Good morning, everyone. My name is Yatin Suneja. I welcome you all to our inaugural Healthcare Innovation Conference. Our next presenting company is Vigil. From the company, we have a few executives here in the room. With me, we have Ivana Magovčević-Liebisch. She is the President and CEO of the company. We have David Gray, who's the CSO as well. So this is a fireside chat format, but I will have Ivana make some opening comments. Just tell us the story of Vigil, what are some of the upcoming milestones for the story, and then we go into the Q&A. Sounds great. Thank you so much, and thank you for the opportunity to present today. So who is Vigil? Vigil is a clinical stage microglia-focused 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. So microglia are responsible for the health and well-being in the brain, and they control a number of neurological functions to prevent neurodegeneration. What's exciting about Vigil is that there are three things that I think differentiate us from others in the space. First and foremost, we have a precision-based approach to neurodegeneration. What I mean by that is that we focus on indications where there is a very strong genetic, mechanistic, and biochemical association to microglia dysfunction because we believe that reduces the downstream translational risk and also allows us to get to that proof of concept quickly. The other thing that differentiates us is that we're the only company out there that has two TREM2 modalities. So we have a fully human monoclonal antibody TREM2 agonist as well as a first-in-class small molecule TREM2 agonist. Because we have these two modalities, it really allows us to be very thoughtful on how we build our pipeline, and we'll talk about that. We actually, our most advanced asset is the antibody. It's called Iluzanebart. It's in phase ll for rare neurodegenerative disease called ALSP. The reason we chose it will become clear as we talk about it today. And then the small molecule, which is orally bioavailable, highly CNS penetrant, as I mentioned, first-in-class, is currently in phase one study for Alzheimer's disease. So we have an opportunity to position our molecules both in rare indications as well as in large indications. The other third thing that I think is also extremely exciting is that we're the first company to have clinical data to support TREM2 as a potential therapeutic for treatment of neurodegenerative diseases. We had an extremely exciting year this year. A lot of exciting milestones that happened. First and foremost, in our ALSP program, we had some very productive conversations with the FDA, and the FDA has left the door open for potential accelerated approval and our biomarker strategy, and I'm sure we'll talk about that more. We also released interim data from our phase one study with our small molecule, which supports continued development. And then also we had a strategic investment from Sanofi, $40 million strategic investment around our small molecule program, which extends our runway into 2026. Ahead of us, very exciting, 2025, we'll be releasing top-line data from our phase one study in Alzheimer's, as well as we'll have the readout from our phase two study in the first half of 2025. So I think I'll leave it there and. Yeah, there's a lot coming up in the next, let's say, few months to the next 12 months or so, but let's just review what you have generated in ALSP. Could you remind us some of the key findings from that six-month? The type of patient, I think you've categorized the patient a little bit differently there. So just articulate to us what were the findings and what is leading you to change and go, not change to go for this Accelerated Approval strategy. Sure. So maybe to step back. So currently, as I mentioned, we're in a phase two study for ALSP. This is an open-label study, 12 months in duration, 20 patients, two doses, 20 and 40 milligram. So what Yatin is referring to is we had our first interim look when we had six patients' worth of data at six months. And there what we saw that in patients who have progressive disease, we're actually able to see slowing of progression across all of the biomarkers that we were looking at, which is obviously very exciting this early in the process. And you mentioned what we learned about the patients. So the patients we enroll are mild to mildly moderate ALSP patients. This is a rare neurodegenerative disease, fast progressive, no treatment available. So obviously, and what happens from symptoms to loss of ambulation is only two to three years. From symptoms to death is six to eight years. So very fast progressing. What you want to enroll are patients who are mild to mildly moderate. What we realized in that first six patients that we looked at, we actually had three different sets of patients. We had patients who have that progressive disease, so high NfL levels, cognitively impaired already. Those are the patients where we saw slowing of progression across all of the biomarkers. Then we had surprising two patients which had normal NfL levels and were still cognitively okay. That's not very likely because the people don't stay in that stage for very long. The reason we know that is because we're also running a natural history study, which is a first study of its kind in this patient population. We're learning a tremendous amount, not just about a patient journey, but also how the biomarker and clinical endpoints are moving in this patient population. How do biomarkers correlate to the disease and progression? So we know that patients do not stay in that stage for very long, but we did