Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. As you know, it's the anniversary of 9/11, so we'll observe a moment of silence. 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 CEO Ivana Magovčević-Liebisch and CSO David Gray. Welcome. Thank you. So for those who may not be as familiar with Vigil, can you provide a brief introduction? Thank you, Morgan Stanley, for that, for the kind invitation to present this morning. So, what I always like to start with is really talk about three things that we believe differentiate us from other companies out there and in the similar space. And that is first and foremost, Vigil has a precision-based approach to neurodegeneration. And what we mean by that is that we focus on indications where there is a very strong genetic, mechanistic and biochemical association to microglia dysfunction, which we believe reduces the downstream translational risk and allows us to get to that clinical proof of concept quickly. The second, very exciting thing is that we are the only company that has two TREM2 modalities. So we have both a fully human monoclonal antibody, called VGL101, and we also have a small molecule TREM2 agonist, which now has a name, VG-3927. And we believe that with the you know with these two modalities, we have an opportunity to really build a deep pipeline of both rare and common neurodegenerative diseases. And then, very excitingly, we have the opportunity to be the first company to declare clinical proof of concept in a patient population with a TREM2 agonist. So now moving to who is Vigil? Vigil is a microglia-focused therapeutics company. The goal is really 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 most advanced asset, which I'm sure we'll be talking about a lot more today, is VGL101. That is the fully human monoclonal antibody, has an excellent therapeutic profile, and that's currently in phase 2 study in a disease called ALSP. It stands for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. It's a rare neurodegenerative condition, huge unmet medical need, no treatments available, and we're very excited that we'll be able to share the first set of data from this study in the fourth quarter. We also have, as I mentioned, a small molecule, and now it has a name. It's VG-3927. This is orally bioavailable, highly CNS penetrant molecule that is about to enter the clinic next month. So, it's a first and only TREM2 small agonist to be entering clinical development. We're also very well funded. As of end of June, we had $150 million in cash, which gets us into 2025 and through some of these really exciting milestones. So I'm gonna stop there and see if there are any questions. Great. Well, you mentioned TREM2, and so maybe that's a great place to start. How are you TREM2 agonists different from others? I'll let David take that. Sure. I mean, so we can start with the antibody that it has its you know individual binding epitopes that we've talked about, and it's a fully human monoclonal antibody with a Fc function modified so that it has reduced interaction there. And you know specifically for rare diseases like ALSP, we think this positions really really well diseases that have compromised blood-brain barrier function and especially in interactive disease. The small molecule is obviously very different in that it is freely brain penetrant like you would want in a small molecule, orally bioavailable. And we'll talk actually more about that at an upcoming R&D event on Wednesday in the morning between 7:30 A.M. and 9:00 A.M. But there's a couple of things that are unique about the small molecule, and one of them is that it has a differentiated mechanism of action. So it acts to stabilize the TREM2 signaling complex, and then importantly, it acts in synergy with natural damage ligands. And so fundamentally, what that means is we're seeing a lot of evidence of increased activity in and around areas of active pathology. And that synergy with the natural, with the natural ligands, we think, could be really important for increased therapeutic index and also for increased safety margins with that specific molecule. And then obviously, you know, the PK and the convenience and access of a small molecule we think fits really well with a large indication like Alzheimer's. Now, last month, one of the competing TREM2 candidates was discontinued. Are there any potential read-throughs to your TREM2 candidates, or were they specific to that compound? We believe it's specific to that compound. You know, we have a typical monoclonal antibody that's an engineered molecule that has a transferrin on one end. No, we don't see any read-through to TREM2. David, anything else? ...Yeah, I mean, I, I can just add that I think ultimately this comes down to the, the significant amount of safety data that we have clinically with VGL101, as well as the Alector molecule also being in phase 2 for Alzheimer's with our antibody. That molecule referred to are nothing that we've seen, nothing that has been reported with Alector. And then fundamentally, preclinically, both both our small molecule and our antibody have excellent profiles. We've not seen those types of signals. You talked about VGL101 and ALSP. So can you just talk a little bit more about ALSP and why that was an attractive initial target for 101? Sure. So ALSP, as I said, a rare neurodegenerative disease, hits in the prime of adulthood. It's actually monogenetic disease. It's caused by mutations in CSF1R gene, which is a trophic receptor that sits on microglia. The reason we picked it is because that mutation directly impacts microglia dysfunction. So there is a direct evidence that mutations in CSF1R gene lead to reduced number of microglia and also to microglia that are less functional. And so what we are trying to do is, TREM2 is also a receptor that is expressed on the microglia. It's the major sensor of the damage in the brain. And so what we're doing is by overactivating TREM2, we're actually compensating for the CSF1R deficiency, because these two receptors have a downstream signaling that meets. And so that is, that is the idea, and we have a lot of preclinical data that we have