We're good to go? Awesome. Well, thanks, everyone. Thanks for sticking around. We're happy to be here. It's a pleasure to be joined with Vigil. I'm James, one of the associates at Stifel, and with Vigil, we have David Gray, CSO, and Jennifer Ziolkowski, CFO, so thanks, everyone, for being here. I have a bunch of questions, but if anyone has anything, feel free to jump in, so maybe just to start, we can just, I don't know, maybe David, if you want to just give kind of an overview of Vigil 101, kind of where things stand with ALSP and kind of the small molecule program as well. Yeah, I think I'll start with that. That's all right. Yeah. So as you know, we're Vigil, and we're a CNS company focused on microglia, and our first two targets are in TREM2. Our most advanced program is iluzanebart, or we call it IBART for short, and it's a monoclonal antibody TREM2 agonist. We are currently in a phase II clinical trial in a disease called ALSP, which is a rare, devastating disease where there are no treatments for today. We had data in six patients, six months, at 20 mg/kg back in November, so a year ago today. And since then, we completed enrollment of 20 patients in the trial, and we're going to have a readout in the first half of 2025 for that program. And as far as our small molecule TREM2 agonist, we call that VG-3927. For that one, we had interim data in the summer of this past year, supported continued development, and we will have data in the first quarter of next year. Awesome. Awesome. Maybe we can start with ALSP first and then dive into Alzheimer's. So yeah, it was, you know, you had six months of open label data initially in ALSP. Maybe it'd be great just to kind of walk through those data and kind of one or two, like the most kind of key data that stand out as kind of compelling relative to, say, natural history that is supportive of an effect. Yep, sure. Our clinical trial is actually the first interventional trial in ALSP. We're the first company to do so. It's a phase II trial. Its primary objective is safety and tolerability. We're also measuring PK and PD as measured by CSF biomarkers, as well as MRI biomarkers like ventricular volume and whole brain volume. We're also looking at cognitive measures like MoCA and CDR-SB, Sum of Boxes, et cetera. As you said, we had data in November of last year. Using that data, as well as very informative, has been ILLUMINATE, which is our natural history study that you referenced and is the first natural history study in ALSP. Through that, we determined that there were really multiple segments of ALSP patients that we had enrolled in the first set of data, and that in the progressive disease patients, we saw that there was slowing of disease. In the more mild patients, we saw stabilization. The natural history study has been really important in really helping us understand the overall trial. It is a 36-month study. The goal of that study is to understand the patient journey and both the biomarkers, fluid biomarkers, as well as MRI biomarkers that characterize the disease. From that, we determined that at 12 months was the best time to look at cognitive measures. We'll be looking at that at 12 months in IGNITE, or our interventional trial. Interestingly, from some of the takeaways we saw in the natural history study was that at 12 months, we saw that there was a statistically significant correlation between changes in MoCA scores and changes in MRI, which is really good for us in terms of aligning disease progression and biomarkers as we talk about or as we continue our conversations with the FDA. Generally, I guess the important takeaway is that it's really the totality of the data, both studies that are really impactful for us. Yep. Yep. No, that makes sense. And you mentioned the FDA there. So you recently decided to not do a second interim and instead are kind of running full ahead with the study after meeting with the FDA. So it'd be great just to kind of understand what the interaction with the FDA was and kind of the rationale behind that decision. Yeah. As you said, we were originally going to do a 12-month look at the six patients that we had looked at last November, but after discussions with the FDA, and we had a type C meeting with them that was very engaging and encouraging, and we determined that it would be better for us to do some additional analysis and show them additional data that we had, and also pre-specify the endpoints would be important to do before we looked at the data again. It is technically not a blinded study, but we are looking at the data just so that there doesn't need to be any additional bias assumed in the trial, so we're going to continue to put that analysis together and have that dialogue with the FDA. We'll expect to have an update on that around when we have the new data in the first half of next year. Okay. Yeah, that was going to be my other question, which is kind of what the back and forth looks like. And so are we going to know before we see the data, or is it going to be like at once you think will be like what the primary analysis that you aligned on is and kind of what the data are? Yeah. No, well, so it's an interim process with the FDA, so we're still figuring out exactly what that looks like. So it'll definitely be before. It's the possibility that it will be with the data as well. But we're continuing to discuss and have to get a better idea and have some more dialogue with them. Yep. Okay. That's great, and then, yeah, I guess what are some of the possible scenarios, I guess, in terms of