Good morning. Welcome to the 42nd annual JP Morgan Healthcare Conference. My name is Edwin Zhang. I'm a member of the JP Morgan Healthcare team and the moderator for this session. Today, I would like to introduce you to the team from Vigil Neuroscience. Please join me in welcoming our presenters, Dr. Ivana Magovčević-Liebisch, President and CEO, as well as Dr. David Gray, CSO. Good morning, everyone, and thank you for joining us today, and thank you, JP Morgan, for the invitation and opportunity to share the Vigil story with you. Before I proceed, I just wanna remind everybody that I will be making forward-looking statements today. Who is Vigil? Vigil is a clinical stage microglia-focused 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. We plan to do this through a precision-based approach. We have identified TREM2 as a key regulator of microglia biology and plan to explore it in multiple different indications. Despite being a very young company, we have established a highly differentiated profile based on a number of firsts. We're the first and only company to have two TREM2 modalities. We have both a fully human monoclonal TREM2 agonist, as well as first-in-class small molecule TREM2 agonist. We are also the first company to show clinical data on TREM2 agonism as a potential therapeutic for treating neurodegenerative diseases. We are also the first company to put a small molecule into the clinic. So we have a very exciting year ahead of us with a number of value-driving milestones, and I will share those with you throughout the presentation. So why focus on microglia? As I mentioned, they're sentinel cells in the brain immune system. They're responsible for maintaining the health and well-being. They're the ones that respond to damage insults, and they transduce those signal to a number of downstream processes such as survival and proliferation, phagocytosis, lysosomal function, lipid and cholesterol metabolism. TREM2 is a receptor that sits on microglia and is a key environmental sensor in the brain. It is the first compelling and tractable molecular target for modulating microglia biology, and as you can see on the right-hand side, what a TREM2 activation accomplishes is actually conversion of microglia from their homeostatic state to disease-associated microglia or DAMs, which are the ones that confer the neuroprotective phenotype. When there's a loss of function of TREM2, the microglia are compromised. They're not able to convert to this neuroprotective state, and this leads to accumulation of debris and ultimately to neurodegeneration. This next slide is an important one because it outlines our precision-based approach to neurodegeneration. What do I mean by that? What I mean is that we focus on indications where there is a very strong genetic, mechanistic, and biochemical association to microglia dysfunction, because we believe that that reduces the downstream translational risk and also allows us to get to proof of concept quickly. So based on that, we have identified ALSP, a rare, devastating microgliopathy as our first indication. It's called ALSP, and we plan then to expand into additional leukodystrophies, focusing on genetically defined diseases where the blood-brain barrier integrity is compromised, which positions them extremely well for antibody therapeutics. Then, staying true to our precision-based approach, we plan to expand into larger indications, focusing on genetically defined subpopulations, because we know, for example, that TREM2 variants in Alzheimer's disease significantly increase the risk of disease and also have a more, more aggressive progression. Taking all this data together, we plan to learn from that and expand into broader populations in these larger indications. The reason we can maximize on this strategy is because, as I mentioned, we have two TREM2 modalities. So our most advanced asset is iBart. I will be calling it ILBART from now on. It is a fully human, as I mentioned, monoclonal antibody TREM2 agonist. It's currently in a phase II proof-of-concept study for ALSP, and this is actually first in the investigational study in this patient population. We have recently released some very exciting interim data from this study, and our next data readout will be in Q3 of this year. Then we also have, as I mentioned, first-in-class, small molecule, TREM2 agonist. This is orally bioavailable, highly CNS penetrant molecule, and we believe that it can be a next-generation Alzheimer's therapy and a game changer in this space, and we'll talk more about that. And that asset is currently in healthy volunteer study, and we expect to report interim data in the second half in the middle of this year. So having these two modalities has actually allowed us to build already a pipeline with multiple shots on goal. With respect to iBart, we have already completed a healthy volunteer study. As I mentioned, we are now in an open label phase two study in ALSP patients. And very importantly, we also have first of its kind natural history study called ILLUMINATE. This is a very important study. We're gonna talk a little bit more about it throughout my presentation, because it really provides a basis for our strategy, which is a biomarker-based development strategy, and ultimately can help