Good morning, everyone. My name is Yatin Suneja, one of the senior biotech analysts here at Guggenheim. Welcome to our SMID Cap Biotech Conference. Our next presenting company is Vigil. From the company, we have a few executives here, but I will be chatting here with Ivana Magovčević-Liebisch. She's the President and CEO, and I also have a Chief Scientific Officer, David Gray, here with me. I'm gonna pass it on to Ivana. Ivana, why don't you make some opening comment, talk a little bit about some of the upcoming milestones. You have generated some very interesting data on the small molecule very recently. If you wanna touch on that, you can touch. Otherwise, we can go into the fireside chat session with that. Wonderful. Thank you so much, and thank you for the opportunity to share the Vigil story with everyone this morning. For you who don't know us, we are a microglia-focused clinical stage therapeutics company. The 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. Our focus is in neuroinflammation. We believe that the neuroinflammation is the next frontier of drug discovery in CNS. We have identified TREM2 as the key target to modulate microglia biology. It's the only genetically validated target. What differentiates us from other companies is that, first, we have a precision-based approach to neurodegeneration. What we mean by that is that we really focus on indications where there's a very strong genetic, mechanistic, and biochemical association to microglia dysfunction. We are also the only company that has two TREM2 agonists both in the clinic. Our most advanced asset is VGL101, or iluzanebart. It's a fully human monoclonal antibody TREM2 agonist, which is in Phase 2 study currently, for a rare disease called ALSP, which stands for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. The reason we picked that indication is because it checks a lot of those, precision approach, things that we're gonna be talking about. Then, very excitingly, we think we have the next generation, first-in-class small molecule, TREM2 agonist for treatment of AD. That's what you mentioned. We actually just recently released positive Phase 1 data from that study. We have, now a very well-characterized molecule, as I said, Phase 2 ready. I'm sure we'll talk about the details of that study, but safety, tolerability, PK, PD, everything supports moving this molecule into AD. So we've had a very exciting start to the year, and we have a lot of milestones ahead of us. We'll be presenting the full data set from that study at the AD/PD conference in Vienna in April. We will be releasing the top-line data from our VGL101 study in ALSP in the second quarter. And then, very exciting, we'll be initiating a Phase 2 study for our small molecule in Q3. Very good. Very good. Okay, before we go into the program, maybe just a couple minutes on the target, like, what is unique about it? What is the excitement around it? What is this target doing, in these relevant diseases? Okay. I think I will let David share that with you. David? Yeah. So the interest in TREM2 goes back to human data, to human genetics and human biomarker data that strongly implicate dysfunction in microglia, and specifically dysfunction in TREM2, a loss of function of TREM2 as being a significant increase in risk for Alzheimer's, as well as for other neurodegenerative diseases. And follow-up research to those initial human observations have shown us that we, you know, we know microglia are central to the health of the brain. They maintain homeostasis. They clear debris. And specifically, we now have therapeutic validation from the immunotherapies that are approved that having microglia, you know, can actually clear plaques. And so that's the mechanism by which those work. So fundamentally, all of that human data and additional biomarker data as well that, for example, shows that increased TREM2 is neuroprotective has taught us that what TREM2 does is it senses damage, and then it converts microglia from a sentinel state into an active neuroprotective state that can actually address the damage. So they have a dual role as both sensor and as active, you know, clearance mechanism for these different kinds of debris, and that's mediated by TREM2. Got it. It's broad, so it isn't just specific to amyloid. It also can be, you know, there's many kinds of neuropathology that contribute to AD, and that's, that's really the excitement about the next generation moving beyond just targeting single toxic species. Very nice. Very interesting. When you engage this target, whether it's with an oral small molecule or an antibody, is there, are there different consequences or different pathways that it engages if you, depending on the modality you go after? It does not engage a different pathway. It engages the same pathway, but our antibody binds at a different spot than does the small molecule. And what we see with our antibody is that it has an additive effect in presence of natural damage ligands, where the small molecule, because of the nature of how it binds and stabilizes the complex between TREM2 and DAP12, actually also has a synergistic effect. So we actually see a really nice synergy when we do that. They do act on the same pathway, but they do act in different ways. And we certainly do see downstream that they have the same impact. They activate similar genes and, you know, which then result in production of very similar proteins. But the small molecule is extremely potent because of that synergistic effect, and we believe that that's gonna have a really important impact in the areas of active pathology because we think that it will allow it to provide the additional spatial specificity, which can result in a need for lower doses. And we actually think it's also gonna be very helpful to differentiate on safety as well. All