All right. Welcome everyone to the 41st annual J.P. Morgan Healthcare Conference. My name is Matt Bannon, and I'm a healthcare banker here at JPM. I'm really excited to be setting the stage for our next presenting company, Vigil Neuroscience. Presenting on behalf of Vigil, we have CEO Ivana Magovcevic-Liebisch. I'd just like to remind folks that we will have a Q&A portion following the session, unlike prior years, we'll stay in this room. Without further ado, Ivana. Good morning, everyone. Thank you for joining us, and thank you J.P. Morgan for the opportunity to share the Vigil story with you today. Before I get started, I do wanna highlight three things that we believe differentiate us from other companies in this space. First, and very importantly, we have a precision-based approach to neurodegeneration, which we believe increases the likelihood of success. Second, we're the only company with two TREM2 modalities. We have both an antibody TREM2 agonist, as well as in a first-in-class small molecule TREM2 agonist, which we believe provides us with an opportunity to build a very robust pipeline. Most importantly, we have the opportunity to be the first company to declare clinical proof of concept in a patient population with a TREM2 agonist this year. I will be making forward-looking statements today. Let me start with who is Vigil. Vigil is a clinical stage microglia therapeutics company. Our 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. Microglia maintain health and wellbeing in the brain. They regulate a host of neurological functions to prevent neurodegeneration. What I want you to imagine just for a minute, a world where we have solved for one of the great unmet needs of modern medicine, that is how do we slow down or even better halt or reverse the course of neurodegeneration? How is Vigil tackling this problem? Our strategy is to first develop precision-based therapies for rare microgliopathies to provide us with insights and learnings to then expand into larger indications. We have identified TREM2 as the key regulator of microglia function, and we plan to explore the multiple different indications as well as look as additional targets in this really important area of biology. We're a very young company. We've been around for only 2.5 years a nd, but have accomplished a tremendous amount. We are well-financed with cash into 2025. The reason for our success to date is our team. We have an incredible group of passionate, committed industry veterans who have been executing flawlessly on our strategy, and I have every confidence we'll continue to do that. This slide is an important one. I do wanna spend a few minutes on it because it outlines our strategy, which is our key differentiator. As I mentioned, our approach is a precision-based approach to neurodegeneration. What do I mean by that? What I mean is that we're focusing on indications where there is a very strong genetic, mechanistic, and biochemical association to microglia dysfunction. As such, our first indication is a rare microgliopathy called Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or ALSP. We then plan to expand into other microgliopathies, focusing on genetically defined leukodystrophies. These are the diseases of brain-wide matter, where the blood-brain barrier integrity is compromised, which positions them extremely well for antibody therapeutics. Staying true to a precision-based approach, we plan to expand into larger indications such as Alzheimer's disease, but again, focusing on genetically defined subpopulations. For example, we know the TREM2 variants have a very higher risk of Alzheimer's disease. Taking all these learnings, we then plan to go into broader populations in these common indications. This iterative sequential approach is our key differentiator because it allows us to reduce the downstream translational risk, it allows us to get to the clinical proof of concept very quickly, and it also allows us to apply the learnings as we expand into additional indications. The reason we're able to maximize on this strategy is because we have two TREM2 modalities. As you can see on this slide, we have a fully human monoclonal antibody TREM2, VGL101, as well as first-in-class small molecule TREM2 agonist. VGL101 is our most advanced asset. We're taking it into ALSP. We actually have a first interventional open label phase 2 ongoing right now in this indication. We're the 1st company working in this space, and importantly, the reason we like this indication is because it has very strong imaging and fluid biomarkers, which we believe will get us to that proof of concept, as I mentioned, and have the ability to declare clinical proof of concept this year. On the other side, we have 1st-in-class small molecule TREM2 agonist. These are orally bioavailable, highly CNS penetrant molecules. We're not aware of anybody else who has small molecules in development today, and we believe that this can be a game changer when it comes to large indications such as Alzheimer's disease. Having these two modality allows us to have a pipeline