lead to accelerated approval. We believe that the proof of concept in ALSP can have a readout to other rare microgliopathies, and we're doing some preclinical work in that space. Then with VG-3927, as I mentioned, this is our small molecule. We're in a healthy volunteer study currently. So now let me tell you a little bit more about ALSP and why we chose this indication. So based on the epidemiology, there are about 10,000 patients in the U.S. This is based on 10% of all adult onset leukodystrophies being ALSP. As I mentioned, it's a rare neurodegenerative disease, very fast progressing, huge unmet medical need, currently no, no treatments. We actually believe that the 10,000 number is conservative, based on all the things we've learned to date, and I'll highlight some of those points later. It is an autosomal dominant disease. The reason we chose this, as I mentioned, is that it meets all of our precision-based criteria. It's a monogenic disease that's caused by mutations in the CSF1R gene that lead to a reduction in number of microglia and their function, which is the underlying cause of ALSP. And I'll show you some very nice elegant data from in vitro studies, where we've been able to rescue the CSF1R deficiency by administration of iBart. In terms of clinical phenotype, this disease hits in the prime of adulthood. We're talking about fourth decade in life. The most common symptoms are cognitive, neuropsychiatric, and motor. Unfortunately, the disease gets misdiagnosed as many other neurodegenerative diseases, such as mostly MS, AD, FTD. So only about 30% of patients are properly diagnosed today. Just to share one of the examples with you is Cleveland Clinic recently published a report where they looked at 400 MS patients, genotyped them, and found that 0.5% are actually ALSP. So if you extrapolate that to the MS population in this country, there are already 2,000 patients just sitting in MS clinics, and this is one of the reasons that we believe that this is a very conservative estimate of 10,000 patients. It's a very rapidly progressing disease. From symptoms to loss of ambulation is only three to four years, and from symptoms to death is six to eight years. As I already mentioned, no approved therapies or any other experimental treatments currently in development. Now, let me focus on the biological rationale and in vitro proof of mechanism. So if we look up in the upper left corner, the hallmark of the disease is actually microglia loss, and these are postmortem sections of patient brains. And you can see the microglia are stained in brown, and you can see with the red arrows that there are very few microglia in ALSP patient brains versus the healthy controls. If we look on the bottom, this provides the rationale of why we believe that TREM2 has a therapeutic potential in ALSP, and that's because mutations in CSF1R, underlying cause of the disease. It's a receptor that also sits on microglia. It's a trophic receptor. It serves a similar function to TREM2, and they actually have a converging downstream signaling pathway that converges through SYK. And so we believe that by over-activating TREM2, we can actually, you know, recover the deficiency in CSF1R. We've done a number of experiments to actually show that, but one of the really elegant ones, I call this ALSP in a dish. What we did is we took iPSC-derived human microglia. We introduced a copy of one of the mutations, and this is a mutation that's found in patients. And what we see by measuring phosphorylation of the receptor is that we get 50% reduction in the activity. And then when we administer iBart, we can actually restore that activity to even higher levels than what we see in wild type. And this, obviously, I'm not showing that data, but this also leads to increase in viability of microglia. So we believe that this provides very compelling in vitro proof of mechanism for use of iBart in ALSP. Now let me switch gears and move to the clinical data. So as I mentioned, we completed a phase I study in healthy volunteers. iBart has shown excellent safety and tolerability. We have linear and predictable PK. We have half-life that supports monthly dosing, but most importantly, we have been able to show target engagement in the CNS. So we have robust and durable response in target engagement biomarkers in the healthy volunteers, and we're actually the only company that's shown the durability of response in a clinical setting. The other thing that's come out of this study is that we identified 20 mg and 40 mg of pharmacologically active doses, and these are the doses that we're taking into our IGNITE phase II study. So before we go to the phase II study, I really wanna talk about our natural history study. As I mentioned, it is a critical component of our development plan. It is a global study, first of its kind. It's enrolling up to 50 patients, 24 months in duration. We're enrolling both prodromal and symptomatic patients. The only difference between the two is the symptomatic patients have at least three clinical symptoms of the disease. What really the goal of this study, in addition to obviously, you know, learning more about the patient journey, is really to look at biomarkers and clinical endpoints, and also see how the biomarkers progress with