maybe what an endpoint might look like or what exactly the comparator may be? Just kind of curious what you're thinking through as the possible kind of options here. In the most optimistic case, we're hoping that this data can serve as the trial that we use to file on. We've always been pursuing a biomarker strategy. Going with accelerated approval, the FDA has left the door open to MRI, and we think that ventricular volume is a good measure. It's very measurable. You can see it clearly, so we're going to continue that discussion, but as far as exactly what the trial looks like, we're really still in the early stages of those discussions, but our conversations have been productive, and we feel like we know what the next step with them is, and we'll see how it goes, but our optimistic view is that we can use this as the trial we file on. Yep. Okay. And it would be like a natural history comparator. Yes. Exactly. And that's why it's so important that we have ILLUMINATE. We've been running that study for quite some time. It's 36 months, or almost 48 months that we have data for, I think 36. And it's been hugely impactful and helpful for us. And we actually had the six patients that we shared in November of last year. They all were on the natural history study. So they were able to serve as their own run-in to the study. But overall, the general population of patients, of which there are about 50, we're hoping can serve as a synthetic control arm for the trial. Yep. Okay. And yeah, I mean, I guess from those kind of initial data, I mean, I guess how are you thinking about what is kind of defined or what the FDA might find as clinically meaningful effect size on ventricular volume or any sort of one of these MRI measurements? Just kind of how are you thinking through that, and again, based on what you saw in these initial data. Yeah. I think David, do you want to take that one? Yeah. So that's very important, the correlations between any biomarker that you would want to use for accelerated approval and then being able to show that it correlates with the kinds of clinical endpoints that are meaningful to patients. And Jen referred to this, but a big part of the learning from the natural history study is being able to build those correlations where we see that both cognitive and functional scales are highly correlated with the progression on MRI. And so that is, in a large part, the bulk of the data around which we have these regulatory discussions, because we're not looking at the phase II data. What we're really doing is saying this endpoint, we think, is a very good endpoint as a surrogate for what's going on in ALSP by establishing the strength of those correlations. As I said, those include both cognitive and functional correlations. Yep. Yep. That makes sense. And then, yeah, maybe one last question, and you kind of touched on it earlier with there's kind of two phenotypes of patients here, those that are kind of stable and those that are progressing. I guess any consideration around there in terms of these next six patients, if they're going to be progressing or more stable, or just kind of curious what the sort of ultimate patient population you want to kind of study is? Yeah. Go to the FDA with? We showed the six patients that we've enrolled 20, so our next readout will include quite a bit more patients. Actually, from our natural history study and also enrollment in the trial, there are more patients that are of the more progressive disease. We were actually surprised a little bit to get a couple of patients that were so early in the first data set. The majority of the patients are in that more progressive. We'll expect to see. You can expect to see more of that in the final data set. Yep. Awesome. Great. Okay. And then I guess looking beyond the trial, obviously, there's another question here around the prevalence of ALSP and where these patients are treated and how they're identified, et cetera. So yeah, I mean, it'd be great to kind of just understand your current thinking around prevalence and some of this kind of market-building work that you guys have been doing. Yeah, we have been spending a fair amount of time with that because ALSP was only defined well, the CSF1R gene actually is what when it's not working properly is what causes ALSP. And that was only defined about a little over a decade ago. And so there's definitely populations that are being misdiagnosed. And so it can be a little challenging to get hands around those numbers. But we've been so we previously thought actually there was 10,000 patients in the United States. And then recently, there's a number of newer publications that have come out that we've triangulated to show that that population is actually much bigger. So first is that one of our KOLs who's very prominent in the field, Dr. David Lynch, did a study with the UK Biobank that actually showed that ALSP-causing CSF1R variants were much higher than we thought. We know also that 16% of leukodystrophies are ALSP. And we know that in MS clinics and AD clinics, they're often misdiagnosed, like 0.5% for MS and 0.3% for AD. So when you really triangulate all of that data together, we come up with 19,000 patients in the U.S. that have the disease, and then about 29,000 in Europe and the U.K. combined. But it's also a rare disease, so based on the definition. And so finding these patients and getting the prevalence can be tricky until you have a treatment, which, of course, we hope will be in existence for these patients sometime soon. Yep. Yep. Awesome. Yeah, I