right. Anything to add there? Yeah. I'll add one other thing, which is, again, I completely agree that all the work we've done showed that downstream, the conversion to a microglia to protection is the same, but there's another difference which has to do with target access. So there's advantages to the small molecule in, from the standpoint of not engaging with soluble TREM2, which is present at high concentrations local to where the microglia are, and so that combined with the positive allosteric modulation that Ivana just mentioned are modality-specific advantages to the small molecule. Got it. Very good. Very helpful. So let's review the data, the Phase 1 SAD-MAD full data that you recently presented, including the AD patient. Like, what were some of the key highlights of that data? What have you seen on the biomarker front? I'll start and I'll pass it on to David. We conducted a very large study. We wanted to characterize this molecule very well, and we wanted to make sure that we had the package that was ready for Phase 2. This study actually was 115 individuals, out of which 89 received the drug. There were 14 cohorts, eight SAD, four MAD, and then in addition to that, there was an elderly cohort as well as a single-dose biomarker AD cohort. So extremely well-characterized molecule. After that, you know, we saw favorable safety and tolerability, no SAEs, no discontinuations. All the AEs that we saw were mild to moderate, self-resolving, no clinical signs, normal EKG. So a really nice profile to take into Phase 2. In terms of PK and PD, a really beautiful relationship between the two. The PK supports once daily dosing. And on the PD, as you know, for us, soluble TREM2 is the key biomarker here because it's not just the target engagement biomarker, but it's also a functional biomarker. And we saw a dose response, and we also saw very robust and sustainable reduction in soluble TREM2, which was up to 50%. And I didn't mention, but the doses we studied in the SAD was up to 140 mg dose. In the MAD, it was up to 50. And based on the pharmacology we've seen, we believe that 25 milligram is the dose to take into Phase 2. The other important thing is that we did an elderly cohort, and we saw that in the elderly, we saw the same reduction in soluble TREM2 that we saw in healthies, and the same was with the AD cohort. The purpose of the AD cohort, because it was a single-dose biomarker cohort, was really to look at and confirm what we saw preclinically, which is that our small molecule is active against all genetic subpopulations in Alzheimer's disease. And we actually confirmed that with this cohort. So we plan to take the molecule into all comers in the AD study. Anything that I missed, David? That was really comprehensive. One thing that maybe people don't appreciate, just to kind of add some color to what Ivana just said, is that soluble TREM2 is a uniquely very good biomarker for us. And that is for a couple reasons. One is that it's exclusively expressed in the brain on microglia. So we know that when we see those changes, we know that they're coming from our desired cell population and our desired target. And as Ivana mentioned, the reason that we see that it's a functional biomarker, the reason we see a decrease is because agonism leads to internalization, which protects the soluble fragment from being cleaved. So we have this. It isn't just about binding. You know, rarely do you have these kinds of biomarkers that really can tell you that you're actually activating your mechanism. In this case, we have that. It's something that gives us more than just target engagement, but also gives us function and agonism. Got it. I think, so my understanding is that, at least on soluble TREM2, you are actually seeing even more robust response with a small molecule than even an antibody, right? Like, is it a fair way to look at it, at least looking at the percentage that you saw? Yeah. That's correct. So in our single ascending dose, we had previously shared some data from that we reached a plateau in the middle of that dosing. But when we move to the multiple ascending dose, we get a couple really other key pieces of information, including what you just mentioned, which is that the absolute magnitude of modulation goes up, you know, notably to what we believe is a maximum modulation of the target. So we think we're fully engaging the target, and that comes not just from the clinical dose response and the PK/PD modeling, at the doses we tested. As we went up higher, we also, you know, reached a maximum. But it also lines up very nicely with our preclinical data, showing a very similar maximum, and we have a good understanding of why that maximum is there. So we're confident that at 25 milligrams, we are fully engaging the pharmacology. Yeah. As you mentioned, the absolute magnitude is higher than what. Yeah. you know, than what we observed previously. So, I think you, so your plan is to go into AD study. The question is, are there other biomarker or what is the most relevant biomarker as it relates to AD? Because that sort of is where you're planning to move. Yeah. I mean, AD is challenging from this kind of simple biomarker standpoint because we still are at a place as a field where we don't have, you know, single protein biomarkers that are correlated with efficacy. And as we look ahead to Phase 2, we certainly will be including the key biomarkers in a Phase 2 study that can inform on efficacy. What we are able to establish here in the Phase 1 very, very, very clearly is that we are engaging TREM2. Mm-hmm. That we are having the, you know, the desired functional effect on microglia, as I mentioned, because of the soluble TREM2 component. The other biomarkers that people have maybe been looking at this in this space are not TREM2 specific across all modalities. You know, we've put