Hi, good morning, everyone, and thank you for joining the H.C. Wainwright 16th Annual Global Investment Conference. My name is Anand Ghosh. I'm an H.C. Wainwright associate. With that said, I would like to welcome Ivana Magovčević-Liebisch, CEO, and Jennifer Ziolkowski, CFO of Vigil. So with that, we can start the fireside. I welcome both. So, you know, let's start with Vigil has been one of the earlier proponents of targeting neuroinflammation for neurodegenerative diseases like. And so it would be great if you can briefly introduce the vision of the company, and where does the company see itself in the next years? Thank you, Anand. Thank you for the opportunity to share the Vigil story with you, this morning. 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. Microglia are responsible for health and well-being in the brain, and they control a number of neurological functions to prevent neurodegeneration. You know, we, as you mentioned, Anand, we really focus on a precision-based approach to neurodegeneration. We believe that neuroinflammation and microglia is the next frontier in CNS drug discovery, and there are a couple of things we believe differentiates us from others in the space. As I mentioned, first is that precision-based approach. We believe that following diseases where there is a very strong genetic, mechanistic, and biochemical association to microglia dysfunction reduces that downstream risk and also allows us to get to a proof of concept very quickly. We're also the only company that has two TREM2 modalities, both a fully human monoclonal antibody, which is currently in a Phase II study for a rare neurodegenerative disease called ALSP. I'm sure we'll be talking a lot more about that. But we also have what we believe to be a next-generation AD therapeutic in our small molecule TREM2 agonist, which is first in class and is currently in Phase I study. And I think the fact that we have these two modalities has really provided us with an opportunity to build a very interesting pipeline and position these molecules in the right indications. And then, also, we are the first company that has clinical data that shows that TREM2 agonism could potentially serve as a therapeutic for a number of neurodegenerative diseases. So the summer has been very busy for us. We had a number of exciting announcements that happened. First, in our ALSP program, we had a very good interaction with the FDA, where the FDA left the door open for accelerated approval. And so we'll, I'm sure, talk about a little bit more about that and how we're now thinking about the study and how we're positioning the study going forward. We also released interim Phase I data from our small molecule program, which both in terms of safety, tolerability, PK, PD, everything we're seeing supports continued development in Alzheimer's disease. Again, very exciting milestone for us. Then, third, we also announced a very important strategic partnership with Sanofi, where Sanofi has invested into the company, and for the right of first negotiation on our small molecule program, which we think, again, it's acknowledging what we're doing, and as well as our assets, and we can talk about more of that. But it was a $40 million investment at a very significant premium for that right of first negotiation. So we're in a very good position. We have a number of milestones coming up. Next year, in the first quarter, we'll be releasing Phase I data from the full set from our small molecule, and then also in the first half, we'll be releasing the final data set from our Phase II study in ALSP. The important thing with the Sanofi $40 million is that it allowed us to extend our runway into 2026, which is obviously provides enough room between our milestones and that event. Besides that, we have built in the company. We really want to become the experts in microglia biology. We have built a very important microglia platform, which we now believe we can interrogate for different targets and different indications. We can take the knowledge that we have now amassed from these two programs to help, really help us think how we wanna continue to build our pipeline. So I will stop there, and happy to answer any questions. Yeah, great. I think with that as an introduction, we can, you know, jump to the ALSP program. You know, one of the question is, like, what was the hypothesis that led to the development of the ALSP program? And then maybe quickly talk about also the debate regarding the prevalence of ALSP and the diagnosis. Sure. So, ALSP stands for adult- onset leukoencephalopathy with axonal spheroids and pigmented glia. It's a rare, you know, inherited neurodegenerative disease. It's caused. It's a monogenic disease. It's caused by autosomal dominant mutations in the CSF1R receptor, and those mutations result directly in decrease in number of microglia, as well as their function. So there is a direct correlation between the mutation and the actual underlying causes of the disease. Now, you might ask, "Well, what's TREM2 got to do with it?" Well, TREM2 and CSF1R are both receptors that sit on microglia, and they share downstream signaling through phosphorylation of Syk. So the hypothesis is by the over-activating TREM2, we can compensate for the deficiency in CSF1R, and we have now shown that through a number of different in vitro. My, you know, experiments where we have shown that we can increase soluble CSF1R levels by over-activating TREM2. There's also evidence that comes directly from human genetic disease, and that is a disease called Nasu-Hakola, which is caused by mutations in TREM2. And so that disease has a similar onset, very similar presentation and progression as does ALSP. So that gives us additional confidence that we're going after the right target. And then you asked us about the prevalence. So as you can imagine, this