mean, I guess is there anything else within ALSP? I guess, obviously, the next catalyst is these data, but I guess kind of what would kind of the next catalyst after that be or kind of the process after that look like? I think that once we have more data, we'll obviously be able to have continued conversations with the FDA. I think the question that we'll have is, what is that phase III or confirmatory, or what does that look like? It's a little bit too early for us to speculate on what that would look like. We have ideas in our head, and we're glad that the FDA has been so engaging and really seems to understand the disease and the challenges that the patients in this population have. There was actually an FDA listening session, patient listening session earlier this year that the FDA held, which we thought was helpful, and they really seem to want to help. I think that's encouraging, and we continue to develop those relationships. Yep. Awesome. Great, well, I guess we can jump over to Alzheimer's now, and obviously, one of the most topical things on our mind is the Alector IV data, which should be, in theory, coming anytime soon, so yeah, I mean, it'd be great just to kind of understand or hear your thoughts on kind of your expectations for that readout and what the read-through may or may not be to kind of your whole TREM2 platform. Yep. Well, we hope they're successful. We think that is going to be great for them, great for us, great for the field and for patients. But maybe, David, you could go into a little bit more about what we think about the Alector readout. Yeah. I mean, what I would say at a high level is that there's been interest in immune-based approaches, so neuroimmune modulation, and specifically TREM2 as the top leading target in that for some time ever since the really strong human genetics came out, starting to show and then being replicated over and over again that compromised TREM2 function was a big risk for AD, that it impacts AD progression. And then more recently, biomarker data showing that increased levels of TREM2 are protective. So all of that causal human data is strong and is one of the reasons I think everyone's looking forward to the readout because this is, to some extent, represents this next generation of potential AD therapies and going beyond where we're at right now, which is we have some approved therapies, but there's still a lot of residual need and there's still a lot of residual progression. So basically, we're all in on TREM2. As you heard Jen describe, we believe this is a really important target on microglia. I think what we're also saying is that our specific approach is a small molecule approach, which is very different in a lot of different ways, not just around modality, but also around some of the ways that the target is modulated. And like any CNS target or any target in general, ultimately, what's important to test a hypothesis like this is to get enough target modulation to actually move the biology and be able to make sure of that. So you ask what we would be sort of looking to or how we'd frame the data, one big thing that I'll be looking at is looking at some of the biomarker data and some of the other data for evidence that there is actually modulation of microglia. Again, as Jen said, we believe we have a differentiated and superior molecule with our small molecule. We can go a little bit more into some of those specific differentiations potentially a little bit later because they're quite important. But because of that, again, we hope they're successful. But if they're not or if there are challenges with the data, we think it's important to look at the fact that when you run a study like this, you're testing both the molecule and the hypothesis and that they aren't sort of fully linked together. Yep. Yep, and yeah, maybe it'd be good to go through kind of the small molecule, which you've described as a molecular glue versus a mAb and kind of your confidence that or I guess maybe, yeah, just the difference between the two and that kind of your confidence that a mAb working might read through favorably to the small molecule. Yeah. So we're uniquely positioned to be able to understand this both because of our expertise in microglia and because we have both a clinical stage antibody and a small molecule. So I think we do understand the differences. And we've chosen to position our small molecule in AD because of some of these differences. And I'll give you a couple of the really important ones. So they bind differently to the target, and they have very distinct binding sites that are non-overlapping. And what we've noticed is that these differences have some functional translation into the way that the target is modulated. And one of them is that the small molecule acts as a positive allosteric modulator in addition to being an agonist. And that is not a profile that we've seen with the TREM2 agonist mAb. So that additional spatial enhancement and specificity that comes from the engagement of the normal TREM2 ligands, among which are things like A beta, ApoE, other damage-indicating lipids, those are found in higher concentrations near to the pathology. And so that PAM effect, we think, is potentially important for overall modulation. A second has to do with the interaction with the receptor itself. The antibodies bind to the extracellular domain of TREM2, which is the same part that gets cleaved off to form soluble TREM2. And when that cleavage happens, the antibodies continue to bind to that domain, which forms a type of a sink, sort