a lot of effort into that. But ultimately, soluble TREM2 is exclusively expressed on microglia, and so we're able to be confident that we are fully engaging the target and the mechanism. Got it. The things we'll be looking in the AD study, we'll obviously be looking at GFAP. We'll be looking at the reduction in amyloid. Yeah. Right. Those are the type of things that we definitely will be looking in Phase 2. But we are confident today with what we've seen with soluble TREM2 that we have a very active molecule that obviously is extremely well-characterized at this point. Got it. So the 25 milligram dose, that's a QD dose? Yes. Correct. It's once a day. Okay. So at the upcoming AD/PD conference in April, what should be the expectation? What, maybe if you can articulate for us what you are hoping to present, what we should be focusing on? So we actually are very excited because we have two back-to-back oral presentations at AD/PD. So not only will we be sharing the top line Phase 1 data, so you'll obviously see the safety, you'll see the PK, you'll see the PK/PD response, you'll see the actual, you know, data showing the dose response with soluble TREM2. But in addition to that, we're really gonna, you know, characterize our molecule, overall, and in addition to that, really highlight the differences that exist between the small molecule and the antibody modalities and why we believe that the small molecule is the right modality to take into an AD patient population. Anything else? Yeah. I mean, I think a lot of what we've covered here, telling the story, explaining why soluble TREM2 is such a good biomarker and how these things are differentiated. Got it. So what is the eventual plan for this asset? I know Sanofi has made a significant investment, a strategic investment in you last year. Like, is there a time within which they would have to opt in? I'm just curious how you're thinking about it. Yes. So thank you for highlighting that. Yes. Last year, very exciting middle of the year. After seeing some of our SAD data, Sanofi actually decided to make a strategic investment. They invested $40 million at a 100% premium for right of first negotiation on the small molecule program. We haven't disclosed really, you know, how that process is gonna work in detail, but you can imagine that there are timelines that are associated with that. And obviously, we've been engaged with Sanofi along the way, and we're excited to potentially have a partner because we know that something like AD, it makes a lot of sense to partner, and this is the right time to be doing that as we think about Phase 2 design and moving this program forward as quickly as possible. Okay. Are you going to have any FDA interaction on this program to figure out the Phase 2 plan before sort of you decide to partner? I'm just curious where the regulatory discussion is and, and any update on that we should expect this year. You know, right now, all we've said is that we will be initiating a Phase 2 study in Q3, and we're taking into account there, obviously, any alignment with a partner as well as any regulatory interactions. Are you saying anything about the size, scope, design, anything about the Phase 2 yet? Not at this point because we wanna make sure we obviously, we have a lot of ideas and thoughts, and, as you can imagine, there are things that you could do quickly to show some really nice differentiation. You could go into a, you know, a large, Phase 2 study. So that's all on the table. We really wanna make sure that we align with a partner on that. Got it. Before we share the details. Got it. So I think that's all I had on the oral program. I wanna move to ALSP and the VGL101. Can you talk to us, like, where are we, on that program? I think there is some update coming when you have full data. So just curious for you to articulate. Yes. So obviously, extremely exciting for us is that in the second quarter, we'll be releasing top line data from our ALSP study. That's our Phase 2 open label study called IGNITE. It is 12 months in duration. It's monthly IV dosing in 20 patients, two doses, 20 and 40 milligram dose. In addition to that, as you know, we have been running a first-of-its-kind natural history study in this patient population called ILLUMINATE. That study now has over 50 patients, and it's a critical pillar of our clinical development strategy because that study has really allowed us to learn a lot more about this disease progression and identify the right biomarkers that correlate with the disease progression because we are on an accelerated pathway, or we wanna be on an accelerated pathway. So it was critical for us to have those conversations with the agency, and we have identified MRI as the best biomarker for this disease, and we believe that it's the right biomarker to use as a surrogate endpoint. We have engaged with the agency in you know establishing that as a surrogate endpoint, and I'm really pleased to say that the agency so far has been open to both MRI serving as a surrogate endpoint and for the accelerated approval pathway. So obviously, we'll be releasing the data, and depending on the strength of the data, we plan then to go to the agency, and see if we can execute on that accelerated pathway. So this is 12 months on all 20 patients. Correct. At the 40? 20 and 40. 