the disease progression. And the other important thing here is that we want to have this study serve as a potential synthetic control arm, and the data obviously can help us in disease modeling. So we're getting some really, really exciting data from this study, which I'm gonna share with you, now. The first thing I wanna focus on is the biomarkers. So these are fluid biomarkers, and what you're looking at here is baseline levels among different populations. So on the far left side, you're looking at levels of soluble TREM2, which is the most proximal target engagement biomarker, and you can see that it, the levels are unchanged among healthy volunteers versus prodromal versus symptomatic, which is obviously very good news because there is a target there to engage. If we look at the middle panel, what you're gonna see is that there is a striking reduction in soluble CSF1R, which is a biomarker of microglia activity, and it's significantly reduced in both prodromal and symptomatic patients. And based on the data that we're seeing from our natural history study, this biomarker is really emerging as a biomarker of disease pathology. And then on all the way on the right, what you're looking at are the NfL levels in this patient population. NfL is a biomarker of neurodegeneration, and you can see that it's highly, highly elevated in symptomatic patients. So not in prodromals, but in symptomatics. And these are levels higher than we see in any other neurodegenerative disease, and the levels are correlating really well between the serum and CSF, so we believe that going forward, we can use serum levels of NfL as a very good measure. And what's emerging from the study here is that NfL actually is a biomarker of disease severity. So now moving to the other measures, other biomarkers. We are also focusing on imaging biomarkers. These are turning out to be the most sensitive, as we look through data from our study, and we're very excited about this because actually, the FDA left the door open for MRI to serve as a surrogate endpoint. So we know that in these patients, MRI changes happen very quickly, and here we're focusing on changes in ventricular volume and gray matter volume. And what you can see that at six months, compared to baseline, we're seeing very meaningful, quantifiable changes emerging in, symptomatic patients. And then as the disease progresses, at 12 months, what we can see is we are also able to, pick up significant changes in their MoCA score, which is a Montreal Cognitive Assessment, which is a well-established cognitive score. So what we're seeing is that we can, detect these changes. They're highly sensitive, and what's really, really exciting and really important for our strategy is that we're actually now seeing a really nice correlation at 12 months, which is statistically significant, between these changes in volume, in ventricular volume and gray matter volume, and the worsening in MoCA score. And this is exactly what the agency wants to see. They wanna see the correlation between the biomarkers and the progression of the disease. So we believe that MRI and this particular two measurements represent a really nice efficacy biomarkers for us as we proceed. Now, before I move to the data, just to set up the design of the phase II study, it's a open-label, proof-of-concept study. It's up to 15 patients. These are symptomatic patients, 12 months in duration, two doses, 20 and 40 mg doses. We are administering the drug at IV, monthly, and the primary endpoint is safety and tolerability. We have a number of other assessments, as I mentioned, efficacy biomarkers, target engagement biomarkers, obviously clinical endpoints although based on what we're seeing from the natural history study, we don't expect to see any changes on the clinical endpoints until the end of the study. The other important thing to mention here is that we actually enriched in this study for patient population that's rolling over from the natural history study. And why that is important is because they have a run-in period of observation that's not on drug, and we can use that, so we can use that as their own controls as we analyze the data. As I mentioned, we already reported our first interim analysis, and we'll go into that next, six patients, six months, and 20 mg. The next look in the study is going to be all patients, six months in Q3 of this year. So in terms of safety, iBart continues to be safe and well- tolerated. There have been no discontinuations due to AEs, no severe AEs, no SAEs. The only SAE was a hospitalization due to food poisoning, which was unrelated to drug. We see no hematologic AEs, and we see no imaging abnormalities, so no ARIA. We wouldn't expect it because these patients don't have amyloid deposits, but nonetheless, we're not seeing any of it. So before I show you the data, the other thing that's emerging from this study is that we actually have two different patient populations at the baseline, which was a bit surprising to us. So the first patient population are patients who have high, very high NfL levels and are cognitively impaired, when they enter the study, and believe that they have progressive disease at entry. Then surprisingly, we had these two patients which had, normal level NfL, and were not