catch them. And in those patients, what we saw is that at six months, they looked unchanged to what their baseline was. And the other thing I should mention, the reason the natural history is really important is because it also allowed us to move patients from the natural history into the phase two. So some of these patients have about six months' worth of data before they get on drug. So we're able to compare what does their progression look like before they get on drug and then what happens once they're on drug. So in those two patients, actually, we did not see any meaningful change, so obviously, that will be extremely exciting that if at 12 months that continues, then we have a way of actually identifying these patients hopefully sooner because we know that NfL in this patient population is a biomarker disease severity, and then to your point, there was one more patient which we believe we caught in that active transition from having low NfL levels to very high NfL levels because what happened is in the previous six months prior to getting on the study, the NfL levels doubled, and in that patient, because we think they're in such active state, that it's going to take a little bit longer to see things, so what I want to say is six months, extremely encouraging. Obviously, 12 months will be telling, and that was with 20 milligram. We also have a 40 milligram dose. Now, the other thing that's really important is the natural history study. The natural history study is really what's allowing us to think about accelerated approval and biomarker strategy. Because there, what we're seeing is that at 12 months, we see statistically significant correlation between changes in MRI and clinical changes, so for example, if you see an increase in ventricular volume, what you're seeing is statistically significant correlated decrease in their MoCA scores, so these are the kind of things that the FDA really wants to see when they think about biomarkers as surrogate endpoints, so what we did is once we had that six-month worth of data along with all the data from the natural history study, we actually went to the FDA and had a very productive conversation. And based on that data, the FDA said, "Yes, the door is open to Accelerated Approval, and please come back with more biomarker data." So we're very encouraged by that. And that's why we decided not to take another look at that study, but actually wait till we have full 12 months' worth of data because we really want to preserve that data set, and we want to make sure that we align with the agency on how we're going to analyze the data set before we actually take a look. So that will be happening in the first half of next year. So those were the first six patients, then there is another next six patients. How are they or how are these patients? In which of these categories do they fall, and is there a reason to believe that TREM2 is more sensitive to one category versus the other? So the answer to that is no, but our patients, most of our patients, are mild to mildly moderate. So in that first group that I talked about that have that progressive disease where we saw the slowing of progression, the study is actually 20 patients in size. So the next data set will have all of the 20 milligram patients out to 12 months, and then all of the 40 milligram patients out to 12 months as well. Got it. And then did the 20 patients went up to the 40, or they all remain at 20? No, we haven't disclosed exactly where the breakdown, but we have patients. We have one cohort that's 20 and another cohort that's 40 for a total of 20 patients. Got it. Got it. Got it. Very good. Now, when you talked to the FDA, was there any discussion around the endpoint? So what would be a biomarker? Is MRI a biomarker that you have to rely on, and then you have to do a correlation with MoCA? So yeah, so we talked to the FDA. Obviously, that was one of the big things is we do feel after looking at our natural history study that MRI is the most sensitive and most dynamic biomarker in this patient population. We see quantifiable changes on ventricular volume, on brain white matter volume as early as six months, so that's the data that we took to the agency, and that's the focus of the conversation because natural history is a critical pillar of our development strategy, and not only because we're learning so much about biomarkers and which ones are the most relevant, but also because we want to try to use the natural history as a synthetic control arm and be able to compare the patients from our phase two study to the natural history. So the conversation is really focusing around MRI and the correlations we're seeing with the changes in MRI. Got it. So maybe talk about the disclosure. What will you disclose to us when you present, when you have completed 12 months on all of these patients? Will we get enough to sort of get a sense that there is activity here, or would you go to the FDA first and then disclose it to the broader community? So, no. So our conversations with the FDA are around how to analyze the data. So when we do put the data out, we obviously will be looking at the totality of the data, focusing on MRI, but we're also looking at soluble CSF1R, which is a biomarker of disease pathology in this patient population because soluble CSF1R is reduced by 80% in these patients. We'll also be looking at NFL levels. So that's really, so we're talking about the totality of data. And then what we learned from our natural history study is that clinical endpoints are very noisy early on. It takes about a 12-month period to start seeing