40. But we don't know how many. Is it six and 40? We haven't disclosed that. It's about even. Okay. It's about even. Are there particular thresholds that you have established for you to sort of meet in this 12-month readout that makes it a more compelling case when you go and meet with the FDA? So obviously, this is a new disease. Nobody's been here before. Obviously, we're establishing MRI as a surrogate endpoint. So no, there is no predetermined. What we're looking for is what we saw in our first interim look. Obviously, it was a small N and only at six months, but we were extremely encouraged that we saw slowing of progression across a number of biomarkers that we looked at, in patients that have the progressive disease. So we are what we wanna see is continuation of that trend. Okay. So, slowing of progression. If you talk to the KOLs, they will tell you that this, you know, this being a devastating disease that it is and the fact that it progresses so quickly, that any slowing of a progression would be something that they would be very excited about. But also, as you know, in accelerated approval scenarios, you're looking at the totality of the data. So obviously, we'll be looking at MRI. We will be looking as well as NfL. In this patient population, NfL is not the best biomarker in a sense. It's not a dynamic biomarker. So what happens in these patients is that they have normal NfL levels, and then they spike. And once they get very high, they stay high. And so they're not moving with the disease progression. They're just really, really high until, unfortunately, all the neurons are dead, and then it goes down. So we do expect to see a reduction in NfL, but it comes after you see changes on MRI. So what we've seen in the natural history study, that the first thing that happens in these patients is actually quantifiable changes in MRI that are then followed by very high increases in NfL. So the expectation here is, yes, to see slowing on the progression of MRI, and then yes, to see a reduction in NfL. But we know that that takes time. For example, when we looked at our data at six months, we saw in some patients that we were starting to see that reduction. But we know from Huntington's and other diseases where, you know, NfL is not necessarily a mechanism, that it takes some time to see that, that reduction. Yeah, so one more question going back. So there were three buckets of patient: high progressive, cognitive, normal, and converting. So when you, can you remind us where we are on those three buckets, the new patient that you had added at the higher dose, what type of patient, and how do you expect them to behave? Why do you expect them to behave differently? Yes. So what we learned from that interim look, which was extremely helpful, is that, you know, we want patients in the study who actually have high NfL levels and, also, low MoCA scores because for that reason that I said that you can see MRI changes before you see changes in NfL. So what we enrolled in the study are mild to mildly moderate patients, and we really focus once we pass that first six patients. All of our other patients that we enrolled in the study have that profile, which is high NfL levels and low MoCA, MoCA scores because we believe that the dose of the patients where we're gonna be able to see, you know, the change. To your point, we had two patients in the study, which was very unexpected because we think we caught them before they were converted to the disease. So the reason they ended up in the study is because they did have changes in MRI. But there, once we looked back, we saw that their NfL levels were still normal, and they were cognitively normal. So in those patients, what we saw at six months is that there were no change. And so that would be absolutely phenomenal that if we see at 12 months that they continue on that trajectory of no change. But that's not the patients that we really wanna focus in this study. Yeah. So all the other patients are actually the patients that, as I said, have a progressive disease. And just to mention, the patients don't stay in that kind of, State. Early state for very long. They actually convert very quickly. Okay. Two more questions. Will you unblind the, when you unblind the data, will you, do you have to speak to the FDA first before you communicate to the street? I'm just curious what the plans are. No, the plan is to, you know, do the analysis. We had some conversations with the FDA around how that analysis should look. So we will do the analysis, and then we'll take the data to the agency. Obviously, there will be end of Phase 2, end of Phase 2 meeting, but there's no plan to have a conversation with the data prior to. Got it. Sharing it. This is still an open label study. Blinded in the sense is that you just don't know? Correct. It's an open label study, but we are not looking at the data, and we'll do the final integrated analysis once we have all the data in-house. Okay. One more question. I think this is the one, we do get a lot from investors and then help us understand how we address them. Like, what is a read-through if, if there is any from, you know, the competition that, you know, the drugs from AbbVie Alector, if any, to the biology and then your programs? So, obviously, that was very disappointing for the patients and the community that Alector, you know, did not have a good readout. Our view, because we have profiled that molecule extensively, is that they actually did not engage the target and did not test the hypothesis. And the main reason for that is what David mentioned previously. And the main differentiation with our small molecule is that they bind very strongly to soluble TREM2. And in AD, as you get closer to the sites of damage, the soluble TREM2 levels go up. So they effectively act as a sink. I see. For the molecule and we actually have data, in-house where we show that the antibody actually does not reach the target. Got it. One more question. How is the financial health? What is the burn rate and capital? Yep. Situation? So, at the end of the third quarter, we had $110 million, that puts us into early 2026. Obviously, this first half of the year is gonna be very exciting with a number of, number of readouts. And obviously, there's also an opportunity for non-dilutive financing with a transaction around the small molecule.