Good morning, and welcome to Vigil Neuroscience conference call and webcast, highlighting its small molecule program and lead small molecule candidate, VG-3927. Currently, all participants are on a listen-only mode. There'll be a question and answer session at the end of this call. Please be advised that this conference call is being recorded. I would like to turn the call over to Leah Gibson, Vice President of Investor Relations and Corporate Communications. Please proceed. Good morning, everyone, and welcome to our event. Before we begin, a few housekeeping reminders. The webcast is scheduled to end at 9:00 A.M. Eastern Time. In addition to following along, today's presentation is now available on our website in the Events and Presentations section for download. Following our prepared remarks, we will hold a moderated Q&A session. To submit a written question, please fill out the form on the webcast homepage. A webcast replay will be hearable later today on Vigil's website in the Investor section under Events and Presentations. Quickly turning to Slide 4, I'd like to mention that we will be making a number of forward-looking statements within the meaning of federal securities laws. These forward-looking statements are subject to risks and uncertainties, many of which are beyond Vigil's control. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's quarterly report on Form 10-Q for the quarter ending June 30, 2023, as well as the company's other SEC filings. Except as required by applicable law, the company does not undertake any obligation to publicly update any forward-looking statements provided today based on subsequent events and circumstances. With that, I will now turn the program over to our President and CEO, Dr. Ivana Magovčević-Liebisch. Thank you, Leah. Good morning, everyone, and thank you for joining us this early. We're very excited to share data for VG-3927, our small-molecule TREM2 agonist with first-in-class potential. We will also discuss current treatment approaches for Alzheimer's disease and Vigil's clinical approach for AD, guided by a precision-based strategy. Before we get started, I want to highlight three things that we believe differentiate us from other companies in this space. First, and very importantly, we have a precision-based approach to neurodegeneration, which we believe increases the likelihood of success. Second, we're the only company that has two TREM2 modalities. We have both an antibody TREM2 agonist, VGL101, and a small molecule TREM2 agonist, VG-3927, which provide us with opportunity to build a very robust pipeline in both rare and common neurodegenerative diseases. With VGL101, we have the opportunity to be the first company to declare clinical proof of concept in a patient population in the fourth quarter this year, and VG-3927 is the first and only small molecule TREM2 agonist entering clinical development. On Slide 6, let's start with: who is Vigil? Vigil is a clinical-stage microglia therapeutics company. We're a young company, founded about 3 years ago in July 2020. Our goal is to discover and develop novel therapeutics to treat both rare and common neurodegenerative diseases by restoring the vigilance of microglia, which are the sentinel cells of the brain immune system. Our strategy is to first develop precision-based therapies for rare microgliopathies, to provide us with insights and learning to then expand into larger indications. We have identified TREM2 as the key regulator of microglia function, and we plan to explore it in multiple different indications, as well as look at additional targets in this promising and important area of biology. As mentioned previously, we are the only company known to have two TREM2 modalities. As you will see, we have accomplished a lot in a relatively short period of time, and this is because we have an amazing team of highly experienced, execution-focused industry veterans on our management team and board, as well as more than 60 highly dedicated team members. Slide 7 outlines our strategy, which is a precision-based approach to neurodegeneration and is our key differentiator. We are focusing on indications with very strong genetic, mechanistic, and biochemical association to microglia dysfunction. As such, our first indication is a rare microgliopathy called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, or ALSP, currently in phase II study. We then plan to expand into other microgliopathies, focusing on genetically defined leukodystrophies. Then, staying true to our precision-based approach, we plan to expand into larger indications like Alzheimer's disease. We will initially focus on genetically defined subpopulations, such as patients carrying TREM2 variants, who have a higher risk of Alzheimer's disease, which you will hear more about today. We will take these learnings and expand into the broader populations in these common indications. This iterative, sequential approach is our key differentiator because it allows us to reduce the downstream translational risk and get us to the clinical proof of concept very quickly. Slide 8 shows the reason why we're able to maximize on this strategy. As I have already highlighted, we have two TREM2 modalities. A fully human monoclonal antibody, TREM2 agonist, VGL101, is the first disease-modifying drug candidate being developed for ALSP, currently in phase II clinical trial. Our small molecule TREM2 agonist program has produced a lead candidate, VG-3927, which is the focus of today's event. Importantly, it is the first and only small molecule TREM2 agonist entering clinical development, and we believe it can be a game changer for Alzheimer's disease. Having these two modalities allows to generate a pipeline with multiple shots on goal. I'm very excited to share an overview of VG-3927 on Slide 9 before David, our Chief Scientific Officer, and Christian, our Head of Neuroimmunology, walk you through the comprehensive preclinical foundational work we have generated today. As mentioned previously, VG-3927 is the first and only small molecule TREM2 agonist entering clinical development. It has an excellent therapeutic profile, including convenient oral dosing, superior brain penetration, and a PK profile that enables fine-tuning of dose levels. Importantly, it has a differentiated novel mechanism, acting as a molecular glue and potentiating TREM2 response to natural damage ligands. We believe this enables improved potency and specificity against active disease state where there is damage accumulation. This may also support lower doses for potentially more favorable safety profile. We announced last week that the IND is now open, and our phase I clinical trial in healthy volunteers is allowed to proceed. We have a partial clinical hold related to maximum exposure limit, but based on preclinical studies, we believe that this maximum exposure limit exceeds the predicted efficacious dose of VG-3927. Most importantly, at this time, we don't anticipate any delay in our current clinical development plans, and we expect to commence dosing in the phase I trial in healthy volunteers next month. Moving to Slide 10. We're very honored to have two distinguished key opinion leaders joining us today. I want to thank them for taking time out of their very busy schedules to share their insights and perspectives to contextualize our VG-3927 