...Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the Biotech Analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Vigil Neuroscience, with President and CEO, Ivana Magovčević-Liebisch, and CSO, David Gray. Welcome. Thank you. Thank you. So for those who may not be as familiar with Vigil, can you just provide a brief introduction? Absolutely. First, thank you so much for inviting us. We really appreciate the opportunity to share our story with, with all of you. So 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's immune system. So microglia are responsible for the health and well-being in the brain, and they also control a number of neurological functions to prevent neurodegeneration. So what we have done at Vigil is that we, we have identified TREM2 as the key regulator of microglia biology, and we're developing it in a number of different indications. I think there are a few things that differentiate us from other companies in the CNS space, and that is that we really believe that microglia and neuroinflammation is the new frontier of CNS drug discovery. We also believe in a precision-based approach to neurodegeneration. And 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, 'cause we believe that that reduces the downstream translational risk, and also allows us to get to the proof of concept quickly. And we'll, I'm sure, talk a lot more about our most advanced program, which is in a rare disease called ALSP. And the reason we chose that indication is because it checks a lot of those boxes. The other thing that differentiates us is that we're the only company that has two TREM2 modalities. We have both a fully human monoclonal antibody TREM2 agonist, as well as a first-in-class small molecule TREM2 agonist. And that has really allowed us, in a very short period of time, to develop a very interesting pipeline, where we focus the antibody in rare disease space, and we're focusing the small molecule being orally bioavailable and highly CNS penetrant in larger indications, such as Alzheimer's disease. And the third thing is that we're the first company to show that TREM2 activation actually has the potential to be a new therapeutic opportunity in neurodegeneration. We've also had very exciting summer. We've moved our programs forward significantly. With our antibody, we've actually had some really encouraging discussions with the FDA, which have now made us... Given us a path, we believe, to potential accelerated approval, and I'm sure we'll chat about that more. And then in our small molecule, we actually released some interim phase 1 data, which all support us moving this program forward in Alzheimer's disease. And also, we have forged a strategic relationship with Sanofi, where we've been able to raise from Sanofi $40 million at a very significant 100% premium to our stock in exchange for right of first negotiation on our small molecule program, which again, we see as a very significant validation of the program and company and our programs, and I'm sure we'll touch on that as well. And next year is gonna be just as exciting. We'll actually be releasing the full data set from our small molecule phase I study in the first quarter, and then the final analysis for our ALSP program in the first half of the year. And also, the other thing that the Sanofi partnership did for us is that we were able to extend our cash runway into 2026, which is well past some of the milestones we're gonna be talking about. So I'll stop there and pass it on to you. Great, thanks. Let's start with ALSP. Can you just talk about the disease? And you had touched upon this in your introductory comments, but the role of microglia in ALSP. Yes. So ALSP is a rare neurodegenerative disease. It's a monogenetic disease caused by mutations in CSF1R gene, and those mutations lead directly to dysfunction in microglia, both in number and function. It is an autosomal dominant disease that presents in the prime of adulthood, and the symptoms are behavioral, cognitive, and motor. So this disease often, unfortunately, gets misdiagnosed, and obviously, being a more recent disease, meaning the CSF1R gene mutation correlation to the disease has only been around for about more than a decade. It's also under-diagnosed. Very unfortunate for these patients, once the symptoms hit to loss of ambulation, it's about three years, and from symptoms to death is six to eight years. So really devastating disease. It's a multi-generational impact. You know, these KOLs, when they talk about this disease, they don't talk about patient, they actually talk about families that they're following. And we are obviously the first ones into this space, and there's no approved therapies, so huge unmet medical need. What is the rationale for TREM2 as a target for ALSP? All right, I'm gonna let David, our CSO, take that question. David? Yeah. So CSF1R is expressed on microglia. It's important for, as Ivana mentioned, for the health of microglia, and that's the protein that has the mutation that causes the disease. Because of the way the mutation is, that protein is not functional. However, there's a common signaling element between TREM2 and the way TREM2 signals, which is also expressed on microglia, and the way that CSF1R signals. And what we're doing is we're taking advantage of