with multiple shots on goal. This is an overview of our pipeline. Just last November, we presented interim top line data from our healthy volunteer study. The study is designed not only to support our ALSP indication, but other indications as well. We also have the first interventional open label study in ALSP patients ongoing right now. I'm very pleased to announce that we actually dosed the first patient just this past month. Not on this slide, but very important, we'll be talking more about it today is our natural history study, ILLUMINATE, which is also going, and it's a first study of its kind in this patient population. We also believe that proof of concept in ALSP will have a read-through to other leukodystrophies, and so we're doing preclinical research in this space as well. On the small molecule side, we are in IND-enabling studies, and we plan to file an IND and initiate clinical studies in the second half of this year. Now let me talk a little bit about VGL101 and its compelling therapeutic profile. As I mentioned, VGL101 is a fully human monoclonal antibody, has high specificity for TREM2 subnanomolar potency. We've also been able to establish in vitro proof of mechanism in human iPSC-derived microglia, where we've been able to rescue CSF1R deficiency, which is the underlying deficiency in the LSP disease by administration of VGL101. We have shown that the molecule is safe and tolerable with excellent PK and target engagement in healthy volunteers. We have established GMP manufacturing competency. We have very strong IP. Just last year, we were granted both the Orphan Drug Designation as well as Fast Track designation in LSP. Why LSP? What's the rationale for choosing LSP as the first indication? We start in the top left corner. As I mentioned, it's a rare, autosomal dominant disease, huge unmet medical need, no treatments available today. It's a devastating, fast-progressing disease that hits in the prime of adulthood at mid-40s. The disease meets all of our precision-based criteria. It's caused by a mutation in the single gene called CSF1R, which results in microglia deficiency, which is the underlying cause of the disease. As I mentioned, we have been able to show in vitro proof of mechanism by rescuing the CSF1R deficiency by administration of VGL101. Importantly, as I mentioned previously, there are imaging and fluid biomarkers for that quick establishment of proof of concept. We have excellent engagement from the KOLs, physicians, and patients for the continued development of this indication. Now let me turn to the biological rationale and to this proof of concept we have in vitro in human microglia. As you can see on the top left corner, CSF1R is a trophic receptor that's expressed on the surface of microglia, same as the TREM2, which is actually the damage receptor. These two receptor signaling converge on the same protein. This is a protein kinase called SYK, which regulates the downstream processing. What happens in LSP as a result of CSF1R deficiency, is that there is a reduction in the number of microglia, which is shown on the top right-hand in a bar graph, and also the reduction in activation of microglia, which you can see in the far right corner, where these rod-like structures, which you see in the cross-section of normal brains, disappear in the brains of the LSP patients. Now on to our proof of mechanism. What we did is we took human iPSC-derived microglia, and we rendered them CSF1R deficient by administration of either a trophic factor or a Plexxikon molecule, which is a known inhibitor of serine protease domain. On the bottom left-hand, you're looking at microglia which have been rendered deficient by administration of Plexxikon. What happens is that reduces the viability of microglia that's shown in yellow. When we administer VGL101, we're able to rescue the viability, which is shown in the magenta bar. On the right-hand side on the bottom, here we are rendering the microglia deficient in CSF1R by removing the actual trophic factor, the ligand CSF1. We're looking now at the activation of microglia. What you're seeing here in cultures is that in normal control cultures, you're seeing these rod-like structures which are shown with white arrows. Those disappear after the trophic factor is removed, and we can restore the activity on the far right, that's shown again with the arrows. You can see those rod-like structures again. This is a very strong proof of mechanism in vitro, which supports the therapeutic rationale for VGL101 in LSP. Now let me tell you a little bit about our phase 1 data. We have demonstrated that VGL1 has excellent safety and tolerability profile. It has PK that's linear and predictable, and also has a half-life that supports monthly IV administration. We have established target engagement in the CSF of healthy volunteers. Most importantly, we're the first company to show in a clinical setting that not only can we engage the target, but we also have a durability of response after multiple administration, which is obviously critical as our phase 2 study is a 12-month in