program. First, joining us today is Dr. Marco Colonna. Dr. Colonna is the Robert Rock Belliveau Professor of Pathology and Immunology at Washington University. He's also the chairman of the Vigil Scientific Advisory Board. Dr. Colonna has conducted much of the foundational work on TREM2 in microglia. Today, he will start out with an overview of TREM2 biology and the rationale for TREM2 as a therapeutic target for AD. Next, I'm very pleased to introduce Dr. Samuel Gandy. Dr. Gandy is the Mount Sinai Professor of Alzheimer's Disease Research and Associate Director of Mount Sinai Alzheimer's Disease Research Center. He's also the past chairman of the National Medical and Scientific Advisory Council of the Alzheimer's Association. Today, Dr. Gandy will provide an overview of our current treatment options for AD and the unmet medical need that still remain, as well as the human genetic data supporting the TREM2 approach in AD therapeutics. With that, I will pass it on to Dr. Colonna. Thank you. Good morning, everyone. Ivana, thank you very much for your introduction. What I'd like to do today is to spend the next 20 minutes or so about telling you why we think that TREM2 is a fundamental target in the treatment of Alzheimer's disease. But before I do that, let me take a step back and turn your attention onto microglia. Microglia are the brain resident macrophages. They're very specialized cells for several reasons. First of all, they develop very early on during embryogenesis from the yolk sac, and they migrate into the developing brain. After the brain has developed, these cells will proliferate, will populate the brain, and eventually, they will completely cover the entire brain and remain there for the rest of our life, with very little input from monocytes derived from the blood. Another important feature that you can see, highlighted in this scheme is their morphology. They are highly ramified, cells, and with their processes, they cover certain areas of the brain. And finally, their specialized function is to phagocytose the cells, protein aggregates that might be. And this function is important both in development, for example, for pruning synapses and establish connectivity, and also, in diseases, to remove protein aggregates such as, amyloid plaques. So moving on now to the function of microglia. I just want to give you a couple of examples of how microglia can function, both under homeostatic and pathological condition. In the first movie that you see on the left, you see microglia in homeostatic condition are visualized by two-photon microscopy in live brains of a mouse models. You can see the microglia move their processes constantly and survey the area of the brain that they're residing. Now, on the right side of movie, you can see what happens during a lesion. A lesion which is caused by laser, in this case, you can see that microglia proliferate and send the processes towards the lesion, try to wall in the lesion and to limit the spreading. So in the next slide, you'll see that this is exactly what happens also in a in a brain with Alzheimer's disease. On the left, again, you can see a healthy brain with microglia. You can see the soma, the bodies of the cells, and you can see the processes that ramify in certain areas of the brain. And on the right, you can see a picture of an Alzheimer's disease brain, in which the plaques, which contains also very large amount of aggregated ApoE, which is also a ligand for TREM2, is completely surrounded by microglia. That clusters around the lesion and tries to wall in the lesion. So, why we're so interested in microglia? In the next slide, you'll see that many studies, genetic studies have identified risk factor for Alzheimer's disease. Starting from 1992, with APOE4 until recently. Now, on the right side of the, of this figure, you can see that you can see a heat map in which these risk factors are analyzed for their expression on different cell types. And And you can see the vast majority of these risk factor are highly expressed in microglia, less expressed in neurons, oligodendrocytes, astrocytes, and endothelial cells, suggesting that microglia has an essential role in controlling the onset and the progression of the disease. Now, in this picture, you can see a Manhattan plot, again, highlighting the risk factors for Alzheimer's disease. And you can see the TREM2 has a central role in as a risk factor. In fact, many other risk factors are also part of the TREM2 pathway. For example, ApoE, ApoJ, which are also risk factor for Alzheimer's disease, they're ligand for TREM2. MS4A2, which controls the cell surface expression of TREM2, and the shedding of TREM2, is also risk factor for Alzheimer's disease. Another risk for Alzheimer's disease is INPP5D, which controls the intracellular signaling of TREM2. Now, we also know a lot about other neuroinflammatory diseases, for example, multiple sclerosis. We know also risk factor for multiple sclerosis. I can tell you that, the risk factors for multiple sclerosis, you can see highlighted here on the right, are quite different from the risk factors that are responsible for neurodegeneration and Alzheimer's disease. Suggesting that, we really need a specialized therapeutic approach for Alzheimer's disease that is different from other neuroinflammatory diseases. So now, on Slide 17, we turn our attention more on TREM2. Genetic studies have identified a number of variants of TREM2, and all these genetic studies have shown a robust association of the TREM2 variants with Alzheimer's disease. Structural studies has also been performed on TREM2, as you can see in the center of this slide, and many of the variants indeed affect the ability of TREM2 to bind the ligands. Also, gene expression studies have been done in patients with Alzheimer's disease, models of Alzheimer's disease, and controls. When we look at genes that are differentially expressed, we see that a network of gene is involved, and this network has a central hub, a molecule called DAP12, which is essential for signaling of the TREM2. In fact, in the next slide, you'll see that, TREM2 is expressed on the cell surface, but does not signal on its own. It needs to associate with a molecule called DAP12, and this, complex TREM2, DAP12, is important to recruit the intracellular molecule, Syk, a protein tyrosine kinase that drives microglia activation. One point I'd like to make here is that, what is very important for TREM2 mediate the activation is a cluster of TREM2. So all these, TREM2 molecule, DAP12 molecule, and Syk, have to be glued together. This is a concept that will be, reiterated later on by David, and also by Christian in the rest of the talk, because this is one of the mechanism of action of, of the small molecule that activates TREM2. Just to highlight the importance of clustering of DAP12 and TREM2, we also know that there's very rare individuals that have a complete deficiency of DAP12, complete deficiency of the TREM2, and yet these individuals develop a very severe dementia, even more severe than Alzheimer's disease. This disease is called Nasu-Hakola disease, and as you can see on the right side of the slide, this disease has a very severe reduction of neural mass, a very strong dilation of the ventricles, a very strong apoptosis, and also very strong astrogliosis. Moving on to the next slide. We have also