Thank you, everybody, for joining us again this morning at the Citizens JMP Life Sciences Conference. Excited to be joined next by Vigil Neuroscience. Vigil is a company focused on neurodegenerative diseases. We'll get into the details in a second, but excited to be joined by Jennifer Ziolkowski, CFO, and David Gray, CSO. So Jennifer, David, really appreciate you being here. Jennifer, maybe if I just turned it over to you to start with giving us a quick overview of the company, the background. You know, it's a relatively young company, but you've done a lot in a very short space of time. Well, thank you for recognizing that. And thank you for having us. It's a lovely day here in New York City, so we're excited to be here. So about Vigil, we're a clinical stage biotherapeutics company focused on leveraging recent breakthroughs in neuroimmunology for potential treatments for patients with both rare and common neurodegenerative diseases. I wanna start by telling you about three things that we believe are really core to our approach, and differentiate us from other companies in neurodegeneration right now. The first is that we're a microglia-focused therapeutic company. So, microglia are the immune cells of the brain, and we're experts in neuroimmunology. Our programs boost the brain's natural immune system by enhancing the natural protective functions and housekeeping functions of these really crucial cells. In addition, our clinical development strategy and our scientific rationale is rooted in genetics. We select indications where a genetic defect is linked to microglial deficiency, and we select indications where we can first go into a genetically defined subpopulation, which helps us to get to a proof of concept as quickly as possible and to see signals early in the development process. And then lastly, we're the only company that has two TREM2 agonists in clinical development today. So that's helpful for us because we're able to take the appropriate properties, or the properties of each molecule and apply them to the optimal therapeutic application, and we're able to take synergies, both scientific and operational, from both programs and leverage those for enabling us to get to proof of concept quickly as well. So finally, the two programs. We have VGL101, which is a TREM2 monoclonal antibody, TREM2 agonist, that's currently in a phase 2 clinical trial in ALSP, which is a rare neurodegenerative disease, and VG-3927, which is a small molecule TREM2 agonist candidate, which is, we think can be a real game changer in Alzheimer's disease treatment. Okay. Before we jump into the two programs, David- Yeah. ... Maybe could I just ask you to give us TREM2 101 and microglia 101? I mean, what, why, why are microglia so important when we think about neurodegenerative diseases, and why is TREM2 something that we care about? Yeah. So microglia, simply put, are the brain's immune system. They have multiple functions. I sometimes think about them like a Swiss Army knife, that depending on what's going on, they're either doing surveillance or they're actually responding. So core to our approach, and really the interest in TREM2s, stems from the fact that TREM2 is a receptor on microglia that signals to them that they need to convert into a more active neuroprotective state, as opposed to the typical surveillance state. The interest originally came because there's a really strong genetic association that was identified within Alzheimer's disease, where loss-of-function mutations in TREM2 cause a significant increase in the risk of developing Alzheimer's disease, as well as a faster rate of progression for those individuals that are carriers. Subsequently, we've learned that that's because these mutations compromise the ability of TREM2 to sense what's going on in the environment. Yeah. Um- Great. Really helpful. So moving into VGL101, maybe could you just give us a quick overview of ALSP, the disease, the patient burden, and patient numbers? Yep. So ALSP is, stands for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. Kind of a mouthful, so that's why we call it ALSP. It is a rare inherited neurodegenerative disease. It is autosomal dominant, so patients can have a 50/50 chance of passing it along to their children, which, as you can imagine, devastates families for generations to come. Symptoms, symptom onset is in the mid of adulthood, so in the seventh decade of life. Fourth? Yeah. Fourth and fifth decade of life. So thank you. And it's extremely quick-moving. So some of those symptoms include neurodegenerative, motor, and cognitive. And, you know, we... there's no approved treatments for ALSP today. Right. It is diagnosed by a simple genetic test, where we're testing for a genetic mutation in the CSF1R gene. But I think this underscores, this lack of treatment really underscores the need for some treatment in this area. Okay. So then can we just dig in a little bit more and talk about the genetic drivers of ALSP, and then why the focus or the rationale for TREM2, or targeting TREM2 in these patients? Yeah. Yeah. Yeah. Yeah, so, as Jennifer mentioned, ALSP is caused by mutations in the CSF1R protein, receptor. This is a trophic factor that microglia need for their health and survival. So when these mutations are present, it leads to compromised microglial function and numbers of microglia. It's really apparent within ALSP. As I mentioned before, these are critical immune cells, and this mutation leads to compromise. Unfortunately, the nature of the mutation is such that directly targeting CSF1R is not practical. It turns out that TREM2 is also expressed on microglia, and there's a common intracellular signaling pathway between CSF1R and between TREM2 and a protein called Syk. And that common commonality is something that we're taking advantage of with our TREM2 approach to ALSP. You might ask why TREM2 if we're talking about CSF1R? So that is something that we've then validated quite a bit through a number of