duration. We have also established 20 mgs per kg as our pharmacologically active dose. That's our starting dose in our phase 2 study. As I mentioned, we're very pleased that the study has initiated. Our phase 2 study, IGNITE, we dosed the first patient, as I said, just last month. Now on to our natural history study, ILLUMINATE. As I mentioned, this is a first study of its kind in an ALSP patient population. We have three goals with this study. The first one is obviously to learn more about patient journey and look at the clinical and biomarker assessments that are relevant for this patient population. We also believe that this study could serve as a synthetic control arm for our subsequent trials. Most importantly, the study will also serve as a feeder for our clinical studies. This is a study that's 24 months in duration. We're looking at MRI, CNS biomarkers and clinical assessments. These are the same ones we are looking in our phase 2 study, which we believe increases the likelihood of success. We already have some very encouraging data, MRI data and biomarker data for the use as an efficacy endpoint in our phase 2 study. What you're seeing on the right-hand side is actually an MRI images from a patient. This is a 37-year-old female, and you're looking at her images at baseline and then at 6 months. What you can see is that there is already meaningful changes in her white matter lesions, as well as an increase in ventricular volume, which is the indication of axonopathy, demyelination, and overall brain atrophy. We can measure these already. They're quantifiable at 6 months. The other important thing to note here is that her MoCA score is changed from 15 to 9 in a 6-month timeframe, and this is a first preliminary correlation between changes in MRI and clinical signs of the disease. We're very excited about these findings because FDA has left the door open for MRI to be a surrogate endpoint in this patient population. The reason we're excited about MRI is shown on this slide. Here, we're looking at changes in prodromal versus symptomatic patients at baseline versus six months. Prodromal patients are the ones that have MRI changes but no clinical signs yet. Symptomatic patients are the ones that actually have both the MRI changes and clinical signs. What you're seeing on the left-hand side is already meaningful changes in reduction in volume across different brain regions when compared to prodromal versus symptomatic patients. On the right-hand side, you're also seeing significant increases in white matter lesions as well as changes in ventricular volume at six months. Again, we believe positioning MRI is a very important efficacy biomarker in this patient population. This all comes together on this slide. What you're looking here is at biomarker levels at baseline when compared to healthy volunteers versus prodromal subjects and symptomatic patients. On the far right... Left, sorry, you're looking at soluble TREM2 levels. You can see that there are no changes at baseline among these different populations, which is really important because it shows that there is target for VGL101 to activate. In the middle panel, you're looking at the levels of soluble CSF1R. This is a biomarker of microglia activation. What you're seeing here is that there are already significant reduction in this biomarker, both in prodromal and symptomatic patients, showing that the microglia dysfunction is right there. On the right-hand side, we're looking at levels of NfL. What we're repeating here is already what's been shown in the literature. That is that NfL levels are highly elevated in this patient population. You can see significant increases in NfL level compared to healthy volunteers. We're talking about 12x in the CSF and in the serum of these patients, again, positioning NfL as a good efficacy biomarker for our studies. Just quickly, the design of our phase 2 study, it's an open-label proof of concept study, 12 months in duration. We'll be enrolling up to 15 symptomatic patients. The primary outcome is safety and tolerability, but we'll be also looking at MRI and CNS biomarker and clinical assessments in this patient population. Here we have an opportunity to declare proof of concept at three different points. The first one will happen at six months, six patients, and we believe that any directional changes in the biomarkers will be extremely encouraging. The second opportunity is at six months for all 15 patients, and then the final analysis will be at 12 months for all patients. Before I leave this section and talk to you about our exciting small molecule program, I just wanna wrap up by saying that ALSP represents a significant commercial opportunity. The prevalence of this disease is about 10,000 patients in the U.S. alone. The global epidemiology is similar with about 15,000 patients in Europe and 4,000 patients in Japan. We believe that these are conservative estimates because the disease is highly under diagnosed and misdiagnosed and postponed. We believe that with our efforts around disease education and awareness, we'll