cognitively impaired when they entered the study, and we believe that these patients have a mild, milder form of the disease. Ultimately, though, these patients progress very quickly, and these patients will convert to a progressive disease. We think we just caught them before that conversion happened. Then actually, we do have one patient that we believe we caught as they're converting to that progressive disease. And the reason I'm saying that is because when we look at the natural history data and look at their six months prior to entry into the study, their NfL level doubled in that period. So we think they're in that aggressive state. So with that, with that in mind, I'm now gonna show you the data. And, just a reminder, because of, I don't have enough time, I can't show you the individual data. This is a summary of the data, but that is available on our website. So now with that in mind, let's take a look at the patients who have that progressive disease, high NfL levels, cognitively impaired. What you can see is that we're seeing slowing of progression across all of the biomarkers. So we're very, very excited to see this, this early on. So ventricular volume, gray matter, we're seeing significant increases in soluble CSF1R in this patient population, and then we're seeing a decrease in NfL either six months or nine months because we had two patients who had nine months' worth of data. And then in those two patients, which entered the study with no cognitive impairment and age-normal NfL levels, what we're seeing there is that they're remaining there, which is exactly what you wanna see, that they are stabilizing. And if we continue to see this at 12 months, this can be a game changer, because if we can identify these patients early enough based on their NfL levels and start treating them before they are cognitively impaired, that is absolutely what this patient population was. So we're very, very excited that we actually had these two patients in our study and that we see this stabilization. And then in this one patient, which we believe was in active state of converting and their NfL levels were doubling, we think it's gonna take a little bit longer to get them stabilized. So what does this mean for us? What this means is that we believe that based on all of the data that we have from our natural history study, as well as the phase II study, we're extremely well-positioned to execute on our biomarker strategy. So if we start on the top left, and work clockwise, obviously, as I mentioned, ALSP is a rare, devastating, fast-progressing disease, no treatment available, and iBart is the only therapeutic in development. The other thing that's really important is that we've established biomarkers that correlate with disease progression. So we know that MRI is extremely sensitive, and it correlates very well with the progression of the disease. And we believe that NfL is a very good indicator of the disease severity. And then, very importantly, we believe that we've demonstrated pharmacological activity because we see these increases in soluble CSF1R with... Remember, soluble CSF1R is highly decreased in untreated patients. Then we're seeing these really exciting directional changes in both MRI as well as NfL. So we think this positions us extremely well to go and start conversations with the FDA around our biomarker strategy and potential accelerated approval. And as I mentioned, Q3 is our next data readout. So now let me switch to the small molecule. And before I tell you more about VG-3927, I just wanna set the stage as to why we believe that TREM2 has a potential in treating Alzheimer's disease. You probably remember from GWAS analysis that mutations in TREM2 are second highest risk to APOE. And we also know that microglia have this broad effect on neuronal damage in the brain. We know that most recently approved A-beta therapies actually act by recruiting microglia to the site of plaques. So that gives us all a lot of, you know, excitement around TREM2 as a target. But in addition to that, if you look at the left hand panel, we're actually looking at postmortem sections of brain of patient that actually carry one of these TREM2 mutations, the R47H. And what you can see, the plaques are stained in red and in pink, and microglia are in brown. And in wild type, you can see the microglia are clustering around the plaques, and that is not happening in the R47H patients. So microglia lose that ability to be recruited to the site of damage. In the middle, we are looking actually at the mouse disease model, and here, if we look at the TREM2 wild type, you can see the microglia, which is stained in white, are encapsulating the plaque, which is stained in blue. When you have a knockout of TREM2, you can clearly see that microglia are not capable of being recruited to the site of the plaque. And then on the right-hand side is our own data from the 5XFAD mouse model. And again, here, after treatment with VG-3927, what we see is that we have a reduction in plaques, which is stained in red, and then you can see that there is also an increase in microglia. So we think that this gives us a lot of confidence that TREM2 is a target that we wanna go after when it comes to Alzheimer's disease. Now, why all the excitement