left, David Gray, CSO. Welcome, both of you. Thank you. Thank you. Maybe spend a couple of minutes, please, talking about Vigil, what you're working on, and then milestones over the next 6-12 months. Okay, sure. Thanks, Andrew. Thanks for having us. We appreciate it. Mm-hmm. So, Vigil is a clinical stage biotherapeutics company, and we're focused on leveraging recent breakthroughs in neuroimmunology to develop therapeutics for patients with both rare and common neurodegenerative diseases. Just a few things that make us different... So you can hear me. I have a loud voice. I don't usually need a microphone. Yeah. There are a few things that I wanna talk about that make us a little different from other companies working in neurodegeneration. The first is that we're focused on microglia, and microglia are the immune cells of the brain. We're experts in neuroimmunology, and our programs are designed to really boost the and enhance the natural protective and housekeeping functions of these really amazing cells. Secondly, our clinical development strategy and our scientific rationale are based in genetics. We select indications where a genetic defect is linked to microglial dysfunction, and we conduct our clinical trials in genetically defined subpopulations to increase our chance of signal detection early in the development process. And thirdly, we are the only company that have two TREM2 modalities, both a small molecule and a monoclonal antibody, and that allows us to leverage the specific strengths and pharmacological properties of each molecule to the appropriate therapeutic application. So about those programs, we have VGL101, or iluzanebart, or ibart for short, and that is a monoclonal antibody TREM2 agonist currently in a Phase 2 trial in ALSP. And then we also have a small molecule TREM2 agonist called VG-3927, which we believe can really make a difference in Alzheimer's disease treatment. Milestones for those two programs? Milestones, yes, thank you. Mm-hmm. We have for the first one, the next one coming up is for our small molecule program. We'll have that data in mid of this year, and there we'll be looking at safety. It's a phase 1 in healthy volunteers, so it's a SAD/MAD, looking at safety, tolerability, what PK, PD biomarkers for target engagement. And then also in the third quarter of this year, we're gonna have an interim cut, another interim cut, of the data from VGL101 or iluzanebart. Mm-hmm. That's gonna be in the third quarter. We had a readout last year on 6 patients at 6 months in this study, and this is a longer-term look and additional patients and another dose. Very excited about that coming up. Very good. So, maybe we do ALSP first, so the phase 2, and then maybe talk about the small molecule afterwards. So starting with the phase 2, ALSP data that you've seen so far on the initial six patients, what did you exactly see to give you that confidence that, you know, you can get this drug through the goal line? Okay, well, maybe I'll start a little bit just with an overview of the trial design, and then I'll hand it over to David for some more details. So the trial is. We enrolled 20 patients. It's an open-label trial, enrolling symptomatic ALSP patients or those patients that have a confirmed CSF1R mutation. The primary objectives of the study is safety, tolerability, PK, PD, as measured by CSF biomarkers, MRI, MRI measurements of ventricular volume and gray matter volume, as well as cognitive measures. As Andrew mentioned, we had data earlier this year, and in that, we saw some interesting insights. They were consistent with what we saw earlier in our phase 1 trial, which is that it was safe and well-tolerated. We saw target engagement, and interestingly, in this trial, in conjunction with our ILLUMINATE trial, which is our natural history study, just a sidebar on that, is the first natural history study in ALSP. And between those two studies, we've really seen some interesting information that leads us to believe there are two segments of patients in ALSP, and we believe that iluzanebart has the potential to help both. But with that, hand it over to David for more. Mm-hmm. Yeah. So I mean, ALSP is a... We're the first to be studying it, as Jen mentioned, and there's, there's still things to be learned. Obviously, the natural history study is really important in that and really helps us to put in context. So, you know, you asked about what we'd seen at 6 patients at 6 months. That is a lot easier to understand, given the larger data set that we have from our natural history study. But a couple things that I'll highlight, specifically, one is that we learned, as Jen mentioned, that there are, the majority of our patients from the natural history study, as well as, half of the patients from the Phase 2 interim look, are in a typical ALSP progressive state. This is a devastating disease. It progresses very, very quickly, and that's a, that's an important learning, that there's just this rapid degradation. And so in those patients where we see all those declines, what we observed were changes in the rate of decline, and specifically slowing in the rate of decline on MRI biomarkers. Jen mentioned ventricular volume and gray matter volume. We saw slowing in those individuals on those measures, as well as we saw elevation in soluble CSF1R in the CSF in those progressive patients. Now, that is a, the affected protein in ALSP. It is the genetic under or cause of, of the microglial dysfunction and the disease. So it's really encouraging to see a nice, robust increase in those progressive patients. I'll just briefly mention, two of the patients in that study were a little bit of a surprise to us in a different kind of