that common signaling pathway to be able to increase the amount of TREM2 activation in order to compensate for the deficient or insufficient amount of CSF1R activation. And we've shown in a number of preclinical models that in fact this approach does work within microglia. So when you have compromised CSF1R function, you can compensate with specifically with iluzanebart, which is our monoclonal antibody. There's also clinical evidence that links these two targets together. So there's a disease called Nasu-Hakola, which is caused by loss of function in TREM2, and that has a clinical presentation and an age of onset, which is very close and very similar to ALSP. So we have a clinical understanding that there's a relationship between these two targets and the way that microglial dysfunction impacts the brain, and then, you know, a lot of very strong preclinical validation to build it up. So it's a hypothesis that we're now well on our way to testing with the data that we're coming out with next year. Can you talk about what differentiates VGL101 from other TREM2 agonists currently in development? Yeah, so maybe I'll start, and then I'll pass it on to you, David, so our antibodies are fully human monoclonal antibody. I believe the others are humanized. We also bind at the different epitope. We bind at IgV-like domain. And we're Fc neutral, so I would say those are the major differences. But I think where we really differentiate is really around the small molecule versus the antibody. There, I think beyond just being orally bioavailable and highly CNS penetrant, our small molecule actually has a differentiated mechanism of action as well, which we can talk about more in detail. Anything you would like to add? As is the case for many pharmacologies, the details matter. Not all TREM2 agonists are created equally, and this has to do with important things like how they bind and certainly the antibody. Our antibody binds differently than our small molecule, and that has some important consequences. Really, because as Ivana mentioned, we have both modalities and we have an expertise in this area, we've been able to understand our profile, as well as the other antibodies that are out there, and be really thoughtful about positioning the right molecule specifically for its attributes to the indications that we're pursuing. Now, the phase II IGNITE study is ongoing. Yep. Can you just remind us of what you saw with the interim data? Sure. So maybe just to set the stage first, this is an open-label phase II study, 20 patients, two dose levels, 20 and 40 milligrams, one year in duration. It's a monthly IV infusion. The primary endpoint of this study, safety and tolerability, but we are looking at a number of biomarkers, as well as, clinical endpoints. Notably, the most important of the biomarkers is the MRI, because in this patient population, actually, we see through our natural history study, which is a very important pillar of our clinical development strategy, is that the MRI actually correlates extremely well with the disease, with the disease progression, which again, goes very well with the accelerated approval pathway that we're thinking on taking. What we did is in this study, we took a first look, which was our interim look, six patients at six months. The reason we did six months is because in the natural history study, we saw that even as early as six months, we could see quantifiable changes on MRI in these patients. We did decide to take that look, and although numbers are small, and what we did observe, though, is very encouraging, and that is that in patients that have progressive disease, and what that means is that their NfL levels are already elevated and they're cognitively impaired. We saw a slowing of progression across a number of the biomarkers that we looked at. The reason we could actually do this is because what we did is we took patients from our natural history study, so we had a six-month run-in period and then put them on drug, and then we were able to compare. We see some, you know, as I said, slowing of progression, which was very, very encouraging. What would you look for or expect to see as the data mature, you know, for the twelve-month data in the first half of 2025? So obviously, we want to continue to see that trend. The goal is to slow the progression of the disease, and we also wanna look at the totality of the data 'cause we're measuring other things, such as NfL, which here is a biomarker of disease severity, as well as soluble CSF1R, because in these patients, soluble CSF1R, as you can imagine, is significantly reduced. We wanna see continuing increase in soluble CSF1R, which is, as I said, biomarker disease, pathology. So that is what we are looking for, is kind of the totality of the data. And obviously, we have a number of clinical endpoints, but we know from the natural history study that it takes a while to start to seeing the separation on the clinical endpoints. Now, changes in soluble TREM2 have been shown to correlate with disease progression and clinical outcomes. So, what magnitude of improvement on CDR Sum of Boxes would you expect to achieve with the soluble TREM2 reductions that you've seen to date? So it's not soluble TREM2, it's soluble CSF1R for ALSP. So soluble TREM2 for us is not a