evidence that the extensive experimental evidence that TREM2 is important to control microglia responses to amyloid plaques. First of all, studies by single-cell RNA-seq in mouse model of Alzheimer's disease have shown that, microglia converts from a homeostatic state into what we call a disease-associated state, in which microglia express genes involved in chemotaxis, immunometabolism, and importantly, in phagocytosis. And in the central part of the slide, you can see that, in a mouse model of Alzheimer's disease, again, you see plaques in green, a microglia clustering in red around the plaques try to limit the disease. And, in the absence of TREM2, you see a complete lack of the microglia clustering around the plaques, such that the plaques now are free to spread. Now, this evidence is not only true in mouse model, it's also being corroborated in human. On the right side of the slide, you can see a section of the brain of the patients with Alzheimer's disease. You can see a plaque, and around the plaque, with amyloid and also tau, you see an accumulation of microglia. If we measure the density of microglia around the plaques, you can see that in control patients with Alzheimer's disease, we have a significant accumulation. But in patients with a variance of TREM2 that is associated with a higher risk to develop Alzheimer's disease, we see a very strong reduction of the cluster of microglia around the plaques. We also have, in the next slide, evidence that antibodies that activate TREM2 are important in facilitating the activity of microglia and the ability of microglia to contain amyloid plaques. This, on the right, on the left, you see a experiment that we done in collaboration with Alector, in which we tested an antibody, an agonistic antibody, anti-TREM2. You can see it in blue, you can see the plaques. In red, you can see axonal swelling around the plaques, which are indicative of neuronal damage. And when these mice were treated with anti-TREM2 agonistic antibody, we see a significant reduction of the axonal swelling around the plaques. Now, on the right, you can see a further improvement of the strategy in which the ability of antibody to cluster is being increased artificially, and also the brain penetration activity of the antibody is being increased. And you can see that in this condition, treatment with an agonistic antibody can actually strongly reduce the amyloid plaques in the brain. So finally, in my last slide, I'd like to point out that recently, FDA has approved antibodies for the target Aβ plaques. And these antibodies are effective in clearing plaques, and they also have some beneficial effect in the clinics. But the point I'd like to make here is that these antibodies act by cross-linking the plaques with microglia. So microglia is essential for the function of these antibodies. Indeed, if we mutate the Fc portion of these antibodies such that they can no longer engage microglia, particularly the Fc receptor of microglia, then the antibody is no longer effective. And so, also this new therapeutic approach suggests that we have to leverage microglia in order to restore homeostasis in Alzheimer's disease. So let me make some closing remarks. What I show you is that the genetic studies on a large population of Alzheimer's disease patient have pointed out to a role of microglia as a potential target for therapeutics. TREM2 is at a central role in the genetic factors, and this has been implicated not only by genetic studies, but also by gene expression studies. We have extensive experimental evidence and also clinical evidence that TREM2 is important to sustain microglia responses to Alzheimer's disease. We also have pharmacological evidence that agonist of TREM2 can activate microglia and have beneficial effect in pathology. Finally, the recent approval of anti-β therapeutics really provides evidence that leveraging microglia can be a very useful approach in restoring tissue homeostasis in Alzheimer's disease. So in the final slide, I'd like to make a few acknowledgments. I'd like to acknowledge my collaborators at WashU, Jony Kipnis, Dave Holtzman. We have extensive collaboration with Ido Amit at Weizmann Institute. We collaborate with brain banks all over the world, particularly in Niigata, Japan, at the Mayo Clinic in Rochester. We collaborate with pathologists in Italy, particularly Luigi Poliani. We also have extensive collaboration with companies. We collaborated in the past with Alector, with Amgen, and recently, we had a very extensive collaboration in the past few years with Biogen and Eisai. So let me tell you, on a personal note, that I cloned TREM2 about 20 years ago, and at that time, nobody was really interested in this molecule. It was underneath the radar of immunologists and neurologists. I'm very excited now that this molecule has become a center of attention in Alzheimer's disease. And I'm particularly excited to see how our collaborators at Vigil have developed tools to target effectively this molecule in therapeutics. So I thank you for your attention. Thank you so much, Dr. Colonna, for that informative introduction to microglia and to TREM2 biology, and thank you for your outstanding contributions to and leadership in this field. For you and the many others who have been exploring neuroimmune modulation via TREM2, this is a watershed moment. As we see on the next slide, we are now poised to unlock the tremendous potential of this mechanism via an oral small molecule, VG-3927. On behalf of our world-class discovery team at Vigil, it is my privilege to share more about this exciting program that begins with an outstanding actual molecule that has a differentiated profile and a unique mechanism of action that synergizes with natural damage ligands. As we move throughout the presentation today, we will share data which speaks to the way in which VG-3927 favorably modulates microglia with a protective, non-inflammatory profile. We have focused our discovery efforts on a unique series of TREM2 agonists, many of which have stellar properties. On Slide 26, the plot on the left is one that medicinal chemists use to assess compound quality using a combination of multiple parameters. The diagonal lines are established benchmarks, going from good to excellent to exceptional as we move toward the upper left. Each point represents a compound, and Vigil's discovery team has created many good, excellent, and even exceptional compounds by this demanding metric. Now, this quality translates when we examine their pharmacokinetics in preclinical species. Compounds from this series have shown consistently good oral bioavailability, low clearance, and very high brain penetration in vivo. From amongst multiple outstanding options, we selected VG-3927 because of its overall favorable data across all preclinical assessment domains. Starting in the blue section on Slide 27, VG-3927 is a highly potent TREM2 agonist, with which is exquisitely selective for the desired target while avoiding TREM1. Additionally, VG-3927 has a clean profile across more than 350 additional off targets that we've evaluated. Moving clockwise, its measured pharmacokinetic parameters are consistent with projected once-daily dosing. VG-3927 is freely brain penetrant, with measured CSF levels approximating free plasma levels across preclinical studies. Thus far, we have no identified