of another binding element that is not productively coupled to agonism, whereas the small molecule does not interact with that. So that's one advantage. And then finally, the modality itself does confer a really important advantage just around ultimate brain penetration. There's some upper limit around where antibodies you can't get any more into the brain. You've reached a maximum dose, whereas with the small molecule, we're able to dose up as high as we need to. And we have a fully brain-penetrating molecule. We shared a little bit of that at the mid-year update. And so we're confident we can get to modulate and strongly modulate the target in a way that is more difficult with an antibody. Yep. Yep. That makes sense. And yeah, one of the more interesting signals we've thought from the Alector study is the signal of ARIA. And just what we've seen with the Aβ antibodies, it sounds encouraging that it looks like and sounds like it's ARIA, similar to the Aβ mAbs. I guess with your small molecule approach, is that something you would expect to see? Or I don't know necessarily why you would if it's a small molecule and not an antibody, but just kind of curious what you make of that signal and if that has, again, something you would expect to see with your small molecule. Well, we're still in a place as a field where we don't fully understand why ARIA emerges, right? It's not directly linked to efficacy from the standpoint that there are many patients who experience efficacy with no ARIA. And so there's probably two main ways to look at this. One is that when you clear amyloid at significant levels, that there's some increased risk of ARIA development. So it's sort of part and parcel to the efficacy. And in that scenario, any effective therapy that clears amyloid is likely to see ARIA. And there are still some advantages to having a small molecule, and that has to do with the clinical management of ARIA. It is a very important topical thing right now. Clinically, with a small molecule, you can readily down-titrate or quickly adjust dosing. A little harder to do with infusion. More intriguingly, perhaps, is the possibility that ARIA is not linked to plaque clearance. We don't know that yet. So this is the other kind of main theory is that it has something to do with engagement of the immune system by these antibodies, which are present in really high concentrations in all of these studies. You think about the antibodies having the end that modulates the target, but there's this additional component, the Fc component that interacts with the immune system. All of the antibodies that have shown ARIA have an intact Fc domain. And there is preclinical data suggesting that that interaction may be the driver of ARIA through recruitment of other elements of the immune system that have nothing to do with the modulated target, whether it's Aβ or TREM. In that instance, because the small molecule only interacts with the agonist element and has none of these Fc or other interactions with the immune system, we may be able to completely dissociate those things. Very, very interesting. Yeah. Yeah. No, it's very interesting, and yeah, I guess we have some biomarker data from the small molecule program. I think the one thing that we were wondering when we saw the data was there's no impact on CSF1R, which was different than your antibody, and then also what we saw with Alector. Maybe it'd be great to just hear kind of why you think that is and why that's not a cause for concern or anything like that. We don't actually know why that is. There isn't a direct linkage pathway-wise between TREM2 and CSF1R. Observationally, Alector observed it with their antibody, relatively modest increases in soluble CSF1R, and we observed it with our antibody as well. And I can tell you that preclinically, we saw increases in soluble CSF1R with our antibody, but not with our small molecule. So not surprising to us that clinically, we also are not yet seeing any changes in soluble CSF1R. As it pertains to ALSP, CSF1R is very important. This is the mutated element. As it pertains to Alzheimer's, there isn't a therapeutic hypothesis that's connected to an importance of increasing CSF1R. You actually may be aware that some companies are running CSF1R antagonist programs. So there's not a disappointment, let's say, or any sort of expectation that we had around seeing that. The reason that they're different, we don't yet know the answer to that. As we've talked about, there are some differences between them. Yep. Yep. That makes sense. And yeah, I guess with sTREM2, there's a lot of confusing literature out there on sTREM2 and what it might imply. And yeah, it'd just be great in terms of kind of how you interpret kind of the initial sTREM2 signals you've seen and kind of what that implies for how you're thinking about dosing and where you're in terms of at the right dose and sufficiently engaging the target or whatever it might be in terms of kind of getting confidence moving forward. I mean, I love that we have soluble TREM2 as a biomarker because it tells us not just that we're in the brain because we're measuring in CSF, but it also gives us a functional readout. So the mechanism by which soluble TREM2 goes down is the agonist mechanism internalization of the complex, which then protects the domain from being cleaved. So it's a really, really nice readout that we're not just getting to the target and interacting with it, but functionally causing the agonist response. We have seen so far in our single ascending dose data that we've