separation on the clinical endpoints such as MoCA, CBFS. So those are the ones we'll be looking at as well. But the real focus here is going to be around the biomarkers because we know that it takes longer than a year to conduct a study where you really look at clinical outcomes. So the conversations with the agency have been around the need to have an accelerated approval. And actually, I didn't mention, but before we went to the agency, the Patient Association, Sisters' Hope actually led a patient listening session at the FDA, which was extremely helpful because I think the patients provided their perspective on how they see the disease or why it is not possible to have long studies that are placebo-controlled in this patient population. Yeah. Very good. Could you put in perspective the market opportunity in ALSP? Sure. So originally when we started in the space, and just to again mention with the first ones into this space, there's no approved therapies. And it is a rare disease. And as you can imagine, you have to build it from the bottom up. What was in the literature was that they're based on the prevalence from the literature, about 10,000 patients in the US. We've learned a lot in the last four years. And actually, just recently, there was a study published from University College London where one of the KOLs, Dr. Lynch, went into the UK Biobank and looked at the frequency of CSF1R disease-causing mutations and found out that the frequency is actually much higher than what's reported in the literature. So if you look at that frequency based on that frequency, the prevalence would be 94,000 in the US. Now, obviously, we need to think about where does this disease hit, how much penetrance there is. So when we extrapolate, we believe that there are actually 19,000 patients in the U.S., which is the double of the number that we originally thought. And that's also supported by other ways that we triangulate to this number. We now know that the way you think about it is you look at adult leukodystrophies in the country, and then you take the number of those that are ALSP. We thought originally there was 10%. Now there are publications coming out both of U.S., U.K., Japan saying it's 16%. And then we also know that this disease is underdiagnosed and misdiagnosed because the symptoms look very much like other neurodegenerative diseases. So it gets misdiagnosed as MS, Alzheimer's, FTD. We know that about 0.5% of all MS patients are actually ALSP patients and 0.3% of all these. Whichever way you triangulate, you get to that 19,000 prevalence in the U.S. and 29,000 prevalence in Europe and U.K. That's pretty significant. Okay, let's switch to. I'm going to come back to the competition later, but let's switch to the small molecule. I think that's one modality or the space where you have been very excited. So can you put in perspective the data that you have generated? What are some of the next steps? What will we learn in the next, let's say, six months? Sure. I will let, since it's David's favorite topic, David, why don't you take us through VG-3927? Yeah. So I mean, just a little context. So obviously, we have a deep expertise in TREM2 and in microglia. And we've selected the small molecule for Alzheimer's for some really specific reasons that have to do with the modality, but also with the biology and matching that appropriately to the indication. So we are in the middle of a phase one study that is going well. So in the summer, we released interim data from that focusing on the completion of the SAD portion of that study. And in that data, there's a couple of really important things that we learned from it. One is that the safety and tolerability continue to support development. That's obviously a main focus in phase one. We also were able. We have a really nice biomarker in soluble TREM2 that gives us both central target engagement in terms of CNS target engagement, and it also gives us a functional understanding because of the way that that biomarker is measured. And so what we showed, and we showed some of this data, is that what we're seeing is a reduction after a single dose in soluble TREM2, which is the expected directionality. And that when we get into the middle of our dose escalation range, we reach a really nice robust response there, and then we're able to maintain that through the additional doses. We also disclosed that in the MAD, we also are seeing a robust and durable reduction in soluble TREM2. As we look ahead to the data that we'll release here in the first quarter of next year, that will include the completion of the MAD and all of the relevant data there, as well as we've included a single dose cohort of Alzheimer's disease patients as part of that study with, again, a focus on biomarkers. What we're, all of this is, of course, to set up for phase two. This is a mechanism where there's a tremendous amount of enthusiasm because it has such strong human genetic support linking it to Alzheimer's disease. Briefly, we know that loss of function mutations in TREM2 increase the risk of developing Alzheimer's disease. They also increase the rate of Alzheimer's disease progression once the disease starts. And then there's a number of other biomarker and other evidences that all point to the important directionality of increasing the amount of TREM2 function because fundamentally, TREM2 is the damage sensor on microglia that converts them from their sentinel state into their neuroprotective state. So that's what we're trying to accomplish with the TREM2 agonist is encouraging more microglia to enter this protective state