biomarker of disease efficacy. It's a biomarker of target engagement. So soluble TREM2 reduction is not really correlated to the efficacy. We use that to show that we get into the brain and engage the target. Soluble CSF1R is where we're starting to see, like, in healthy volunteers, what we saw is that when we exposed the healthy volunteers to drug, soluble CSF1R increased, but very slightly. Now, in the patient population, we're actually seeing meaningful increases, which we believe correlates to the disease. But David, anything you wanna add? I mean, you asked about CDR sum of boxes, which is an endpoint that's used in Alzheimer's. Just to kinda tie the two things together, soluble TREM2 is an outstanding biomarker for us that's actually relevant to both diseases, and we've been able to measure it clinically in both, in our phase I study for both of the molecules. Just to kind of take a little step back, in looking at soluble TREM2, what we're looking at, as Ivana mentioned, is we're looking at target engagement, and it also is a little bit beyond that because the mechanism by which we see the reduction is indicative of a functional effect. We're seeing a functional target engagement that then gives us confidence around not just brain penetration, but also target modulation. That's a really important component for any neuroscience project, so it certainly applies to both ALSP as well as to our small molecule AD program. It has allowed us, in generating that data in phase 1, has allowed us to be able to think about very thoughtfully around dose selection for both of the programs, to make sure that we're taking a dose in that we know is maximally engaging the target, and then we can confidently go ahead and test the mechanism with confidence that we're on the target and that we've actually selected a dose that is maximizing the pharmacology. Great. Now, you decided to forego the interim look for the study to preserve the data for final analysis. How does this improve your position from a regulatory perspective? And, you know, how has discussions with the FDA on the potential accelerated approval pathway impacted your approach to the Phase II IGNITE study? So what we decided to do, because we were very excited with what we saw in the six patients, six months worth of data, but also what we were accumulating now, our natural history study, we decided it was the time to go and engage with the agency and start to educate them around some of these biomarkers and how they correlate to the disease progression. And so we had that conversation, and that conversation was extremely encouraging. As we mentioned, they left the door open to accelerated approval and actually invited us to come back with more data around the biomarkers. So based on that, we realized that, you know, 20 patients' worth of data is a very important data set, that it made a lot of sense to preserve that data set as we continue to engage with the agency and align around how we wanna analyze the data before we do so, so that we don't get penalized for, you know, going back and forth because we have a number of different things that we could look at. And so the goal is to continue that dialogue with the agency, try to align on how we're gonna look at the data, and then take the final analysis. But extremely encouraged that this early on in the process, we have the opportunity to actually leverage this 20 patients' worth of data in a really meaningful way, and hopefully get on the accelerated approval pathway. And can you just talk about how you're using the ILLUMINATE Natural History Study, and what kind of feedback have you heard from the agency on this program? So as I mentioned, this is a first of its kind in this patient population. It's incredibly important for many different reasons. So we're learning obviously about the patient journey. We're looking how these biomarker clinical endpoints progress as the disease progresses. And also, what we wanna use this natural history study for is as a potential synthetic control arm. So it serves a lot of different purposes for us. But what we... As I mentioned, what we're really encouraged with is that MRI is really emerging as the key biomarker in this patient population, 'cause in this patient population, the correlation between changes in MRI and, for example, changes in cognition, which is one of the main complaints in this patient population, correlate. They're statistically significant. And this is the kind of data that the agency is looking for when they consider, you know, biomarkers and accelerated approval. So it's been extremely useful and productive. The other thing that's been very good is that we were able to move patients, at least in the early stages of this trial, from the natural history into the phase 2, so they could serve as their own control, so that we could see how the disease progresses before we put them on drug, and then what happens when they're actually on drug. Anything you wanna add, David? I mean, just to sort of take a step back, and it's so remarkable that going from really not understanding anything about how clinical endpoints and biomarker endpoints might behave in this population, I'm really proud that we've been able to support this study, and through it, be able to then have these kinds of