state. So they were not cognitively impaired, they did not have elevated NfL levels yet, but they had other symptoms of ALSP that qualified them for the study, and, as well as some MRI evidence of progression. And there, we were really encouraged to see that we didn't see a lot of changes on the MRI, and we wouldn't expect to see reductions in NfL and on some of the other biomarkers. So that, you know, given that what we're learning from the natural history study, yes, the majority of the patients are in this devastating progression, but if we're able to catch them early in that sort of early stage, it would be extremely interesting to be able to maintain them in that state. So that's one of the reasons we're really encouraged by the data. Great. And, so this was with the 20 mg/kg dose. The next data update, again in Q3, will have 20 patients. So maybe talk to us about the makeup of the next 14 patients. What dose levels would they be on, and what kind of disease state would they be in? Sure. So the interim data that we had in November of last year was six patients at six months at 20 mg/ kg. So we'll see those at, continue to see those at 12 months. But in addition, as Andrew mentioned, we did enroll 20 patients, so the majority of the additional patients will be at a higher dose at the 40 mg/ kg. And in addition, while David mentioned that we saw people in different stages of their disease, those three that he mentioned in the interim, the majority of the additional patients that we enrolled, that we will see in this interim analysis in Q3, were from that progressive state. So those ones that had the high NfL to begin with, and their MoCA scores were declining, indicating that they were in the progressive state of the disease. Right. And, what would be a positive readout to you guys, then? Well, so again, we're really encouraged by what we saw at the interim, but it was only 6 patients, and we, we acknowledge that it's a small, it's a small sample size. So being able to now expand that to a larger number of individuals, we'll be looking for some of those same trends- Mm. on those biomarkers that we're measuring at six months. So we'll be looking at MRI, we'll be looking at specifically soluble CSF1R, for example. And so one of the things that we expect, and we'll be looking to see, is you know, replication and additional confidence in the signals that we saw at the beginning. For those individuals that were in the original analysis and that we'll now have 12 months of data on, we can expand a little bit and think not just about additional longitudinal, you know, continuation of those slowing trends. But we can also think about looking at some of the clinical measures- Mm-hmm ... and specifically things like cognition. We learned from our natural history study that these measures, even in a really rapidly progressive disease like ALSP, were quite variable within the natural history study when we looked at them at six months. But by 12 months, we began to see clinically meaningful changes that can be measured. And so, in that group, we'll look at that data as well, the clinical data. That's great. So, right, in the initial 6 patients, 6 months, they will have 12-month data. But maybe at the very minimum, within the progressive disease subgroup, ideally it would be great to see some positive data on outcomes like cognitive benefits, rather than simply biomarker changes. Is that fair? I mean, yes. Ultimately, we're in the business of helping patients and really making their lives better, and that it's going to be important. Biomarkers are really an important part of getting to an accelerated development path and a lot of the regulatory components. But of course, it's gonna be important that the patients perceive a benefit and that they're- Right ... they're benefiting from the therapy. Great. Technically, you are pursuing a higher dose, 40 mg/kg, compared to 20. Should we expect a efficacy differential between these two doses? So, you, in our healthy volunteer study, we looked at a number of different doses, and we measured CSF biomarkers, partly in order to—well, a big reason of looking at the CSF there was in order to select doses for phase 2. And on that basis, 20 milligrams per kilogram gave a nice, robust response on the biomarkers that we're measuring, including soluble TREM2, soluble CSF1R, and osteopontin. And so with that, we were confident that 20 milligrams per kilogram is a pharmacologically active dose and a good dose to move into the clinic. Now, in the healthy volunteers, we did not see a difference on those biomarkers when we went to the 40-milligram per kilogram level. However, we're now in patients, and it is not just good drug discovery practice, but good, you know, regulatory preparation practice. Ultimately, you know, we will be looking at the data to see if there are differences. One thing I'll just briefly mention is that, we did see a much larger percentage in the increase in soluble CSF1R in the patients, compared to within the healthy volunteers. So that's an example of an endpoint that we might be specifically looking at when we look at the 40 milligram per kilogram dose. Right. And then safety, what did you learn in terms of the safety profile of this drug, and is it safe to assume no news is good news? Yeah, so from a safety and tolerability perspective, safe, well-tolerated, and, you know, the PK is good, and it supports once-monthly dosing. And yes, you're right, no news, good news on the- Mm-hmm ... safety side. Okay. And so as this is going on, you've requested to meet with the FDA to discuss the path forward for this program. And so have you met with them yet, and what are you looking to achieve... with