continue to improve this, and we believe, as I said, that ALSP represents a significant standalone commercial opportunity. Now let me turn to our small molecule program. We have a portfolio of very exciting first-in-class small molecules. These are extremely well-behaved orally bioavailable, highly seen as penetrant molecules. They have excellent physicochemical properties and PK properties, as well as favorable metabolic and tox profile to date. Most importantly, our small molecules have a differentiating mechanism of action from the antibodies. They actually act as molecular glues to activate the TREM2 receptor by clustering the TREM2 signaling complex. In addition to that, they actually potentiate this response in the presence of natural damage ligands. Despite this different mechanism of action, we have also shown that our small molecules act with a similar potency and specificity as our antibodies in vitro models of Alzheimer's disease. I will be sharing some of that data with you right now. What you're looking at this slide is human microglia, and we are looking at activation of wild type TREM2. You can see on the far left that our small molecules have a low digit nanomolar potency. This is highly specific for TREM2 because if you look at the middle graph in a knockout TREM2 cell line, there is no activation. Most importantly, our small molecules also activate T-TREM2 variants across several different variants. Obviously, this is important for our precision-based approach. As I mentioned, we'll be going into Alzheimer's disease first starting with TREM2 variants and some other variants. How do our small molecules work? Today, for the first time, we're actually disclosing that our small molecules act as molecular glues. They activate TREM2 by clustering the TREM2 signaling complex. What you can see in the middle graph is not only do they activate TREM2, they also have the ability to potentiate the signal in the presence of natural damage ligands. On the right-hand side, you can see human iPSC derived microglia, where we can increase the activation and increase presence of the natural damage ligand. The synergy between the small molecule and the natural damage ligands provides for additional efficacy and specificity in a disease state, which could ultimately result in lower doses and contribute to more attractive safety profile. In addition to having this differentiated mechanism of action, though, however, our small molecule agonists are able to recapitulate TREM2 monoclonal antibody effects in Alzheimer's mouse models. Here you're looking at the 5xFAD mouse model. What you're looking at on the graph on the right is unbiased correlation among several hundred brain markers between our small molecule and our antibody. We also have data we're not showing here, that our smaller molecules induce the same set of neuroprotective genes as do our antibodies. What we have demonstrated that in vivo we have very similar potency and selectivity as compared to our antibody, but with a superior brain penetration and oral availability. Where do we go from here? We've done translational work as well in non-human primates. Here you're looking at a biomarker soluble TREM2 in the CSF of non-human primates. You can see on the right-hand side that, with a single administration of our small molecule at very low doses, we have very meaningful reductions in soluble TREM2, which positions TREM2 as a PD marker for our ongoing clinical trials. In summary, our small molecules are very potent and selective for TREM2. They act as molecular glues and potentiate the effect in the presence of natural ligands. We have the same similar specificity and potency as the antibody in in vivo models of Alzheimer's disease. We now have PD marker that can take us into clinical development. As I mentioned, our molecules are in IND-enabling studies. We plan to file an IND and initiate clinical trials in the second half of this year, starting with genetically subgroups of genetically defined subpopulations of Alzheimer's disease, mainly focusing on TREM2 variants. We believe that this approach reduces the clinical risk and also will allow to get to proof of concept quickly. Where do we go from here? What is our long-term strategy? We call this our wheel of opportunity. Right now, we're focusing on the indications in green. We believe that proof of concept in ALSP will have read through to additional indications such as CLD, Krabbe, and MLD. Obviously small molecules are going into Alzheimer's disease. There are many other indications where microglia dysfunction has been associated with the disease state, and we have an opportunity to explore TREM2 in FTD, PD, MS, and even rare epilepsies. What's in store for us this year? Very exciting year ahead of us with a number of value-generating milestones. We will be reporting a full set of our phase 1 data in the second half of the year. We will be reporting our six-month proof of concept data from our phase 2 study, and we'll be initiating clinical studies with the small molecule in the second half of the year. In summary, we