metabolic liabilities. After a series of robust preclinical evaluations, the safety profile of VG-3927 is favorable. It has been well tolerated across species, and we're very happy with the safety margins that have been established as we move into phase one, including on cardiovascular and on many other endpoints. Overall, as a molecule from a physico chemical property standpoint, and when measuring predictive factors such as solubility, permeability, avoidance of efflux transporters, and so on, VG-3927 has all of the characteristics of an excellent CNS drug candidate. As illustrated on Slide 28, the data provided today will take you through the differentiated profile of VG-3927, starting from in vitro systems and in human microglia, and then into functional characterization in more complex systems and in vivo. All to support its potential as a novel neuromodulating therapeutic for Alzheimer's disease. So first, let's start here on Slide 39 with the primary pharmacology of VG-3927. On the left of the slide, we are looking at the in vitro potency of VG-3927 for its ability to induce phosphorylation of tyrosine protein kinase, Syk, which acts as a key intracellular signaling node downstream of TREM2, and provides a functional readout of TREM2 activation. Also plotted here in this same graph is the complete lack of response at TREM1, illustrating impressive selectivity among these family members. Moving to the right graph, we confirm the specificity of this endpoint by comparing responses in microglia that have wild-type TREM2 to those in microglia that lack TREM2. In the TREM2 knockout, VG-3927 has no effect on Syk phosphorylation, highlighting the TREM2 dependence of this response. Moving to Slide 30, at Vigil, our core strategy is to follow and leverage human genetics across all of our programs. Beyond identifying TREM2 as a target, individuals who carry AD-associated variants of TREM2 define a clinical subpopulation within Alzheimer's disease. As we heard from Dr. Colonna, individuals with AD who carry these variants show compromised microglial barrier function around plaques and other evidences of insufficient microglia response. As illustrated by the graphic on the left, we believe that initially targeting a genetic subpopulation may increase the speed to proof of concept for VG-3927, and afford us the opportunity for increased signal detection and/or differentiated efficacy as a starting point for proving our clinical hypothesis. To support our precision-based clinical development strategy, we've profiled the potency of VG-3927 in the common variant of TREM2, and also across the most relevant risk-associated TREM2 variants. A representative selection of that data is plotted here, and you can see by visual comparison that VG-3927's potency is retained across these variants. This also holds true for additional neurodegenerative disease-associated TREM2 variants that are not shown here. We've developed a deep understanding of VG-3927, including where it binds to TREM2 and how it works to activate this receptor. This compound has a special ability to potentiate the signaling of natural damage-associated ligands, leading to a synergistic effect on potency, which we think could be a game changer for fully exploring the potential of TREM2, as shown here on Slide 31. Let me take you through the graph on the left, which combines several dose responses to illustrate this synergy. On the x-axis, we are varying the concentration of sulfatide, which is a glycosphingolipid that, among other things, facilitates the removal of Aβ peptide and is one of the many naturally occurring damage ligands that can activate TREM2. The y-axis shows TREM2 functional activation via Syk phosphorylation, expressed as a percentage of the max effect of the natural ligand. The gray control line shows activation of TREM2 by this natural ligand sulfatide alone. However, when we add VG-3927 to this experiment, at a low dose, we see the response shift up to the lighter blue curve, and at a higher dose, to the darker blue curve. This progression allows us to see the synergistic activation quite prominently. The combination of VG-3927 with sulfatide results in the level of TREM2 phosphorylation that far exceeds the max effect of the natural ligand alone. We can visualize this another way in the middle graph. Now, while VG-3927 can and does activate TREM2 by itself, when it is present with sulfatide, we get a clear synergistic effect that is very impressive. Going back to Dr. Colonna's explanation of how microglia function within microenvironments, we see this combined pharmacology as directly, as directing the efficacy of VG-3927 into pathological microenvironments. To further emphasize this point, think about how important it is to have a specificity of response in the areas where damage signals are present. That can translate into a potentially increased therapeutic effect and therapeutic index, and is something that we believe is due to the unique mechanism of action of VG-3927. Now, on Slide 32, I'll extend this with another very impressive piece of data, where we see the ability of VG-3927 to act in the same synergistic way, but now in the context of TREM2 disease-associated variants. So first, let's understand a little bit more about the R47H TREM2 variant. This loss-of-function variant is located in the ligand-binding domain, where it interferes with TREM2's association with its natural damage ligands, thereby compromising the microglial response to damage. When we express human microglia with this variant and look at response to sulfatide, we can see this playing out. The figure in the middle of the slide shows a sulfatide dose response in different TREM2 variants. The data for the common variant is in green, and we define its max effect as a 100% response. The heterozygous expression of R47H results in an approximately 50% response, and notably, the homozygous expression of R47H is nearly insensitive to sulfatide. The impact of R47H on TREM2 response is very clear from the summarized plot on the right side of the slide. Now, remember that as we look at the way that VG-3927 completely changes this picture. In the study shown on the left of Slide 33, we are looking at data from human microglia with homozygous expression of the R47H variant of TREM2. At the bottom, the gray control line again shows very little induction of Syk phosphorylation by the natural ligand sulfatide alone. Adding a low dose of VG-3927, we get the curve shown in light blue, and at a higher dose of VG-3927, the darker blue curve. In both cases, VG-3927 addition rescues TREM2 activation and increases it well beyond the defined 100% level... In the figure on the right of the slide, we've summarized this data in the dark purple bar. We've also added data from parallel experiments in microglia expressing one copy of R47H in light pink, and from the common TREM2 variant in green. Think back to what this plot looked like on the last slide. Impressively, the synergy with natural ligand is present in all cases. VG-3927 may have a unique ability to synergistically activate TREM2 in both common variant and also in risk variant carriers. Now, on Slide 34, I'll go back to when Dr. Colonna talked about the way that TREM2 signals as a complex, requiring the clustering of multiple TREM2 receptors, each with one or more DAP12 domains, for