preclinical studies. We've shown that IBART, which is the clinical molecule, or the clinical antibody, can in fact rescue the CSF1R deficiencies under a number of different conditions. So when you generate in the lab different kinds of settings where CSF1R is deficient, we can compensate for that with IBART, we can increase microglial numbers and function, and that's the basis for our approach. We've gone a little bit further preclinically, and we can show that we actually see phosphorylation on CSF1R after treatment with IBART. And then, I think really excitingly, recently, we now have clinical data. So we know that this is the effective protein, and it's significantly reduced in ALSP. And with our... In our interim analysis of phase 2 data, we did see a nice increase in CSF1R caused by IBART, so really kind of tying all that together. So just before we jump into the phase 2 results in detail, I think it's important to remember that we're still learning a lot about ALSP. Really, you said no approved treatments. One of the key sources of the learnings about the, the disease state has been your natural history study, ILLUMINATE. So can you just give us an overview of that study and what what you've learned so far from it? Sure. So ILLUMINATE, importantly, is the first natural history study in ALSP that we've started. And so it's a 36-month study, and it's evaluating symptomatic ALSP patients. We've been enrolling about or approximately 50 patients. The goal of the study is to better understand ALSP, as well as the biomarkers and clinical measures that indicate disease progression and clinical effect, and most importantly, is to understand the patient journey. So to that end, we're measuring MRI, CSF biomarkers, and clinical measures, and also, the natural history study has served as a run-in period for certain of our patients who have transitioned from ILLUMINATE to IGNITE, which is our interventional trial. And in addition, we're seeing some interesting observations at baseline in these patients. Their biomarkers are altered. So for example, CSF1R is significantly reduced in ALSP patients, and NfL is highly elevated in ALSP patients at baseline, and also, their ventricular volume is increased, and their gray matter volume is decreased. But most interestingly of all, we're seeing that there's a statistically significant correlation between changes in MRI and cognitive decline, as measured by MoCA, and that gives us a good indication that there's a correlation between the biomarkers and the disease progression, which is very helpful for our conversations with the FDA. And we're seeing some patient segments that are emerging from both ILLUMINATE and IGNITE. I know it can get confusing, so just ILLUMINATE is our natural history study, IGNITE is our interventional trial. But we'll probably get into that in a minute. So, I think that's a really important point, though. You're essentially, to some degree, validating the use of MRI as a biomarker. Is that right, the right way to think about it? And how do you think about the potential for the MRI data to be key to securing approval? Yeah, so, you know, in initial conversation with the FDA, they did leave the door open to MRI being a surrogate biomarker for advocacy. Of course, the burden is on us to show that linkage, just as you were talking about, and that is why ILLUMINATE, one of the reasons why ILLUMINATE is so important to that biomarker strategy. As Jen mentioned, seeing a statistically, a very robust statistical correlation between several of the MRI, the volumetric MRI measures, which are, you know, these are quantitative measures that aren't subject to some of the same bias as clinical measures can be. So being able to see that really tight correlation between that and clinical decline, measured by MoCA, as Jen mentioned, but also other clinical scales that we've included, that gives us the data, which is critical, to be able to go and start these dialogues, which we're doing actually now in the first half of this year, to be able to start these dialogues with the agency and start to work toward that alignment. They've left the door open, now we need to sort of put that in front of them and have that conversation. So what expectations should we have to get more data from ILLUMINATE and, you know, can you put any timeframe on when we would get another data cut? Well, maybe just also to back up on the FDA interaction, so, or plans, like, you know, so IBART is the first clinical candidate that has the potential to serve a serious unmet need. And with the data that we've collected from both ILLUMINATE and IGNITE, we believe we have a compelling package to start those conversations with the FDA. We plan on having those in the first half of this year, and we expect it will be an iterative process as we share data and educate the FDA about ALSP, as we get their feedback, and it will be helpful for us as we think through the next stage of the trial. Okay, great. So moving on to IGNITE, you, this is a trial that we, I'll ask you about trial design in a second, but we had a first interim read last year. There's another interim read coming in the third quarter of this year. That's right. So, just walk us through the trial design and what you're looking at? Sure. So the trial design, it's an open-label, 12-month study, enrolling symptomatic ALSP patients. The primary endpoint is safety and tolerability, but we're also looking at PK, PD, MRI biomarkers, and clinical measures like MoCA, CBSF, and FTD-NACC. So far, the data has improved our confidence, increased our confidence in the safety, PD, and PK that we first saw in the phase 1 in healthy volunteers. And now we're seeing it continues to be extremely safe and tolerable, very good PK, stable, predictive, supportive of once-monthly dosing, and interestingly, we're seeing some patient segments emerge, which I think it'd be great if David could share a little bit more about that. Yeah, so we had 6 patients, and maybe I'll