dialogues with the agency, actually showing them data about how the endpoints, in fact, do predict and correlate with clinical endpoints that they're gonna care about. You know, in listening to the patient community, they're very clear because of how rapidly the disease progresses and how aggressive it is, that the feasibility of a typical placebo-controlled study, it does not match up to what their experience is. And they've shared that with the FDA, and that has put us in a really good position to talk about, well, what can you do? And that's where we get to these biomarkers. And I just coming back to my original point, I think it's so remarkable that we now have identified a biomarker that actually does correlate with disease, and we can have data-based conversations with the agency around endpoints that would make sense in an accelerated approval. ... Great. Can you give us an update on your efforts for ALSP patient identification? You know, how many patients have joined ALSP aware, and how many new patients have been identified through your efforts to target healthcare providers in clinics where patients are not properly diagnosed? As you can imagine, with any disease that you go into, especially in the rare disease space where there are no treatments, you have to build that awareness and knowledge and, you know, we've been around only for about four years, but I think we made a tremendous progress in that arena. We are very confident that actually the prevalence of this disease is even higher than what we thought when we originally started working in this space, and the reason for that, we originally thought, based on literature, that the prevalence is about 10,000 patients in the U.S., and about 14,000 in Europe and the U.K., and then there's just a recent publication from Dr. Lynch, where he actually went into UK Biobank and actually looked at the disease-causing CSF1R mutations and found that the incidence of those mutations is actually much higher than what was presented. So if you actually extrapolate that to the US population, you get to 19,000 prevalence in the US and 29,000 prevalence in EU and Europe. Obviously, that's prevalence. That doesn't mean that there are 19,000 patients today identified. The way these diseases work is that as treatments become available, awareness increases, more and more patients become willing to come forward, right? Because if you can imagine, an ALSP diagnosis is a death sentence in a way, so... and has implications not just for the patients, but for their entire families. You know, are they gonna have insurance? What does this mean for you know, how they're gonna take care of their families? What does that mean for their offspring? It has a multigenerational impact. So what we have been doing is really making sure that we're educating both the patient, but also more importantly, the healthcare provider community, because this disease is also because of its presentation, which is usually cognitive, behavioral, and motor. It's often misdiagnosed as some other more known diseases such as MS, AD, FTD. So how do we bridge that gap? And so what we have done is we have actually introduced a program that you mentioned, ALSP aware, which is a... We offer free genetic testing and genetic counseling to patients, but also, in addition to that, offer a twenty-four gene panel to healthcare providers, so that, for example, when an MS physician says, "Okay, I have an MS patient, I think I have MS, but I'm not sure," they have ability to test. And that's been very productive. We now have people coming all the time saying, "I believe I have an ALSP patient," which was never the case before, and we're hearing from care hubs that they're getting more referrals as that awareness increases. So it's a journey, and we're well on that journey, and we're very excited with the progress that we have made. We absolutely believe that if there is an effective therapy, the patients are there, because as I mentioned, it is multigenerational unfortunately. So once you have a patient, and because it's adult onset, these patients do have families. So once you have a patient, unfortunately, there will be a cluster as well. All right, great. Let's shift to VG3927, you know, which is, as you mentioned before, the small molecule TREM2 agonist. Can you just talk about the advantages of this small compound and how it compares to your other programs? David,- Yeah ... this is your favorite topic. Yeah. So, I mean, we're extremely excited about it. I think a lot of people are, as you know, the genetics around TREM2 and harnessing the immune system are so strong as far as Alzheimer's specifically. You know, at a very high level, our antibody and our small molecule are both TREM2 agonists. However, there are very important both modality advantages as well as some important differences. I talked about this a little bit before, how each molecule is different. So let's just talk about the modality ones, because they're really obvious. With a small molecule, you have convenience of once-day dosing, you have easy access, potential to combine, and other benefits of that nature, which are practical. One other thing that maybe is not always appreciated is that the small molecule, our small molecule, binds very differently to TREM2, and it