activating microglia to disease response. Now, we refer to VG-3927 as having a molecular glue mechanism of action, because despite being a small molecule, we understand that it's able to hold together and stabilize the signaling complex in an active form. The graphic on the left illustrates this concept. Now, some of our initial evidence for this mechanism came via native PAGE gel, gel experiments, where we noted the appearance of higher molecular weight, multimeric species upon addition of VG-3927, as highlighted in the dotted blue box in the photo of a gel in the middle. In follow-up, the gel on the right suggests that robust complexing of TREM2 and DAP12 occurs only when VG-3927 is added. From these initial data, we've continued to build a deep understanding of how our small molecule works. We can further visualize this effect by using an induced proximity fluorescence technique represented on the left slide of Slide 35. In this system, we have a two-part dye where each half is attached to a different protein, so TREM2 and DAP12, in this case. So then it is only fluorescent when the different components are close enough to recombine, and thus, observance of fluorescence requires very close and sustained spatial interaction between TREM2 and DAP12. We express this system in human microglia with representative images shown. In the control image, which is the one on the left, we see minimal fluorescence. The image on the right shows the result of adding VG-3927 to these cells. This induces the green fluorescence, indicating proximity of the multimeric complex, and this signal is quantified in the bar graph on the far right of the slide. This is just one of several data sets which provide strong evidence for the clustering and molecular glue mechanism that we see with VG-3927. Moving to Slide 36. Thus far, I've shown you data to establish the primary pharmacology, synergistic enhancement of natural damage, ligand activation, and molecular glue mechanism of action of VG-3927. These data, together with its strong characteristics as a CNS drug candidate, begin to illustrate why we are so enthusiastic about advancing VG-3927 into the clinic. It is now my pleasure to introduce our head of neuroimmunology, Christian Mirescu, who will detail exciting functional profiling of VG-3927 in more complex model systems and in vivo to support its potential as a therapeutic in Alzheimer's disease. Christian? Thank you, David. I've worked in the field of drug discovery for neurodegenerative diseases for the past 15 years. Like Doctors Colonna and Gandy, I was inspired by the paradigm-shifting human Alzheimer's disease genetic breakthroughs that began around 2013, and I focused the past decade of my career on harnessing the power of neuroimmune modulation as a key to unlocking disease modification for patients with neurodegenerative disease. David walked us through the exquisite pharmacology of VG-3927 and highlighted its unique mechanism of action as a molecular glue, which fits in line with what Dr. Colonna described earlier as essential to orchestrating TREM2 signaling. I'm excited to build on the pharmacological profile with a body of work that will highlight the functional characteristics of VG-3927 across an array of preclinical model systems, which collectively support its clinical development for Alzheimer's disease. On Slide 38, going left to right, I'll start by sharing data in Vigil's Human CNS Tri-culture platform, which strengthens our approach by allowing us to measure drug responses in highly relevant human physiological systems, increasing the likelihood that results from the lab translate to the clinic. Then moving from in vitro to in vivo, I'll touch on some promising observations of VG-3927 in an Alzheimer's disease mouse model, followed then by non-human primate data that pave the way forward for VG-3927. Collectively, we believe the fundamental credentials of VG-3927 are there, which is why we're very enthusiastic about its potential as the first orally bioavailable, highly brain-penetrant, TREM2 agonist for disease modification in Alzheimer's patients. Okay, let's dive in a bit deeper together here on Slide 39. So with the goal of mapping downstream drug responses and interactions with diverse CNS cell types, we developed a fully human multicellular system, which incorporates microglia together with their CNS partners, neurons, and astrocytes, to explore VG-3927 function, complementing the extensive pharmacological and mechanistic profiling performed in human microglia. These CNS multi-cultures can be maintained and longitudinally tracked for weeks, can be used to explore crosstalk between different cell types, and can be further challenged with additional neurotoxic stimuli. Therefore, they have been utilized to validate the protective actions of VG-3927, unique from what we've shown thus far, which I'll unpack over the next few slides. To first set the stage and demonstrate that VG-3927 holds its pharmacological profile, you can see here on Slide 40, that VG-3927 reduces soluble TREM2 levels in our tri-culture platform, demonstrating its potent target engagement. As you may recall, the reduction of soluble TREM2 in the CSF by therapeutic TREM2 antibodies is actively being employed in the clinic, including in our own phase I trial with VGL101. Therefore, we have confidence this provides a strong foundation as a potential translational biomarker going forward. On that note, I'd like you each to take a snapshot of this while, and hold in mind for when we get to the non-human primate studies I've alluded to. Having established VG-3927 target engagement, I'll next summarize its downstream biological actions and highlight its favorable non-inflammatory activation of microglia. I will also, for the first time, share that VG-3927, by finely tuning microglia activation, promotes neuroprotection and resilience. So a key measure of the state and character of microglia and immune cells in general, is how these cells communicate with their neighbors, defined in part by factors such as cytokines and chemokines. In these experiments on Slide 41, we challenge human tricultures with VG-3927 and measure the secreted response from microglia within this diverse human system. You can see that VG-3927 not only engages TREM2, but dials up the microglia motility factor IP-10 on the left, while at the same time dialing down classical pro-inflammatory cytokines, including IL-1 β, shown on the right, which has been widely associated with inflammasome activation and neuronal injury. This profile qualifies the microglia activation by VG-3927, is finely tuned, anti-inflammatory in character, and in keeping with promoting the mobilization and neuroprotective profiles highlighted by Dr. Colonna. Therefore, we view this as highly favorable, refuting any concerns about a storm of microglial activation associated with this mechanism. As I mentioned, an additional advantage of having microglia combined with their CNS partners, neurons and astrocytes, is the opportunity to stably maintain these systems and evaluate how microglia are influencing their counterparts. As highlighted on Slide 42 by the schematic on the left, the lab looks at microglial crosstalk to neurons by measuring extracellular levels of neurofilament light, NfL and tau in the presence or absence of VG-3927 treatment. The elevations of