your discussions? Yeah, so we, you know, really important for us to be engaging regularly with the FDA, and, and having the data, in last year really gave us, between the IGNITE data and the ILLUMINATE data, really gave us a compelling package to have those discussions with the FDA to start continuing to educate them on the disease, and also to show them the data that we have that shows the potential of iluzanebart to be a novel treatment for these patients. So we're on track with those discussions and, you know, it is a process. It's an iterative process, but we're on track as we expected, and we're looking to really have a good dialogue and understand how they're thinking about the disease or how they're thinking about, you know, endpoints, et cetera. You know, also interesting to note that we're encouraged because the patient community is also engaging with the FDA, which helps. They had a patient listening session in January to help continue to educate them, and we're just encouraged that the FDA seems very invested and supportive. We'll have more information on this. Right ... in future. Right. And it's important that people know it's not... You're not, you're not just bringing six patients' worth of data to the FDA. You have this natural history study that you can compare to, to show possibly— you know. Yeah. Differences. Yeah, exactly. Okay. And as I mentioned before, the ILLUMINATE is the first natural history study done for these patients, and you know, it's been very interesting and very informative both for the Phase 2, for the regulatory path, et cetera. That's a 36-month study. We enrolled approximately 50 patients, and those are for also, you know, confirmed ALSP patients. Great. Maybe one, just one quick question is just, this Phase 2 is technically adaptable. Is that right? Meaning can you prolong it? Can you enroll more patients to make it more of a pivotal type study? I don't know. I think what I'd say about that is, yeah, I mean, so we, we have a lot of experience within Vigil on rare disease development, and this dialogue that Jen described, it's really important to maintain flexibility. So yes, we have constructed the protocol and just our general approach to it to have flexibility to respond as needed. Okay. All right, so there's that going on, and then we'll shift over to the oral small molecule phase 1 data coming up mid, middle, so actually earlier than the ALSP. So maybe before that, talk about the profile of this compound. Why is it so differentiated and exciting for Alzheimer's? Yeah, David, that's your favorite topic, so I do really like the small molecule. It's an amazing thing. And just as an aside, TREM2, and as just a little bit of a nerd moment, but TREM2 signals as a multi-protein complex, and to be able to have a small molecule that can activate that multi-protein complex is... continues to be really impressive to me. So one of the interesting things of... we have both an antibody TREM2 agonist and a small molecule, and the small molecule really is differentiated. And what I mean by that is not just the modality, the patient convenience. These are really, really important in Alzheimer's, as we're seeing right now in terms of access and those types of things. However, our focus really is on the fundamental biology and the function that we're observing. So the small molecule, VG-3927, binds to a different location within TREM2, and in doing that, acts to stabilize that multi-protein complex that I was talking about. And, among other things, this renders it very sensitive to the natural ligands that TREM2 normally interacts with. And we've shown some of that data, that we see a really impressive synergy with the normal things that TREM2 interacts with. These are elements that signal, distress and damage within the cell, and that enhancement of efficacy, really local to and in and around regions where there's damage, is something that we think is a real potential advantage for the small molecule because, it could lead to better therapeutic index, even enhanced potency, and so on. So that's one key differentiator. Another is that it does not have an Fc component. So we're able to engage the function, and I've shown this a number of different ways, without directly, you know, interacting with Fc. And this is, you know, also has some potentially important consequences, depending on the mechanisms that ultimately underpin ARIA. And so, you know, we'll continue to... We have a lot of information that has led us to specifically select the small molecule for Alzheimer's disease. I, you know, we'll continue to share some of that as appropriate. Right. And as we think about the landscape, you have the only TREM2 for ALSP, whereas others, you know, they're all working on Alzheimer's. And then secondly, you have... But then you have the only oral Alzheimer's TREM2 out there. That's right. Okay. Yeah. What should we expect in the upcoming phase 1 data? So the phase 1 data, as we mentioned, it is, it's a phase 1 SAD/MAD. So we're, you know, enrolling patients, and we expect to show... The primary goal is to show safety, tolerability, target engagement, similar to what we did with VGL101. And then in addition, we plan on adding, in the future, a cohort of Alzheimer's disease patients so that we can test our biomarker approach, learn more, and plan for our phase 2. Is it appropriate or not appropriate for the street ultimately to compare the amount of biomarker changes you're seeing relative to the other TREM2 antibodies in Alzheimer's in phase 1? ... So, I mean, I completely get the why you would wanna do that. What I would say is this, is that, there are differences in the assays- Mm. that ultimately make it so