is a rare disease. The disease, the gene was only identified about 12- years ago. So just like any other rare disease, there's very little known about the prevalence in the literature. So originally, based on the literature, we believed that there were 10,000 patients in the U.S. Now we actually have some very exciting additional data that actually makes us believe that those numbers are much higher. So there's been recently work published from Dr. Lynch at the University College London, where he looked at the UK Biobank at the incidence of CSF1R, disease-causing mutations, and found that the incidence is much higher. So if we extrapolate that to the U.S. population, we actually get to 19,000 prevalence. We also originally believed that it was about 10,000 of all adult leukodystrophies that result in ALSP. Now, there is data coming out of both U.S., Japan, and Europe, that it's actually more like 16%. And then we also know that this disease is misdiagnosed because the presentation is very similar to other neurodegenerative diseases. The symptoms are usually cognitive, behavioral, or motor. So often the disease gets misdiagnosed as MS, AD, FTD. So we know because there's been publications, about 0.5% of MS patients are actually ALSP, and about 0.3% of AD patients are actually ALSP. So we have three different ways, which now give us very confident in the fact that, that 19,000 number is a good prevalence number. And if we look at Europe, that means that there are about 29,000 patients in Europe, between Europe and UK. That's very helpful. You know, as a company that is the first one to target ALSP, you had to understand the disease process and establish clinical parameters to lead the program, right? So can you tell us about the learnings from the natural history data and the significance of the data with respect to it? Yeah, so natural history, obviously, first of its kind, ILLUMINATE. It's called ILLUMINATE. It's now been going on for 3- years. Critical part of our clinical development strategy because, to your point, not much was known about the disease, so it really provides us with an opportunity to follow the patient's journey, but more importantly, look how the biomarkers and clinical and endpoints work in this patient population. So what we have learned so far is that, TREM2 levels remain the same, soluble TREM2 levels between healthy and patients. Really important because that tells us that there is target for us to activate. The other thing we have learned from this study is the soluble CSF1R levels are significantly reduced in this patient population, so soluble CSF1R is actually a very good biomarker of disease pathology. And then we know that NfL becomes very highly elevated in symptomatic patients, which again, is a very good biomarker of disease severity. But what's really emerged as a top most important biomarker is actually MRI. We see MRI as being the most sensitive, most dynamic, most consistent biomarker, and what we're seeing in the study that at 12- months, we're actually seeing a statistically significant correlation between the changes in MRI and the loss of cognition. So this is the kind of data that's really, really important when we start talking to the agencies we are, about MRI being our surrogate endpoint. So this study is really important from that perspective. It also can serve, for us, we want it to serve as a synthetic control arm, in our studies. And then we really also had an opportunity to move the patients from the natural history study into our Phase II study, and because of that, they were able to serve as their own control, so we can see how they behave and how their disease progresses before they get on drug, and then what happens once they're on drug. So absolutely critical part of our, as I said, clinical development strategy, and that's the data that we actually took to the agency, along with our early interim data from the Phase II study, and that's what allowed us to have such a productive conversation with them, where they left the door open for accelerated approval and for MRI to serve as a potential surrogate endpoint. ... Thanks. And, you know, that brings us to, like, the on IGNITE, and, like, what were the key takeaways from IGNITE interim data readout concerning PK safety biomarker? Yes, so, just a reminder for everybody, the IGNITE is a Phase II open-label study. It's 20 patients, two doses, 20 and 40 milligrams, one year in duration, and a monthly IV infusion. What Anand is referring to is we had an early interim look, which was six patients, 6- months. Obviously, excellent safety and tolerability, which carries from our Phase I from one study. PK supports monthly dosing. The other very interesting thing that we saw is that because in this patient population, the blood-brain barrier integrity is compromised in the areas of active disease, we actually do see more of the antibody getting into them, so we saw in Phase I that the antibody gets into the brain, engages the target, but now what we're seeing is we're actually getting more of the antibody into the areas of active disease. And then, most importantly, even though it's small n's, only six patients, in the patients which have the progressive disease, we actually saw slowing of progression across a number of biomarkers, for example, MRI. And then we saw increase in soluble CSF1R, which was higher than what we saw in healthies, which is what we would have expected. So we're very, very encouraged with that early look, and we're obviously excited to report on the full data set, which will be in the first half of next year, and that will be all patients at 12- months. Right. And you know, we thought that it was prudent to, you know, to wait for the final 12-month data with the high dose of 40 milligram of the ALZ001. You know, especially in the light of FDA's willingness