these are considered biomarker proxies for neuronal degeneration and are likely familiar because of their wide use in the clinic. In the case of NfL, reductions have in fact been a key basis for recent drug approvals, while modulating tau has been a long-standing area of Alzheimer's disease therapeutic investigation. On the middle panel is the VG-3927 effect on NfL, and on the right, the impact over time on extracellular tau. What's clear from these two graphs is that VG-3927 significantly reduced both neurodegeneration biomarkers. This response has been robust and repeatable, which speaks not just to Vigil's rigorous scientific standards, but to the high quality of this molecule and why we, we view this as a very promising profile. This enhances our appreciation of VG-3927 as it favorably modulates multiple neuronal health endpoints in a fully human CNS model system. So our small molecule not only engages TREM2 and drives the non-inflammatory microglial activation, but also promotes neuronal health, and in fact, even confers resilience as well, which leads me to the next set of exciting findings with VG-3927 in the system. Another way to pressure test our findings is to dial up neurotoxicity and astrogliosis by stimulating neuroinflammation, as highlighted by the schematic on the left here on Slide 43. By adding VG-3927 in this system, we're able to determine whether the favorable anti-inflammatory profile of our small molecule is further protective in this setting as well. In the prior slide, we're looking at the modulation of neuronal biomarkers, but here we're looking at the microglial crosstalk to astrocytes by measuring an intermediate filament uniquely expressed by these glial cells. Similar to NfL and tau, elevated GFAP levels in CSF and blood is considered a biomarker of human neurodegeneration, reflecting the extent of astrocyte activation, called astrogliosis, in patients. As you may recall, Dr. Colonna mentioned that astrogliosis is a core feature in the brains of that rare neurodegenerative condition called Nasu-Hakola disease, and it's a core pathological response, even in the brains of several more common neurodegenerative diseases, such as Alzheimer's disease. Importantly, recently approved anti-Aβ therapeutics reduce GFAP levels in patients. Shifting your attention now to the right panel, the application of VG-3927 and its associated activation of human microglia promotes astrocyte homeostasis in the face of further neurotoxic pressure, as evidenced by the robust reductions in extracellular GFAP levels. Yet more evidence of broadly neuroprotective effects of VG-3927. Carrying this theme forward on Slide 44, we also show that neuronal degeneration biomarkers, NfL and tau, were similarly reduced, demonstrating that both neurodegeneration along with astrogliosis are suppressed by our TREM2 small molecule agonist. This suggests that VG-3927 not only triggers an anti-inflammatory response in microglia and not only suppresses astrocyte-related inflammatory reactions, but again, promotes a neuronal health in the face of enhanced neuroinflammation. These collective findings highlight VG-3927 as a potent and selective small molecule TREM2 agonist with a potential to finely tune microglial function and interactions across multiple CNS cell types, broadly promoting beneficial responses on neurons and astrocytes. Moving on from our CNS tri-culture platform, over the next few slides, I'll pivot to sharing more promising evidence from a mouse model of Alzheimer's disease, illustrated here on slide 45. First, highlighting some data from single dose studies with VG-3927, and then tracing the pharmacological responses out further to share some of the early signs of benefit we're seeing after just six weeks of dosing. Like the last one, this section continues the theme of establishing translatability of agonist pharmacology to function and benefit in neurodegenerative disease states. But what should stand out from the subsequent slides are key differentiating features of VG-3927: its oral bioavailability, established brain penetrating properties, and activity in preclinical Alzheimer's disease states. Before we dive in, I want to briefly mention that what you're seeing here on S lide 46, and over the next several slides, is work that we've been doing in the well-established 5xFAD AD mouse model. This transgenic mouse was first developed by Dr. Bob Vassar at Northwestern University and is widely utilized as a model to explore the dynamics of, and changes associated with, progressive amyloid deposition. This model system was then further genetically modified by Dr. Colonna to express human TREM2 in the place of the mouse version of TREM2 and generously shared with Vigil as part of an active collaboration. In the middle panel, the data you see here are plots of unbiased changes in neuroimmune-associated genes following injection of a positive control TREM2 agonist antibody, compared to oral delivery of VG-3927. The plot depicts pharmacodynamics in the form of fold changes across hundreds of genes. As you can see, there's a robust correlation between the response of VG-3927 on the y-axis versus the positive control TREM2 antibody on the y-axis, which tells us that oral dosing of VG-3927 is able to recapitulate the activity of an injected TREM2 agonist antibody. And on the heat map to the right, when we dive into the data a bit further and pull out key signatures, we can see that the neuroprotective disease-associated microglial signatures that Dr. Colonna highlighted at the beginning of the event are boosted by VG-3927 in a dose-dependent manner following just a single oral dose. Also, keeping in mind that antibodies, by their bivalent nature, function as molecular glues to cluster TREM2 and orchestrate signaling. These data further confirm that in the brain of an Alzheimer's disease mouse model, the mechanism of action of VG-3927 translates to the in vivo preclinical Alzheimer's disease state as well. Moving on to S lide 47, well-positioned with data identifying pharmacologically active oral doses to carry forward into longer term studies, I'll use this in the next few slides to share hot-off-the-press initial data highlighting the impact of VG-3927 on endpoints more directly related to Alzheimer's disease neuropathology, such as modulation of amyloid plaque burden in this mouse model. Now, I want to start by highlighting a few key points. First, these studies were performed with a therapeutic intervention in mind, meaning that oral dosing was started in mice with pre-existing amyloid beta burden. So even a full cessation of disease progression would still be associated with residual neuropathology based on this real-world design. Second, to keep in mind, the duration of this study was just 6 weeks. While even longer long-term dosing studies will help optimize the extent of preclinical benefit of VG-3927 in this Alzheimer's disease model, we maintain this pilot work is sufficient to draw conclusions about directionality and sets the stage for more work to come. Onto the data. On Slide 48, to the left are bullet points outlining the data I'll be sharing over the next 2 slides. I'll first bring our attention to the first bullet point, the effect of VG-3927 on amyloid pathology. Both graphs to the right highlight a consistent overall trend of reducing Aβ deposition, using