get to your question about, you know, what's coming up in the third quarter. But we had 6 patients that were in the interim analysis that we talked about in November, and within that group were three that fit kind of the general sense of ALSP in terms of having progressive disease, cognitive impairment, a lot of the other things that Jen talked about before. And within those individuals, it turns out that all of them were previously in our natural history study, so we had their own data to compare to. Within those individuals, we see that the rate of progression on these MRI biomarkers is slower during the treatment period as compared to their pre-study rates of progression. Similarly, as I mentioned, we see a nice, very nice, robust increase in the amount of soluble CSF1R that we measure in the CSF of these individuals. So these are key along with, you know, data we've seen on NfL. Within that segment, that's what you would wanna see. There, the disease is progressing, and you'd wanna see that slowing down. Yep. Now, there were other patients, three other patients, that did not have cognitive impairment at the time of enrollment. They had other symptoms that qualified them for the study. They had evidence on MRI of some initial progression, but they hadn't converted into kind of that full stage, and so we think about that as a different segment because this is a group where you can think differently about the treatment goal. In fact, you don't want them to progress into that more, you know, kind of, the progressive classical stage. And to date, in the six months that we have, again, comparing to each of their own individual baselines, we don't see much change. There's not much change on ventricular volume or gray matter volume. And that is, in this case, a really good thing, and that's something that we're really excited about. And as we continue to follow these patients now, to get to your question, at this next interim analysis in, at the third quarter, we will have 12 months of data on those, you know, on all six of those individuals, and that will allow us to, you know, continue to look at the trends that we saw from the beginning, including on those earlier subjects, and see if we can... If we can continue to prevent them from going into that aggressive stage that we know is the typical course of the disease, that would be a real game changer. And then in addition to that, we will have data from, at six months, from the patients that have completed six months at 40 mg per kg, which is a higher dose level. Okay, great. And are you expecting to see a dose response? So what I would say is that in the healthy volunteers, we did look at both 20 and 40, and we did not see any kind of really meaningful difference between 20 and 40 on the biomarkers- Yeah ... that we're measuring. That said, we're now in a patient population. Yep. You know, specifically, for example, on CSF1R, we will be looking to see if there is a difference. That's the reason why we included two doses. No real expectations one way or the other, other than it's an important thing to do to establish, and there's certainly potential that we could see something at 40. I guess just to make sure we have this clear, so you enroll the patient population that was symptomatic, and half of the patients had cognitive decline. The patients that had cognitive decline, you saw a slowing with treatment, and then patients who didn't yet have cognitive decline, you didn't see any progression into cognitive decline. If I've got all that right, how do we apply that to the broader ALSP patient population? Is it? Do you expect it to be 50/50, or how do you think about the different patient segments? And then, is there a way of identifying patients before they go into cognitive decline to make sure that you have the most, the biggest impact on potentially a patient's disease? I think it's important to mention that we were surprised by the mix that we got in the six patients, and that the majority of the additional patients that are in IGNITE that we'll see in Q3 of this year are of that progressive stage, which is where we would expect. So anything to add to that, David? Yeah. You know, we think it's a transient, kind of you know, uncommon, smaller group in terms of those that didn't have cognitive decline. There's another measure that goes along with that, which is their NfL levels. So, for several of those subjects, they had actually pretty normal low NfL levels. So we do think there are some biomarkers that we could use to identify very early in disease, you know, when you might want to intervene with treatment for somebody that was a genetic carrier. That, again, it's kind of an opportunity that presented itself. We do see a little bit of this in the natural history study, but the bulk of the patient population is the more advanced group. And then, just thinking about that group at 12 months for the second readout, how should we think about expectations for that rate of slowing of decline? Do you think it remains consistent? Could it remain consistent? Do we just need to wait for data in that progressive population? David? Well, I mean, as many of these diseases, you don't really know the trajectory of efficacy. We're very encouraged by seeing changes on some of these biomarkers early, you know, as early as six months. I can just say that, you know, the KOLs we've talked to, that's one of the things that they comment on a lot, is that seeing, you know, some evidence of some changes at six months is quite impressive to them that the disease, some of the aspects of it, so, like, how long does it take to fully clear NfL, for example, we will learn. But ultimately, we, you know, we think we have the right mechanism. We think we have the right molecule, and, you know, we'll we're excited for the data. Got it. So if we can switch over to the small molecule, let me ask an obvious question to start with. When you're thinking about a patient population like Alzheimer’s