does not have any involvement or any potential involvement of the Fc components of the immune system that are normally interacting with antibody therapeutics. And so, the ability to really be completely clear of those types of interactions is a unique feature of the small molecule and, you know, may be important, for example, in ARIA. There may be involvement of ARIA, for example, not proven, but suggested. And so that's a big differentiator on the modality side. When we go to the more specifics about the binding site, one of the things we know is that because of the way that it interacts with TREM2, we have a synergistic interaction with the normal ligands that normally activate TREM2, and these include things like A-beta. These are ligands that indicate that there's something going wrong or some sort of damage. The fact that the small molecule is able to act as an agonist by itself, but that it also enhances the activity of these other ligands we think is very important, and it differentiates from the antibodies, which we've seen have sometimes an additive effect with some of the ligands, but that don't have this really powerful synergy. So that's one example of a really clear differentiation between the modalities, and there are others as well that we've shared some of. I think I'll just stop there for now, but we really like the small molecule, and we think it's very well suited for Alzheimer's specifically, both because of its modality and its pharmacology. Can you just remind us of what you saw in the interim data in the healthy volunteers? Yeah, that's also super exciting because, as I mentioned before, we have soluble TREM2 that we're collecting from CSF as a biomarker to tell us about target engagement in the, in the CNS. And so we measured that, we showed the data from the SAD portion of that study, which is complete, and we were able to see a reduction in soluble TREM2, starting in the middle of that dose range, and then continuing on as we escalated further, and that the magnitude of that effect was, in the same range as what we saw with the antibody. So really exciting to have the small molecule be able to reach the same level of, of very potent modulation that we saw with the antibody. What should we expect to see from the complete phase I data and AD patient cohort data in the first quarter of 2025? You know, how many patients worth of data should we expect to see? Yes. So right now, actually, we said that when we released the interim look, we actually had 80 healthy volunteers, out of which 60 received our drugs. So obviously, already a very robust data set. But we are in, you know, progressing with our MAD portion of the study right now, so there'll be additional individuals there. And then also, what we're doing in the phase I study is we have added an AD cohort. This is a single-dose biomarker cohort, and what we're trying to do here is really trying to see if there are any significant differences in biomarker responses, among these different genetic subpopulations. For example, TREM2 variant versus APOE versus wild type, to help us inform the phase II design. What you can expect to see is the full SAD, MAD, data set, plus the AD cohort data in the first quarter, and there will be obviously more than 80 individuals that we already reported on. Then for the AD cohort, you know, what proportion of patients will have TREM2 variants versus the other disease-related variants? How do you expect the response to vary based on, you know, genetic background? Do you want to take that? Yeah. Yeah, so we haven't shared the exact breakdown of it. You know, it's a relatively small study, and what we're looking for is our big would be big differences. Preclinically, we have shown that our 3927 molecule is able to potently modulate all of the important TREM2 variants, so there isn't an expectation, for example, that we wouldn't see an effect. However, this we're able to do this in a really efficient way within the context of the phase I, so we thought it made sense to just double check and confirm that response. And again, looking for any really big changes, some of which would be a surprise for sure. Then on the APOE side, again, we don't expect it to have a significant difference, but this gives us an opportunity to check in on the patient population, just make sure that our phase II inclusion/exclusion criteria is informed by some data. Yeah, there's no reason to expect that, you know, activation of TREM2 would be specific. We actually believe that activation of TREM2 and TREM2 being the key modulator of neuroinflammation has an impact not just on beta amyloid, but actually tau processing and other things, right? Microglia are the ones that are clearing all the damage in the brain. So we don't necessarily expect to see a difference, but we think it's worth doing that experiment before we go into the phase II study. Great. Maybe one last question. Can you just remind us of your cash position and the runway? Sure. So, at the end of Q2, including the Sanofi transaction, which brought $40 million, we had about approximately $110 million, which gives us a cash runway into 2026, as I mentioned, well past some of these milestones we discussed. Great. Looks like we'll leave it there. Thanks so much for your time. Thank you. Thank you.