generated, where we've shown the proof of mechanism that we can in iPSC-derived human microglia, we can restore the function by, you know, administration of our antibody. David, anything else? Yeah, I mean, just to add on more to that. Preclinically, we're able to model components of ALSP by either inhibiting CSF1R directly in the kinase domain or withdrawing the ligands from growth. Or more recently, we've actually generated microglia that have one of the mutations that's present in ALSP. And in all three of those settings, we're able to take VGL101 and essentially restore the health of microglia, which is compromised by those different models. So very nice proof of concept within microglia, that this TREM2 module strategy reads through to CSF1R, has an impact on microglia as a whole. Now, what's the split of symptomatic versus prodromal patients in ALSP? And do you expect that VGL101 would be better suited to treat one subpopulation or the other? So the focus, obviously, of our clinical studies is on symptomatic patients. The ones we are enrolling in phase 2 study are mild to mildly moderate because we believe that earlier in the disease progression, the better. Obviously, this gene has a very high penetrance, so ultimately the prodromal patients will convert. We are enrolling prodromal patients in our natural history study. We actually, I should have mentioned that we have a natural history study ongoing called ILLUMINATE. That's been going on for a while now, and it's a very important study for us because obviously we're learning about the patient journey, but we are also learning about how the biomarkers and the clinical endpoints respond in this patient population. It's very important for us to include the prodromal patients in that study because we'll learn more about, you know, when and how that conversion occurs. But for the phase 2, it is focused on symptomatic patients. I should just say that we have actually enriched our patient population in phase 2 with patients who actually roll over from the natural history study so that they have some run-in data once we take that first interim, interim look. Oh, I think we covered it. So with the phase two, you have interim data in the fourth quarter. Can you just talk about the study, what measures we see later this year, and what would be considered positive results? So phase 2 is an open label study. It's one year in duration, up to 15 patients, as I mentioned, symptomatic, mild to mildly moderate. The primary endpoint of the study is obviously safety and tolerability, but we'll be also looking at the efficacy biomarkers. From our natural history study, we know that MRI and NfL are very good efficacy biomarkers in this patient population. We have shown that even within a six-month timeframe, we can see quantifiable changes in MRI in this patient population, specifically focusing on white matter lesion volume, and ventricular volume. And then, this patient population has very, very high levels of NfL as well. And we will also be looking at clinical endpoints. This disease presents itself like many other neurodegenerative diseases. It's usually cognitive changes, behavioral changes, motor changes. So we're using clinical endpoints that have already been well established in other diseases. Our first look is our early interim look, which will be 6 patients at 6 months at 20 mg per kg. The reason we're taking this look is because we wanna look for any kind of signals, because if we see any changes or any, you know, directional changes in MRI or NfL, we believe it will be important to take that with our natural history data to the FDA and start the conversations about what would it take for, you know, accelerated approval, breakthrough therapy. And so that's the reason for that first look. But the study indeed is a year in duration and up to 15 patients. You mentioned the 20 mg/kg dose. That was started as the pharmacologically active dose, but now you also have a 40 mg/kg cohort. Why was this done? So obviously, as you know, dose exploration is something that's important to do early on in a clinical development, and we know that the FDA likes to see that as well. So we've now shown that the drug 101 is safe all the way up to 60 mg/kg MAD. And so we thought it made a lot of sense to add another dose, so that we have the most robust data package when we go and talk to the agency. And we'll also actually, I should say, today, be presenting our complete phase 1 data set at ANA in a poster presentation. And you'll see an announcement as soon as the embargo is lifted, and you'll see from that data set that there are no surprises in there. You'll see that 20 and 40 look very, very similar. So the rationale really was to create as robust a package as possible for our conversations with the agency. So how confident do you think you can be with the data from the first six patients, when you ultimately have 15 patients with long duration? And how predictive do you think the six-month data are for clinical measures at 12 months? So again, as I said, it's an early interim look. It is only 6 patients. What we are really looking for here is any type of a signal, right? So... And obviously, safety and tolerability. This is the first time that the drug has been in a patient population, so that's going to be very important to show that it's, you know, safe and tolerable, and then any kind of signal, we'll be very excited to take that forward and have a conversation with the agency. But there is a reason that we did this study 1 year in duration and obviously have more than 6 patients. The one good thing here is obviously that, as I said, we're enriching for the patient population that's already been in the natural history study. So they have already some data that's running into this study, so they can serve as their own controls, which will be very helpful. And then we do plan to look at each patient individually at this point. With a full phase 1, single, multiple ascending dose data, like, how might that data impact the phase 2, if at all? You mean the data that we'll be- Yeah. -presenting? So no, as I said, there's no surprises in that data set. We've