we, you know, we don't know that. But I would certainly, from a scientific perspective, caution against a numerical head-to-head comparison. What is clear is that the directionality is the same, and that's when, you know, we focus on soluble TREM2, for example, as a biomarker of target engagement. And in our hands, we have very, very robust target engagement, downstream gene signature changes, and a number of other things. So we're really happy with the amount that we're modulating it and the way that those assays translate into the clinic. And so the directionality is absolutely what we're looking at in terms of the biomarker. Mm. Let's just say, biomarkers do trend in the right direction. How quickly can you start the next study in Alzheimer's patients? Well, just the one part is that the AD, this is not necessarily the next study, but as part of our phase 1, we could have additional cohorts. One is, which would be the AD cohort that I mentioned. We also might do an elderly cohort, so we have those sort of things. And then, on the phase 2. Yeah, I mean, generally, the field's in a much better place for doing studies in AD, compared to some years ago when I was doing this before. So, you know, I think we're encouraged that there are some really good designs and biomarker options, good understanding of the kinds of patients that we wanna enroll. But on the other hand, we have this really important next-generation mechanism in terms of engaging the immune system. And so we do wanna make sure we're very thoughtful about the patients that we select, that we think about, you know, any potential genetic or subpopulation enrichment. That's a big focus for us right now, not just on the biomarkers that we collect, but also in terms of the, you know, different kinds of endpoints that we're looking at that we might include beyond the standard things that people look at in Phase 2. And then in fourth quarter, Alector will have their own Phase 2 readout for their IV antibody in Alzheimer's patients. So, you know, if the study works, probably a positive readthrough to you guys. But if it doesn't, you know, what would you say? Why is there no read-across or minimal read-across to your program? Well, I mean, you know, first focusing on the positive. Again, having been in this space for a long time, that, that's really that would be fantastic for patients, fantastic for, for, you know, kind of our understanding of, of these kinds of immune-based therapies. However, as I mentioned a little bit when I was talking about the small molecule, it really is a different, modulation. It is really differentiated from a functional and pharmacological perspective. It is they are, you know, both have TREM2 agonism, but there, you know, we see a number of differences. And so we believe that those differences are potentially very important. And so, you know, as we look at that data as it comes out, there's, I would say, likely, well. From my personal opinion, I, you know, I don't believe you can test this very important, fundamentally, genetically re-rooted hypothesis with just one single entity and, and one single study. In terms of the other compounds, Denali, you know, they had a TREM2 in Phase 1, saw anemia. Just to confirm, you're not seeing it, and Alector is not seeing it. Why is that? So I mean, it's always difficult to talk about other people's data. Mm-hmm. What we know is that, you know, they observed this after a single dose in phase 1. The molecule that they saw that with had a TREM2 component, but it also had a transferrin component. You know, there's understanding that potentially can be linked to those types of toxicities, specifically the transferrin component. Our own data, and I'm including all of our preclinical data, all of our clinical data, what we know from Alector is that, you know, pure modulation of TREM2 has no association with anemia or blood toxicity. And then ultimately, what kind of Alzheimer's population would you be pursuing it for with, with this oral? Mild, moderate, or a genetics, obviously, maybe a TREM2 variant. Like, how big is the population or the market opportunity? So, you know, I'll just from a from a sort of a scientific and mechanistic perspective, engaging microglia has the potential to be effective actually across the entire disease spectrum, including later in disease, where you know, we don't typically study. However, the methodologies and clinical understanding about how to run good and sensitive trials is certainly skewed more toward the early stage. That's also where you can have the most patient impact by slowing and stopping the disease early in disease. So, you know, our intention from development is to develop initially as a monotherapy and to focus on the earlier stage of disease, you know, similar to other programs that are out there. But from a purely scientific perspective, there isn't a reason that it may not also be very interesting later or in, you know, different kinds of sequencing or combination settings. Mm. That's helpful. And I should have asked earlier, for ALSP, how big is that market opportunity? Yeah, we believe that we see about 10,000 patients in the United States, and then you can see similar amounts outside the U.S. as well. Okay. And then last question, cash. Yes. You have enough cash? Well, we have cash. We have $100 million in cash at the end of March, and that's gonna... Thank you for asking. That's my favorite question. And that will be enough to get us through into the second half of next year and through these milestones that we talked about. Okay. So- Very good. Thank you so much for the updates. Fingers crossed in the upcoming data sets. Thank you, everyone, for listening in.