believe the microglia biology and neuroimmunity is the new frontier of CNS drug discovery, and that with our approach and our assets, we're extremely well-positioned to open the doors to this new frontier and develop life-changing therapies for patients. Most importantly, we have a team that can execute. Thank you. I will open it now for Q&A. Thanks, Ivana. We do have an online Q&A portal for folks who wanna submit questions. I'm having some issues with it, so I think it's safer if we just raise our hands, and we've got a mic runner. We'll bring the mic over to you. We do have two seats up here. Any questions? I'm being joined by Evan Thackaberry, who is our EVP of Pre-clinical Development, and Jennifer Ziolkowski, who is our CFO. I've got a list here we can tick through. What should we expect from the interim VGL101 phase 2 data? I didn't see on the slide when exactly it's expected this year. The first time point is six months, do you think that's sufficient duration to give you POC? Based on our natural history study, and the data that's coming out of there with respect to MRI and NfL, and MRI is actually going to be our primary efficacy endpoint for the proof of concept in phase 2. We are able to see significant changes in white matter lesions as well as in changes in ventricular volume, which are quantifiable. We feel very confident that at six months, we'll be able to see some directional changes. Same with NfL. As you've seen on the slides, these patients have significantly increased levels of NfL, way above the normal levels and actually much higher than any of other neurodegenerative diseases. However, just remember the way our phase 2 study is designed, we have an opportunity for three looks. Our first look will be six patients at six m onths, which, as I mentioned, will happen in the second half of this year. We have 2 other looks, with all patients at six months and then at 12 months as well. Got it. Maybe you could just talk a bit more about MRI and NfL as biomarkers. Are there efforts to identify more that are potentially easier to, like when it comes to the commercial stage, to diagnose and track patients? Actually, when we talk about the commercial stage, there is a genetic test. There is actually a test where you can test for the CSF1R mutations. It's actually globally available. It's not expensive. We have actually partnered with genetic testing company to make this more available to patients. I think what we are talking about here is the biomarkers for, you know, phase 2 and ultimately for registrational studies. As I mentioned, the FDA has left the door open for MRI to potentially serve as a surrogate endpoint. As I said, based on our own natural history study, but also we've done systematic literature review and retrospective chart review, MRI is really emerging as an excellent biomarker in this patient population because, as I said, they're very meaningful changes that are quantifiable, that happen very quickly. Got it. Then you just mentioned the natural history study. We know this disease, ALSP, is quite small. Do you think there's upside to the number, and how much disease awareness education can be done? Yes. absolutely think that there is upside to that number of 10,000 patients in the U.S.. Just to set the stage correctly, the gene was only identified in 2012, we're talking about only 10 years. There's been a lot of underdiagnosis and misdiagnosis of these patients. Because of their symptoms, which are usually cognitive, behavioral, and motor, they tend to end up in FTD clinics, AD clinics, even MS clinics. There's recently been a study from the Cleveland Mayo Clinic where they looked at 400 of their MS patients and found out that 0.5% of them were actually ALSP. You extrapolate that, there's 4,500 patients just there. We, as a company, because we're the first one in the space, have spent the last 2.5 years really building the patient advocacy, the KOL awareness. We actually helped start the first patient association called Sisters' Hope. We have a disease awareness website called lspinfo.com. As I mentioned, we have partnered with genetic testing companies. We know every KOL in this space. We have generated patient education materials. We have, you know, clinical trial websites that are directed to patients. We're doing everything to continue to increase awareness. We already have identified several hundred of these carriers, and so we do definitely believe that the numbers are conservative. Got it. These figures are for the U.S. only, I'm assuming? Those are U.S.. The prevalence is the same, globally, so we expect that there are at least 15,000 patients in Europe and U.K., and then about 4,000 patients in Japan. We're constantly finding clusters of patients 'cause this is an autosomal dominant disease. Once you find a patient, you actually, unfortunately, have a cluster because of their family members, and we're finding large clusters in Latin America as well as in China. Sounds good. Can you talk a bit more about the patient journey? You mentioned that sometimes they show up at FTD clinics