for an accelerated approval pathway for the program, what biomarker data do you think might fit as a surrogate endpoint or endpoints, given that you do see, you know, positive trends in NfL, CSF1R, MRI? Yeah, so as I mentioned, we see MRI as the most sensitive, dynamic, and consistent biomarker, and as I said, we're seeing these really, really nice correlations. So the focus for us is MRI, but as you know, in any accelerated approval, it's totality of the data. Obviously, we will continue to look at soluble CSF1R, and yes, we started seeing some decrease in NfL, and we expect that, you know, that will continue as we continue to dose. But the real focus, I think, here, and the focus in our discussions with the agency, is around MRI. Mm-hmm. Okay. That's helpful. Let us pivot to the TREM2 program now. You know, if you can briefly explain the scientific rationale for oral TREM2 and what, I mean, oral TREM2 activators, and what differentiating factor it brings with respect to the landscape. Yeah, so as I mentioned before, having these two modalities has really given us the opportunity, having both the antibody and the small molecule, to really think about where we can maximize the value of these of these assets. So we believe that antibody is really well suited in these rare diseases where the blood-brain barrier integrity is compromised, as I mentioned. The small molecule being orally bioavailable, highly CNS penetrant, we think makes a lot of sense in larger indications, and obviously, we're very excited about moving this forward in Alzheimer's disease. Our small molecule, in addition to being orally bioavailable and highly CNS penetrant, also has a differentiated mechanism of action, which makes us really excited. What we see with the small molecule is that we have a synergistic effect with natural damage ligands. TREM2 is the major damage signal in the brain, responds to a number of signals, such as APOE, Abeta. We see that in the presence of those damage signal, we actually have that synergistic effect, which we believe will translate to better efficacy and, and safety as well. That's... If you think about the antibody and a small molecule, you can almost think like a Venn diagram, because what we see is that our small molecule has very similar functional effects downstream. We're seeing activation of similar, gene, genes, that are expressed, but there are some very important differences, and we think that those differences will serve us extremely well when we get into a disease like Alzheimer's disease. Very nice. You know, with that, if you can briefly summarize, like, the key takeaways from the SAD data, also some of the important observation which came from the in vivo preclinical data? Sure ... from So what Anand is referring to, we released interim data from our Phase I study, which was really focusing on the SAD portion of the study, 'cause that's the completed part of the study at this point. Safety, tolerability, PK/PD all support continued development in Alzheimer's disease, so very exciting. In terms of safety tolerability, we do not see any SAs, no severe As. All the As that were mild, moderate, resolved on their own without any intervention. In terms of PK, PK supports daily dosing, also very exciting. And then, most exciting is that we're seeing PD response. So we're seeing a very robust, sustainable reduction in soluble TREM2. And what's really exciting is that we're seeing the same levels as we observed with the antibody. So we really are... What we have in our hands is a true small molecule agonist, which is extremely exciting to see at this point of, of the, of the development. We are now completing our MAD portion of the study, and we're also working on an AD cohort, which is gonna be a small cohort, single-dose, biomarker-focused. The idea is really to look at if can we see differences between different subpopulations in order to inform our Phase II study. There's no reason to think that TREM2 would not act across all, AD patients, but we think it's important to see if we can see any differences before the final, final design. So extremely excited with the stage we are at with the, with the small molecule, and as I said, the final data set, which will include SAD, MAD, as well as the AD cohort and an elderly cohort will be in the first quarter of next year. Got it, and with that, I think we break, you know, we are at the last question. If you can briefly tell us about the strategic collaboration with Sanofi. I know you already mentioned at the beginning of the- Yes ... talk, but maybe you can end the talk with, you know, the significance of the Sanofi strategy. Yes. I think the Sanofi transaction was important for us because I think it checked a lot of boxes for us. Obviously, you know, having Sanofi as a partner, this early on strategic partner, in terms of, you know, their desire to have the first right of negotiation on our small molecule program, I think validates the company, validates the programs we have, obviously validates our approach to these diseases, so we're very excited about that. The other thing is, obviously, ultimately, there's an opportunity to have them as a partner, and obviously, you know, they bring a lot of knowledge and expertise in this space, so that's very exciting. But also, we got an infusion of cash, which was very important to us to extend our runway into first quarter of next year. I mean, sorry, of 2026. I'm already in 2025. Of 2026, which provides us a really nice runway between the milestones we talked about and that runway. So I think it puts us in a very strong position, and it's a very nice validation of what we are doing, so very excited about that partnership. Great. Thank you very much. I think with that, you know, the floor is open for the questions, so if you have any questions, feel free to ask. Thank you.