and be able to cope with the neurodegeneration on a broad scale going beyond any single toxic species. So that's the data that we'll be releasing. In terms of the single dose Alzheimer's cohort, our focus is on biomarkers to make sure that we have the right patient mix as we think about our phase ll in terms of genetic subpopulations and overall to confirm what we expect, which is that we should be able to do an Alzheimer's study, but we want to see that in the data. Got it. So I understand VG-3927 is oral. Other than being oral, how it is functionally behaving differently than an antibody? Love that question. And it's really important. It's important to the reason why we selected the small molecule. So both our agonist antibody as well as others and our small molecule, they are TREM2 agonist. They both activate TREM2. But they bind at different sites. And that turns out, as you alluded to, to have some really important biological and functional consequences. So one of them is that the small molecule uniquely acts as both an agonist, but also as a positive allosteric modulator, which enhances the activity that normally for the ligands that normally activate TREM2. So these are things like Aβ, ApoE, sulfatides, different components that signal to microglia that there's some type of damage or some type of pathology. What we've seen is that the small molecule very much enhances that interaction, which we believe will give an element of spatial specificity where these ligands are present for more activation of microglia in those areas. We think that's important. There's another important difference as well that has to do with the binding site. And that is that the antibodies bind to the extracellular domain, which is the same piece that gets clipped off to form soluble TREM2. Soluble TREM2 is not biologically active. And so when the antibodies bind to soluble TREM2, that represents a type of a sink or a sort of a distraction in terms of the productive agonist activity where the small molecule does not interact in any way with soluble TREM2. And so all of the small molecules are free to interact with the relevant agonist target. Got it. With regard to the Alzheimer's cohort, how big it is and it's just single dose, how much we can learn from that one cohort and single dose? Like what exactly we need to be focusing on when you present the data in early next year? So I mean, our expectation, as I mentioned, is that we will see soluble TREM2 reductions in that Alzheimer's cohort as well. We are including some genetically defined subpopulation individuals. It's not a large study to answer your question. It's a small focus study. And from our learnings in phase one, we know we can get really good biomarker data from just a single dose. So we're really just looking to make sure that the molecule does in fact modulate TREM2 in, for example, an ApoE heterozygous population or in a TREM2 loss of function mutation situation. Got it. So now, I think we all know there is a competing antibody which is in development. They are running a pretty big phase two study which is going to read out. So what should be the read-through, if any? Should it read through only to the antibody or there is a read-through to the oral? Eventually, if the AD study is successful for the competitor, how your development strategy could change for both oral and the antibody? So obviously, positive data is good for the field. Most importantly, it's good for patients because we know there's still a huge unmet medical need. In terms of ALSP, we really don't see any read-through. It's a different indication. And also we already have data that's extremely encouraging. When it comes to the small molecule, we obviously want them to be successful because we have a superior molecule orally bioavailable, highly CNS penetrant. But we, to David's point, see these very important differences, right? The antibody obviously is not fully brain penetrant. So you're talking about grams versus milligrams. Then once the antibody gets into the brain, TREM2 is a sink, which we don't have. So the question here, we know that TREM2 activation will activate the microglia to their neuroprotective state. The question for the antibody is, can enough of the antibody get to the target? So if their data is not good, we think that is the challenge. And that's been shown in the past. Actually, David worked on a molecule and Aβ antibody that was famously unsuccessful. And the reason was it was binding to the monomer and was just not, and it's not that Aβ was not a good target. It was just not a good molecule. So we believe that this is a read on their molecule, not on the target. And as I said, we want it to be successful because we think we have a superior molecule with superior horsepower for the reasons that David said. But if it's not, we think that there's going to be good explanations. And obviously, we'll learn a lot from their study and it will be extremely helpful as we design our study. But regardless of their outcome, we're full force ahead with our small molecule. Okay. So in the interest of time, just one more question on the ALSP regulatory pathway. Let's say if you pursue the accelerated approval pathway, would you have to have the phase three study running when you file, by the time you file? Yeah. So usually the way it works is you have to do a confirmatory study and that study would have had to be started by the time you get, but the focus would be obviously on trying to get approval on the phase two package. All right. Very good. That's all I had. Thank you so much. Thank you. Thank you so much.