shared that the magnitude of this sTREM2 response that we get with our antibody and our small molecule are very similar. We're able to achieve that in the middle of our dose range with the small molecule. We've also said that we also see a durable effect in the MAD, and we saw that also with the antibody. I would generally caution about making cross-assay comparisons with this assay. It turns out to be relatively tricky to measure accurately, especially or particularly when the therapeutic also binds to soluble TREM2. I talked about that before. That can potentially influence the data. Although we don't have any direct comparative data, it's very appropriate to compare that data within our two programs because we're using the same assay. We can't really comment on whether our assay is comparable to the one that they're using. Yep. Yeah. Makes sense. And kind of on that as it relates to dosing, there originally was a partial clinical hold related to exposure caps, and that was always below kind of the sort of threshold you thought you needed for efficacy. But just curious, does that change how you're thinking about dose exploration or anything like that now that that's been lifted, that partial hold? So, it didn't really change the way we executed the program because we didn't have any delays associated with the cap. The partial hold cap was still, like you said, high enough that we felt we could get to where we needed to go to. It's always good to have the full range of being able to go higher. And so we'll lean into that as we complete the rest of the MAD and the rest of the study. But didn't really change too much of the strategy of what we were doing. And just as a reminder, that was never related to any toxicology. We've tried to be clear about that, that they're sort of just more exposure-related. Yep. Yep. Makes sense. So yeah, I guess kind of what are the next steps in timing with the small molecule and what may we learn next year kind of looking ahead? So we will complete the entirety of the phase I, which we've already shared data from the SAD and include the rest of the MAD and healthy volunteers. It will also include a single dose study that we're currently dosing in Alzheimer's disease patients. And just to be clear, I mean, this is a single dose study, so it's not an efficacy study, but we are, again, able to leverage the soluble TREM2 biomarker for a specific purpose. So what we're looking for here is we're enrolling individuals that have a genetically defined element, so either TREM2 loss of function mutations or some ApoE4. And what we're looking for would be very large differences in the biomarker response, specifically the soluble TREM2 response, relative to what we see either in the common variant AD patients or what we saw in healthy volunteers. Now, to be clear, we don't really expect those differences, but this gives us an opportunity to clinically kind of confirm that the biomarker response is intact and our target modulation is intact as we define the population for the phase II study, and if we would see some large differences, we would incorporate that either exclusion or inclusion criteria. And I was going to ask, Alector is obviously studying just a general Alzheimer's population, not a genetically defined one. Just kind of curious how those data might also inform kind of what exactly you would study in phase two in terms of a patient population, if it looks great in kind of a broad Alzheimer's population? I mean, we've said, I think, a lot of times that we don't expect that there wouldn't be any reason we couldn't do an Alzheimer's. That's sort of our plan A and primary plan. But again, this study gives us an opportunity just to look at that and confirm that. And I guess I don't expect that they will have large numbers of any of the genetic variants to where that would maybe I'd be wrong about that, but we'll see. Yep. Yep. Awesome. Well, last thing on the small molecule, Sanofi made a strategic investment and has a right to first negotiation on the small molecule. I guess maybe it'd be great just to kind of understand practically kind of what that actually means in terms of Sanofi's rights to negotiate. Yeah. So in the summer, we did announce that we did a strategic deal with Sanofi, which we were really happy to do. They made the $40 million equity investment in the whole company. So that's not specific to any program. But the right of first negotiation that you mentioned is specific to our small molecule program, including VG-3927. So that gives them the right to see some additional data that we don't necessarily have that hasn't been disclosed now and have the right to negotiate with us a global license for the small molecule. So it doesn't preclude any other deals we might want to do, and it is specific to the small molecule. But we are happy to be working with them, that they seem to have an appreciation for TREM2 and our small molecule in particular. This just gives us a good mechanism to continue to engage with them going forward. Yeah. Yeah. That makes sense. And then I guess in the last 30 seconds here, unless anyone else has any questions, just be great to get kind of cash, current runway, and kind of where things stand there. My favorite question. Yeah. So at the end of September, we had $110 million in cash, and that will last us into 2026. So through our very active schedule that we have next year. Yeah. Absolutely. Well, great. Looking forward to it. Thank you. Thanks so much for being here. Thank you for having us. Thanks everyone for joining.