two approaches to quantify this response. The middle panel is an optical measurement from various sections using a fluorescent amyloid beta probe to measure plaque area. While the panel to the far right is a complementary biochemical approach by preparing insoluble brain extracts and quantifying amyloid beta levels using immunoassays commonly employed in the field. Alternative readouts, same overall trend, favorable trend toward reducing Aβ pathology after just six weeks of oral VG-3927. While we can't comment directly on how these changes compare to other therapeutic benchmarks, I do want to reiterate that these mice already had preexisting amyloid pathology prior to VG-3927 intervention. So the magnitude of these changes here, from our perspective, are impressive and promising. As I mentioned during the triculture section, VG-3927 is able to broadly modulate multiple biomarkers of neurodegeneration. Here on Slide 49, I want to build on that theme by sharing preclinical preliminary evidence that our TREM2 small molecule agonist can modulate more than just amyloid beta levels. To lay the groundwork for this, I want to highlight that the amyloid plaque niche consists of more than just aggregated Aβ. In Alzheimer's disease brains, ApoE is found in an aggregated and insoluble state and found colocalized within plaques, while in a healthy state, ApoE normally exists in its soluble form. This was highlighted by one of the images in Dr. Colonna's section. Focusing on the middle panel, we can see a trend toward reducing insoluble ApoE levels as well. It was encouraging to see agreement across the amyloid measures on the prior slide, and here now, another hallmark of plaque pathology moving in the same direction with oral dosing of VG-3927. Moving to the schematic on the right, these data help us to formulate the basic elements of a working model for how VG-3927 may be modulating plaque-associated pathology. Again, in AD states, ApoE and Aβ are in complex together. ApoE is a known ligand for TREM2 and can serve as a bridge to coordinate TREM2 amyloid beta interactions by microglia. As a reminder, we know VG-3927 potentiates TREM2 sensing of damage-associated ligands, and we know that this not only drives signaling but also internalization, leading to reduced extracellular levels of soluble TREM2, which we hypothesize may drive clearance of pathology in this model. We will continue to refine this model with future studies, but already at this moment, considering that ApoE and TREM2 are both causal genetic drivers of AD, considering the exquisite on-target pharmacology of VG-3927 that David highlighted, and considering that ApoE is a known TREM2 disease-associated ligand, as Dr. Colonna has pointed out, the potential that an orally bioavailable brain penetrant molecule could be modifying two causal genetic drivers of Alzheimer's disease bears highlighting and more follow-up. Moving on to non-human primate studies on slide 50. Now, remember that snapshot I asked you to hold in mind all the way back from tricultures? If you could pull that back into focus now is the time. Here we leverage VG-3927's profile of reducing soluble TREM2 levels as a translational biomarker of target engagement in the CSF of non-human primates. In the middle panel are CSF drug levels of VG-3927 achieved following 2 oral doses to cynomolgus monkeys, with the dotted line indicated the in vitro potency of VG-3927. You can see drug levels exceeding that at both high and low doses, validating the excellent pharmacokinetic profiles of our molecule. On the right is the corresponding soluble TREM2 pharmacodynamic response. This non-human primate data is really important for a few reasons. It demonstrates we can dose-dependently engage TREM2 in the CNS, quantify that response, and confirm pharmacologically active doses in CSF of non-human primates. Going back to the scope of preclinical systems shown here on Slide 52, I would just like to reiterate that soluble TREM2 has been adopted in phase 1 studies with TREM2 agonist antibodies. So the reduction of non-human primates CSF soluble TREM2 bodes well for its implementation in the clinic, setting this molecule up nicely, heading into development plans, which David Gray will speak about later. So in closing, on Slide 52, on behalf of Vigil Discovery team and our partners who helped generate all this exciting data, we hope you can appreciate how differentiated our molecule is. A highly potent and selective molecular glue with a unique capacity to potentiate signaling of TREM2 natural ligands, whether the target is the common or an Alzheimer's disease TREM2 variant, and a functional profile that exhibits broad benefits to tune microglia, impact neuropathology, and promote neuroprotection. We look forward to initiating clinical development with VG-3927 to begin the process of interrogating its full potential for Alzheimer's disease, which David Gray will highlight later. But before that, I'll hand over to Dr. Sam Gandy, who will share with us his perspectives on Alzheimer's disease treatment and current unmet needs. Thank you, Christian, for that introduction. So I'm here today in my role as a clinician. I'd like to begin by just pointing out that I also co-direct a basic science lab, where our group works on DAP12, the microglial molecule that is also the target of this, of the molecular glue mechanism of 3927. So I could not be more enthusiastic about the Vigil approach to Alzheimer's disease. I'll start now by just reviewing the pathology. There are multiple pathophysiological pathways in Alzheimer's disease. On this slide, what you see in the upper left is the typical beta amyloid plaque. The orange material is the beta amyloid that builds up in between nerve cells. On the upper right, the dark brown material that you see are neurofibrillary tangles inside neurons and composed of the protein tau. The lower left figure highlights inflammation, another hallmark of Alzheimer's and the focus of today's presentation. The cells that you see here are the innate immune cells called glia, specifically microglia, and they're involved in disposing of damaged debris that accumulates in the brain. They tend to surround this material, such as amyloid deposits or debris, then internalize and digest them. So the green spheres that you see are the cells, and the red dots are materials that these cells have eaten. So these are microglia that are eating debris and perhaps amyloid from their environment. So in general, the loss of microglial function is the problem, and the goal is to either normalize or restore or stimulate microglia so that they function normally. And this will halt neurodegeneration. Next. The next slide. So Alzheimer's presents a spec... A significant unmet need in the U.S. and worldwide, as you see here on this slide. There are an estimated 6.7 million Americans living with Alzheimer's, and the cost of the illness in both emotional distress and economics is enormous. I estimate that each patient with Alzheimer's disease will incur a healthcare cost of about $500,000-$1 million. Because the annual cost of either of care, either in the home or in a nursing home, is about $50,000-$100,000, and the disease lasts about 10 years from diagnosis to death. Delaying the onset and progression of Alzheimer's by even one year has been estimated to result in 9.2 million fewer