about VG-3927? Well, obviously, it's the first small molecule to go into the clinic, but in addition to that, there's a number of really exciting and special features, all which all combined together support its differentiation and potential as to serve the, you know, significant unmet medical need in Alzheimer's disease, and we believe it has the potential to be the next generation Alzheimer's treatment. The reason for that, if we start again on the, in the left corner and work clockwise, we know that there's a potential for better efficacy than A-beta therapies. The reason for that is, as I mentioned, microglia have a much broader impact on neurodegeneration, and they, you know, impact a number of different processes. We also know that our small molecule has a differentiated mechanism of action. It acts as a molecular glue to stabilize the TREM2 complex, and that results in a synergistic effect with the natural damage ligands, which we believe can lead to a differentiated safety profile as well. We know that ARIA is a known safety risk for A-beta therapies, and here, because there is no Fc region, the PK is very different, will require different concentrations. Regardless of what you believe ARIA is caused by, I think the small molecule has an opportunity to be differentiated. Our small molecule is an oral drug administered daily. Obviously, that's a perfect modality for any future combination therapies. And in addition to that, obviously, patient convenience and oral dosing is something that, you know, is very gonna be important to this patient population. So now let me focus for a minute on this synergy that we're seeing, because I think this is where the very important differentiation sits. So, we know that TREM2 is a damage sensor. So there are ligands that bind to it, and one of them is sulfatide. It's a component of myelin sheaths, and it's released when myelin is damaged. And you can see in the left panel, in the dark blue, that it activates TREM2, and we're measuring phosphorylation of SYK here. Then when we look at VG-3927 alone, we see that it activates it even more. But then when we put the two together, we see this huge synergistic effect, which we believe is gonna have the amplification of signal in the areas of the active disease, which we believe can then lead to need for lower doses and ultimately contribute to that favorable safety profile. Now, let me talk a little bit more about this nice balance that VG-3927 strikes in terms of its neuroprotective phenotype. So what we did here is we developed these highly sophisticated tricultures. So we're looking at tricultures of microglia, astrocytes, and neurons, trying to replicate the brain environment. And in these cultures, we're able to use neuroinflammatory insults such as LPS to induce secretion of neurodegenerative biomarkers such as NfL and Tau. So what you're looking at here is, once you have that insult, you can see that, in untreated cells, the NfL levels and Tau levels are going up day after day. When we administer VG-3927, we are able to bring these down, levels down back to baseline. So very excited to see this. We see the similar thing with GFAP, which is another biomarker for astrocytosis. But also very importantly in these cultures, what we see is that there is increase in neuroprotective cytokines. So we see increase in IL-10, and even more importantly, we see decrease in chemokines, sorry, I meant chemokines. And there is also a decrease in extracellular cytokines in these cultures after being treated. So we can see that VG-3927 is actually helping convert this microglia into those neuroprotective microglia. And then turning to the functional data, this is from 5XFAD mouse model. Here, what we're doing is actually trying to replicate the disease state, so we're actually starting to treat after these mice have already developed the full pathology. They have the amyloid deposits. And after only 6 weeks of treatment, once daily, orally in these mice, we're actually starting to see a decrease in the A-beta plaques. So in the middle panel, we're measuring the plaque area through immunohistochemistry, and you can see a decrease. And then on the right panel, we're looking at insoluble A-beta 42 levels through biochemical measurements, and again, we're seeing a decrease. So with that, what is our clinical strategy? So our clinical strategy is, again, leveraging a precision-based approach to increase the probability of a success in Alzheimer's patient population. So right now, as I mentioned, we are in a phase II healthy volunteer study. This is a study that's assessing safety and tolerability, PK, but also PD. We've learned a lot from our VGL101 work, and so we're gonna be using the same target engagement biomarkers to assess the PD in this, in the healthy volunteers. And then we are also planning to add an Alzheimer's disease cohort into the study, and we wanna take a look at, you know, the biomarker movement in subgenetically defined subpopulations, because we think that we can learn a lot from that as we continue to design our phase II study and beyond. So with that, let me just highlight our upcoming milestones. 