disease, why is an oral so important versus an antibody? Well, so there's a lot to like with VG-3927, which is our oral TREM2 agonist. You know, some of the obvious things are around, you know, ability to combine, convenience for patient, and access, and those kinds of things, but that's actually really not why we selected this modality and this molecule. VG-3927 has a unique interaction with TREM2 as compared to the antibody, and that actually has a functional and biological consequence that we've talked a lot about. But in a nutshell, the way that it interacts does allow for a synergy with the normal natural ligands for TREM2. As I mentioned before, these are the ligands that tell TREM2 to convert microglia into their more neuroprotective state. What we've seen is that when we have VG-3927, it's just a small molecule, it's quite impressive that it can act as an agonist by itself. But when we have it present with also these natural ligands, we see a really nice synergy. And the way to really think about that is that very locally, in and around regions where something is going wrong, that's where you wanna focus and mobilize the microglia. So we think that could lead to increased efficacy and therapeutic index because of that spatial specificity, and it's one of the, one of the reasons we selected it. Another important reason is that it has to do with ARIA, which is an established risk of the current treatments that have been approved. The linkage that's been made is that those treatments have an Fc component, and they have high concentrations in the vasculature of the antibody. Recently, there's data that suggests there may be potentially, and although the mechanism of ARIA is not known, involvement of that Fc-mediated sort of immune function through perivascular macrophages or complement engagement, as a component of what might be driving ARIA. Now, it also might just be because of clearance of plaques. In the former case, there's a real advantage to the small molecule, a huge advantage because we don't have an Fc component. We don't require that, in order to activate TREM2. Even in the latter case, if it's just a consequence of plaque clearance, it's still much easier to manage clinically, which is done by dose adjustment and discontinuation with a small molecule. A lot of reasons to like that approach. Yeah. So then when we think about mechanistic rationale, and the focus here, obviously, is Alzheimer's disease, I think it's more clear or it's very clear in genetic variants of TREM2, but can you just talk about the broader Alzheimer population and what the mechanistic rationale would be, there? Yeah, exactly. So, I mean, again, there's some broad data that's emerged more recently around the importance of TREM2 in terms of being protective. So, you know, for example, essentially, I'll just summarize the data by saying, more TREM2 appears to be protective. Mm-hmm. That's, you know, generally the case, not just specifically for the genotype. The original linkage was made to something like R47H, which is a variant of TREM2 that clearly leads to very elevated risk of Alzheimer's. However, we have in our preclinical work, we've shown that our small molecule equally activates all of the different variants of TREM2, as well as the common variant. So from a potency and in functional engagement perspective, we don't actually expect any difference across the different genotypes. And our, you know, long-term expectation is that you could use a TREM2 agonist across all of these genetic variants, as well as across stages of disease. One of the things we haven't talked too much about is that one of the interests in TREM2 is that it's not specific to just amyloid. So when you harness the immune system, anything that's going wrong becomes substrate for the microglia, and that's just a really exciting element of kind of a next generation approach. But fundamentally, you know, we think that there's potential across all the different genotypes. We will, in our phase 1, include a, an AD cohort within our phase 1 study, and we will look to, you know, include some individuals with some of these genetics that I just mentioned. And the purpose there is for us to gather data so that we can understand and really select the right AD population, you know, including consideration of genetics. Okay. So you're enrolling now in a healthy volunteer portion of the phase 1 study. Just before we get there, and we'll get data the middle of this year. Just before we get there, FDA asked you to gather some more information about to inform the maximal dose. Can you just give us a really brief overview there on what your progress has been? Yeah. So, FDA. Well, I mean, the phase 1 is going, is ongoing, as you mentioned. We continue to work with the FDA to address the partial hold. Now, as it turns out, and we've said this before, the maximum exposure limit that's associated with that allows us to get to and test our projected efficacious dose, and to go above that. So in that context, we continue to move the MAD program forward, or the SAD and the MAD program forward, and gather the data, you know, because we're, we're able to do that, and sort of unimpeded by that limit. Okay. So then just give us a quick overview of what data we should expect to see in the middle of this year. So from VG-3927? Yes. Yep. Yeah. Yep. Okay. Yeah, so, you know, we'll look at safety and tolerability. You know, we'll look at the biomarkers. Again, as Jen mentioned, we have this synergy with our previous program, and that we've collected and looked at some of these biomarkers, and we have a good sense of them. So we'll look at, you know, some of those same biomarkers in our phase 1 study. We'll also look at PK, and, you know, ultimately, that's the data we'll be looking at here at the data release here in the middle of the year. Fantastic. Well, really appreciate you both being with us today, and look forward to the data coming this year. Thanks, Jason. Thank you.