a decoy receptor that helps to modulate to make sure microglia don't activate in the presence of small amounts of some of these natural ligands for TREM2. Mm ... that would bind to TREM2. So for example, you don't want the microglia kinda going into a neuroprotective state if there's just a little bit of something. Yeah. And soluble TREM2 could act as a buffer there, but there isn't an established target that would be important for efficacy. Okay. And so, MAD data should be coming soon. Yes. So we are now continuing to execute on the MAD portion of the study. As well as we have started dosing in an AD cohort. This cohort is not about efficacy. This is actually a single-dose biomarker study. To David's point, we really wanna see if we can see some major shifts in soluble TREM2 among different subpopulations in Alzheimer's disease. So we're specifically looking at some of those TREM2 variants, as well as APOE, and then wild type. So because we think that will be helpful to inform the design of our phase II study. Okay. And what's the minimum you'd like to see? Like, which biomarkers, to actually move forward, or you haven't determined yet? You're talking about in Phase I? Moving to a phase II. No, so we as David mentioned, soluble TREM2 is, we think, the most important biomarker. We've as we said, we've already seen a reduction that's equivalent to what we saw with the antibody, which is very impressive for a small molecule, so we're very excited about that. So, we're not using that AD cohort as an indication whether we should go into Phase II or not. We're just trying to figure out should we enrich for particular patient population. Okay, and you have mentioned that, you know, you're going into TREM2 mutations as well as- Yep ... as well as to a, I guess, idiopathic Yes ... for the phase I, are they idiopathic, or are they actually TREM2? In phase I, in that AD cohort, we will have the TREM2 mutation carriers, as well as some other carriers because we're really trying to see are there big differences that we can detect with, like, for example, soluble TREM2, just to help us design the best phase II. There's no reason to think that TREM2 agonist is not gonna work across all of AD. Yeah. If you think about how broadly microglia work, and considering that they're the control for neuroinflammation in the brain, we believe that it's gonna work across the board. But we also wanna make sure that if there is something to learn from this cohort, it will be good to know that as we design the phase II study. Okay. We have run out of time, but one last question: if we're sitting here twelve months from now, what would you like to say, the accomplishments that you've made? Well, obviously, that we've have the phase I behind us, and we are, you know, in that phase II for the Alzheimer's disease, and then on the ALSP, that we have delivered the data and have a clear path to accelerated approval. And obviously, we're very excited about Sanofi and their belief in us and then in our molecule, and obviously, a relationship there will be great as well around, you know, partnership around our small molecule program. Okay, and you mentioned it... So really quickly, which this will be the last question: How are you thinking about it? Are you thinking about completely licensing it out or co-development? No. As you can imagine, something like AD, you do wanna have a partner who has both the expertise and the resources to maximize your assets, so the idea would be a co-development. We're absolutely looking for a partner in this. Okay. Well, thank you very much for coming to the Cantor Healthcare Conference. It was great to see you, and- Thank you so much. ... hope to see you here next year. Yeah. Absolutely.