shown, as I said, I've already mentioned this before, that the drug is safe and tolerable up to 60 mg/kg, and we don't see any meaningful differences between 20 and 40. So we don't think that there's got-- We both are, I should mention, both are pharmacologically active doses. We see that they, you know, engage the targets in both robust and durable ways. So that's one thing I should mention, is that we're the only company that's shown a durability of a response in a clinical setting. So we showed that not only can we get into the brain and engage the target, but that response is durable past the third dose. No, I mean, that's obviously very important. I mean, the other thing is that the data set that we'll release here today is from healthy volunteers. So we obviously want to be able to have the maximum flexibility to explore that in the patient population. Can you talk about your ALSP patient initiatives and the goal of the ALSPaware? Absolutely. ALSP is a disease where the genome was only identified about 10+ years ago. It's a disease that unfortunately ends up being underdiagnosed and misdiagnosed, because, as I mentioned, the symptoms look similar to many other diseases, such as FTD, AD, MS. We know from our conversations with the KOLs and just our experience, that a lot of patients end up being misdiagnosed and end up, for example, in MS clinics. There's been a recent report from the Cleveland Clinic and Mayo Clinic, where they looked at 400 of their MS patients. They genotyped them, and they found that 0.5% were actually ALSP. If you extrapolate that to the MS population in this country, you're talking about several thousand patients just sitting in MS clinics. So the epidemiology says that there are at least 10,000 patients in the U.S. But today, only about a third are properly diagnosed. We actually believe that's a conservative number. And the reason we launched ALSPaware is because when we speak to the community, both to the patients as well as the KOLs, it became very clear that there was a need for, you know, a genetic test that's easily available to the patients and their families. Because what I forgot to mention is that this is an autosomal dominant disease, unfortunately. So once you find a patient, you have a cluster, because this disease hits in the prime of adulthood, which means the people have families, and then these tend to then be large families. So there was a need to, even though the test is available, it's globally available, it's a straightforward test, there were some barriers for patients. So we have now introduced ALSPaware, which provides free genetic testing and counseling to patients and their families. But in addition to that, to help with the misdiagnosis and increase awareness, we are also providing a 24-gene test to healthcare providers. And we're really focusing on these clinics where we know that misdiagnosis patients are fit to encourage the testing and get to the diagnosis as quickly as possible, because as I mentioned, from symptoms to that is only 6-8 years. So we want to make sure that these patients are identified as quickly as possible. ... Now, you're also looking to treat other leukodystrophies with 101. What, what kinds of indications are of greatest interest, and, and how big are those indications when compared to ALSP? So I'll just say that we are looking at other rare microgliopathies, and the reason we are focusing this space is obviously because we're tying the, you know, the microglia dysfunction is to TREM2, right? So we want to focus on diseases where there's a direct correlation to microglia dysfunction to begin with. And obviously, also, these are diseases where the blood-brain barrier integrity is compromised, which positions them extremely well for antibody therapeutics. And obviously, you'll be hearing more from us. As the ALSP program progresses, you'll hear more about exactly which of those indications we plan to go into. David, anything else? Well, our expertise in and our platform around microglia also really positions us well. So in addition to learning from our ongoing clinical studies and biomarker work, we're able to use that platform to, you know, scientifically inform the selection of which of those additional indications we would prioritize. And yeah, we'll talk more about that at the appropriate time. Okay, great. Well, you also have, as you mentioned at the top, small molecule TREM2 program, now VG-3927. Can you talk about this program and why you're starting with Alzheimer's disease? Sure. So we're staying true to our precision-based approach strategy, even when we think about Alzheimer's disease. So yes, we're taking the small molecule into genetically defined subpopulations of Alzheimer's disease because we know that Alzheimer's patients who have TREM2 variants have a higher risk of, you know, having the disease, but also have a more aggressive disease progression. There's some really nice studies that have been done to show that, you know, microglia that are TREM2 deficient are unable to create those barrier functions around, you know, plaques and therefore not able to protect the brain. So we think that there is a really nice genetic correlation here that makes a lot of sense. Obviously, our small molecule is orally bioavailable, highly CNS penetrant. It has a PK, obviously, which makes a lot of sense. It's going to be a daily dosing, and in addition to that, as David mentioned, has some really exciting characteristics. The fact that it acts as a molecular glue to stabilize the TREM2 complex. But in addition to that, the synergy with natural damage ligands, we think is going to be really critical once we get into patient population, because that specificity and potency in a disease setting should allow us to explore, you know, really low doses and also can contribute to really favorable safety profiles. So we're extremely excited about taking this first and only small molecule into clinical development next month. Anything else, David? Well, so, I mean, looking more broadly, neuroimmune modulation and specifically harnessing microglia, you know, we think is really the next frontier in terms of, of what's