2023 was a year of execution. We hit all our milestones. In 2024, we have two value-driving milestones. As I mentioned, interim data from this phase I study in VG-3927 in the middle of the year, and then in Q3, the next analysis from our ALSP phase II study. So in closing, we believe that microglia biology and neuroimmunology is the next frontier of CNS drug development. And with our strategy and our assets, we believe that we're extremely well-positioned to open the door to that frontier and develop life-changing therapies for patients. And most importantly, we have a team that can execute. So thank you very much. Thank you, Dr. Magovčević-Liebisch, for the wonderful presentation. We will now begin the Q&A portion of the session. So if you have a question, please raise your hand, and we can bring a mic to you. I'm happy to kick off with the first question here. As a follow-up to the IGNITE phase II readout, what conclusions have you drawn from the interim analysis that you reported back in November? Thank you. So, we believe that this is a very exciting and positive outcome to be starting to see directional changes in these, efficacy biomarkers, this early on, is extremely encouraging. We are also very encouraged by the quality and the consistency of the data. There's nothing that we've seen that would, make us change our plans, which is obviously also very encouraging. And, it's not only what I wanna make sure people understand, it's not only the six patients, six months' worth of data. We have this wealth of data from our natural history study, which is now giving us some great data and really encouraging data when it comes to our biomarker strategy. So what we're really excited about is that MRI is emerging as that sensitive efficacy biomarker, and we think that it... with these two datasets, we have enough to start the conversations with the agency around which biomarker we could take forward as our development strategy and talk about accelerated approval as well. So really, really nice data set, and which positions us extremely well, well for next set of development milestones. Gotcha. Thank you so much for that. Thank you, Ivana, for the fantastic presentation. So, a follow-up question about the biomarker. So in terms of Lilly's, for example, the DYNAMIC trial, the MRI data versus cognitive protection, they're not well correlated. So how do you think the FDA will respond for your request? Yeah. So, in early discussions, we did ask FDA about potentially using MRI as a surrogate biomarker. And remember, this is specific in ALSP. We're aware that in other diseases there's different dynamics with some of these biomarkers. But, it is known—I mean, we've shown, and it's been, you know, known by investigators in the area, that this is a very progressive and very rapid disease. So the kinds of changes that we're seeing at six months across a larger data set within that natural history study, and then that continue out over longer periods, as we've had that study going on for now, just over two years, that gives us confidence that specifically in ALSP, we are in fact seeing a very progressive phenotype within those different MRI measurements. The correlation to clinical is, of course, key, because that is the information that we're going to need t o be able to justify any specific biomarker, including MRI. So we're very encouraged by the data that Ivana just showed with that correlation with a cognitive measure, and that it is a very strong statistical correlation that is developed. And obviously, we'll now be initiating dialogue with regulators around getting alignment around, you know, those biomarkers, recognizing that we are blazing some new trail within ALSP. Thank you, David. I have another question about VG-3927. So, you guys mentioned that, because there's no Fc signaling, safety profile is better. Do you worry about maybe plaque removal will not be as efficient as a large molecule, with small molecule, agonist? I mean, we do... We don't see any evidence of that at this point. And as I showed you from the mice, w e actually start to see the decrease in plaques in this very aggressive model, you know, after just six weeks of dosing. So we're extremely encouraged. We also think that, you know, we're fully brain penetrant So, we think that, and with the synergistic effect, we can have that, you know, spatial amplification, which I think is going to be critical as we think about the disease. Anything you want to add? Yeah, I mean, I think, you know, we understand the focus on amyloid, because obviously that's been a really key part of the current approval story. But harnessing the immune system goes well beyond amyloid specifically. So obviously, we have other types of pathology. We have active neurodegeneration and neuroinflammation that is not specific to amyloid, and even clearing plaques entirely does not lead to full progression of disease. So when we think about a next-generation therapy, where we put within TREM2, yes, amyloid removal is important, and we'll be tracking that, and we've shown initial evidence that we can do that. However, we will also be focusing on tau and other, you know, neuroinflammatory markers, and think more holistically about what the immune system can do in active degeneration. Okay, I think that wraps up our presentation. Please give us another round of applause for the team at Vigil Neuroscience.