and things of that nature, and I think it's relatively short lifespan after diagnosis. Correct. How steep is the curve there? How does it present? As I said, these patients present in the prime of their adulthood, usually in their mid-40s. The reason is the CSF1R is actually haploinsufficiency, so we believe that there is some kind of a compensatory mechanism which ultimately gives up, and then there is massive devastation. These patients tend to present with cognitive symptoms, behavioral symptoms, and motor symptoms, and this is why the cognitive symptoms are very similar to FTD. This is why a lot of them end up in FTD clinics. The motor symptoms are similar to MS. The disease is very fast progressing from symptoms to death, it's about six-eight years. What the patient population that we're enrolling in our ph ase 2 study is actually mild to moderate patients because we wanna, you know, get them as early in that process as possible. Got it. Any questions from the audience? Moving on to the small molecule. Sure. Should we expect any additional detail on the mechanism there? You just explained molecular glue, but I'm sure you guys will continue learning and educating. Yes. Yes. We actually are gonna be presenting our small molecule data at the upcoming ADPD conference in Sweden in, I believe it's late March, early April. We definitely do understand exactly where our small molecules bind and what is the mechanism of binding. However, for the competitive reasons, we won't be disclosing those details at this point. There will be a lot more data at the ADPD. Got it. On that note, you do have a competitor in AD. How do you think, Like, what are the potential implications of a data read-through from their program to yours? Yes. There is an antibody that's in phase 2 studies for all comers Alzheimer's population. Obviously, any success they have will be fantastic for us and for the field because we have a small molecule which is differentiated. Our small molecules are, as I said, highly CNS penetrant, orally bioavailable, have that synergistic effect with the natural ligands. I think they're sufficiently differentiated either way. Obviously, success for them is good for everybody. We don't necessarily think that, you know, if they have a negative readout, that that has implications to these molecules which act very differently. In terms of safety, you know, small molecules have obviously a very different PK profile. They don't have Fc region. As I mentioned, because of the synergy between natural ligand and the small molecule in a disease state, I think there's an opportunity for very attractive safety profile. Got it. Maybe one for Jennifer. What's the company's cash position and runway based on that? Yep. As of 9:30 A.M., which is the last time we reported, we had cash of about $200 million. Our cash is expected to last us through the 1st quarter of 2025, which gets us through all these fantastic and important milestones that Ivana mentioned. Thanks, Jennifer. Sure. Maybe just stepping back, can you talk a bit more about microglial biology and how it's evolved over the past decade? Where do you think that's gonna go in the future, and what's the excitement in the community? I think there is an increasing understanding that microglia play a critical role in many of the different processes ongoing in the brain, right? They are the ones that maintain the health and the wellbeing. There is a very strong data in Alzheimer's disease as well, that microglia act as barrier functions and prevent the plaques from spreading and becoming filamentous. They also have an underlying effect on neuroinflammation as well. They're involved in many different processes. I think there is an increased understanding of that in the scientific field today. Also, I think TREM2 is really the first compelling and tractable molecular target that's involved with microglia dysfunction, I think there's an increased understanding around that as well. I think we can expect a lot more. We see TREM2 as the tip of the iceberg. Mm-hmm. This is why we have actually built a microglia platform in the company, which we plan to interrogate with additional targets because we believe that, you know, there is a lot more to explore in microglia biology beyond TREM2. Got it. How clean does the safety profile have to be in ALSP to give you confidence to move into these larger, potentially multi-million patient indications? As I mentioned, VGL one, very safe and tolerable. As you know, this is a devastating rare disease, huge unmet medical need. You know, no treatments today. I think that VGL101 is extremely well-positioned. Then, as I mentioned, our small molecules in Alzheimer's disease because of the different PK, no Fc region, you know, the synergy between the small molecule and natural ligand, again, I think is extremely well-positioned to have a favorable safety profile for larger indications. Awesome. I'm tapped out. Any questions from the audience? If not, thank you so much, Ivana and the Vigil Neuroscience team. Thanks, guys. Hope everyone has a great conference.