coming in Alzheimer's disease, specifically, as well as in other neurodegeneration. And, you know, one of the unique things, well, not unique, but the microglia do not only respond to amyloid pathology. They, they are engineered, and they have a broad set of ligands that activate TREM2 and that get them to respond, you know, to tau pathology, other pathologies that have been shown. And so as we continue to explore VG-3927, that's one of the other things that we're really excited about in terms of, of positioning this in Alzheimer's, is the breadth of response across different types of pathology and how that can, you know, really kind of bring us into the next stages for new Alzheimer's treatments. I will share more of that at our R&D event on Wednesday as well. So you also announced that the phase 1 has a partial clinical hold related to maximum exposure limit. Can you just talk about why the FDA has implemented this limit and what's the process from here? Yes. So, where we are is obviously the exciting news is that the IND is open, and we are allowed to proceed. And as I mentioned, we'll be entering the clinic next month with our phase one study in healthy volunteers. Yes, you're correct. The partial clinical hold is with the maximum exposure cap. The really good news here is that the cap that's been imposed is above what we believe is the efficacious predicted efficacious dose. So we feel that we have enough room to reach that and go above that dose while we talk to the agency. The reason for the cap is, you know, you use different species in tox studies. We calculated our cap with one species. They decided to focus on a different species. We believe that this is something we can resolve with them, easily, and we have data in hand, which we believe will allow us, to do that. So in terms of the small molecule, it's, it's full speed ahead into the clinic. Any plans to develop your small molecule TREM2 for ALSP? And are there certain indications where IV would be preferred over small molecule? So we—no, we have no plans to develop the small molecule for ALSP. This is what I said before. What really differentiates this from other companies in this space is that we have the, I would call it, the abundance of riches. We have two modalities, right? We have both the antibody and the small molecule, which really allows to be very thoughtful, in how we, create our pipeline. And so we have an opportunity to create a really robust pipeline here, both in rare and common neurodegenerative diseases. We think the antibody makes a lot of sense... In this rare microgliopathy space for the reason that we mentioned before, which is that, you know, in addition to all the connections to microglia dysfunction, there is this, you know, lack of, you know, it's a leaky blood-brain barrier in the areas of active disease, which we think will provide us with additional specificity when it comes to the antibody. And then we believe that the small molecule really is a game changer when it comes to larger indications, obviously starting with genetically defined subpopulations. But we know that there are many other diseases where microglia dysfunction is associated with, with the disease as well. Anything else, David? I mean, there's a lot of things we could say, but probably just one thing to highlight is that out of all the genes that have been identified as risks for Alzheimer's disease, you know, well over 30%, well over a third of those are specifically expressed in microglia. So we, I mean, we know we're in the right space. We know from even these recently approved therapies, they act by bringing microglia in. It's actually the microglia that do the clearance of the plaques. So we know we're in the right space. We were able to build on that expertise with our platform and, you know, again, just flesh out this really exciting profile of VG-3927. Great. Well, maybe one last question, and you've touched upon this actually a couple of times, but maybe for those who either missed it earlier, you're hosting the virtual R&D event for VG-3927 on Wednesday morning. Maybe, you know, what should we expect from that event? Sure. So this is really our opportunity to share with the community, you know, why we are excited about VG-3927. We've been talking about it, but now we'll be able to share, you know, a more robust data set, both in vitro and in vivo data, that gives us the confidence around this molecule. But in addition to that, we have two very distinguished KOLs joining us as well, Dr. Marco Colonna from WashU, who has really done all the foundational work when it comes to TREM2 and the role within microglia. And then Dr. Sam Gandy, who is from Mount Sinai, and also very involved in, you know, a clinician, but also very involved in research. You'll hear from both of them why they believe that TREM2 is one of the most relevant targets at this point in this space. One thing that we didn't highlight, but I really want to highlight, is that, you know, microglia and TREM2 really are the main control switch when it comes to neural inflammation in the brain. That's why both David and I are excited, not just in prospecting Alzheimer's disease, but well, well beyond that. Any last comments, David? Well, so maybe just to give you a little preview of just a couple, three things that you think about at this R&D event. So, just to recap, we'll talk about why, at a high level, why it's a really excellent molecule, the molecule itself. We'll talk about the synergy that we mentioned with natural ligands and provide more data around that, and also in the context of the various TREM2 variants and how we've been profiling the, you know, the way that 3927 is able to activate those as well. We'll talk about the breadth of different types of activation that we see in this really kind of non-inflammatory profile, which is quite important. The way that 3927 activates microglia is a non-inflammatory profile, so we'll talk about some of that data. And then, as Ivana mentioned, we'll share some in vivo data as well to kind of tie it all together. Great. Well, looks like we'll have to leave it there. Thanks so much for your time. Thank you.