cases worldwide by 2050. And this can only be addressed by expanding our approach to the disease and broadening the pathophysiology that we're attacking. Next slide. This slide summarizes the current treatment options for Alzheimer's. On the left, you see the traditional symptomatic treatment, and these drugs have been around since the 1980s. They consist of two classes of compounds, cholinesterase inhibitors and NMDA antagonists. The cholinesterase inhibitors help to sustain the level of the transmitter acetylcholine, and the NMDA antagonists modulate signaling through the glutamate pathway. However, none of these compounds affect the pathology, and none of them modify the course of the disease. The clinical benefit is modest at best and wanes over time. On the right side, you see a recent development in Alzheimer's, the development of the re... Sort of revelation of persuasive evidence that anti-amyloid antibodies may be a successful way of intervening in, in the progression of Alzheimer's. So this is, these are antibodies directed against this major amyloid protein that builds up in plaques. In several clinical trials, treatment over about 18 months has demonstrated modest slowing and decline, about 30%-35% decline, which translates to about six months longer at a particular disease level. These agents do not make people better, but they slow the decline. So there's a lot of room for improvement here, both in efficacy and in, in sort of breadth of, of, of approach. Further, these agents require intravenous infusion, either every two weeks or every month, and they're associated with a side effect of ARIA, that I'll talk about in the next slide. Two important unmet needs are to improve the safety and efficacy and broaden the overall approach to the pathophysiology. Next slide. The table here compares, sort of illustrates the fact that the effective antibodies, the effective anti-amyloid antibodies, are always, sort of go hand in hand with the side effect of ARIA, which stands for amyloid-related imaging abnormalities. Usually, ARIA is asymptomatic and often shows up only on surveillance MRIs. In general, there are scheduled MRI scans after every so often during the course of administering these drugs. And by seeing the ARIA on MRI before there are symptoms, we can often either skip a dose or reduce the dose, and that will allow ARIA to resolve with no symptoms at all. So one exciting thing about an attractive feature about these small molecules is the ability to potentially avoid the ARIA, the issue of ARIA altogether and offer combination therapies. So we can combine an anti-amyloid approach and a microglial inflammatory or a TREM2 activation approach. Next slide. So this summarizes the unmet needs, and these are areas that we need to build on. So going sort of clockwise or counterclockwise from the upper left, the magnitude of efficacy offered by these anti-amyloid drugs is modest. There's really room to improve on this, 30% slowing of decline. The challenge with accessing immunotherapies because of their requirement that they be delivered intravenously and periodically. This means that patients have to access either infusion centers or have home infusion provisions of some kind. This is not gonna be very convenient for people who have, who are in remote areas or rural areas, and are not in major cities. We also need to improve their safety. First, because of ARIA that I've already mentioned, but also because the anti-amyloid antibodies are recognized by the patient's own immune response as a foreign molecule, and so they develop their own antibodies against the therapy. So as the therapy proceeds, the patient's own immune system works against it. So this tends to sort of mitigate things over time. And anti-amyloid antibodies only are. They only target one part of, of Alzheimer's patho, pathophysiology, the accumulation of amyloid plaques. As you've seen, Alzheimer's is a multifactorial with multiple pathophysiological molecules, multiple cell types, and a broader approach to but its biology is essential. Next slide. So as you've heard from previous speakers, that the biology of Alzheimer's disease is driven by genetics. That's summarized here in this slide. This emphasizes the fact that about a third of the genes, of the 75-100 genes associated with Alzheimer's disease, about a third of those are either produced selectively by microglia or only by microglia. So they're really at the center of Alzheimer's genetics. This cartoon shows or sort of ranks these genetic factors according to their potency. So the x-axis is the sort of the risk of Alzheimer's. I'm sorry. The y-axis is the risk of Alzheimer's, and the x-axis is the frequency of the genes. So at the upper left, you see the most potent Alzheimer's genes. These are the autosomal dominant forms that always cause disease. At the bottom right, you see a cluster of molecules that these are the more common, sporadic, associated Alzheimer's variants. And each of those has only a minor effect. In turquoise there are the genes that are associated with microglia. But in between the two, you see APOE4, which is present in about half of patients with Alzheimer's disease, and TREM2. These are both equally potent and the two of the most important genetic factors that we understand so far. They both increase the risk for Alzheimer's disease. So optimizing microglial function is essential because we want to modulate the inflammation and improve the efficiency of microglia. Therefore, optimizing their activity or stimulate them, microglia, is really what we want, what we want to do. Next slide. So you heard there are several mutations in TREM2 and other microglial genes that can cause rare forms of dementia. And these are again, sort of recapped here, on this slide. So when either TREM2 or DAP12 is totally deficient, a rare disease called Nasu-Hakola or polycystic lipomembranous osteodysplasia is the illness. There are also mutations in a molecule called the CSF1 receptor, also in microglia. And when those mutations are present, the illness is adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, or ALSP, as you've heard. So these are rare diseases that do cause Alzheimer's, that do cause dementia, but they're not typical. But they do sort of point out the sort of essential link between microglia and dementia. So the genetics really points us to the goal of stimulating TREM2 and microglial function. And that's exactly what VG-3927 provides, is an agonist that stimulates and enhances TREM2 function and stimulates microglial function. That's been demonstrated in animal models, where the TREM2 agonism also improves the barrier function of microglia, where they encapsulate amyloid plaques and sort of wall them off and sort of prevent the neurotoxicity. Next slide, please. So these are clinical data. So on the y-axis below, you see either time in years or age in years. And on the y-axis, you see a sort of representation of severity or cognitive function. So the slopes here represent either the increase in symptoms over time or the impairment over time. And these patients, either patients with Alzheimer's disease or normal controls or patients who have symptoms but don't yet have a full diagnosis. So on the left, you see patients with Alzheimer's disease, and they usually have a red line and a blue line. So the red line is steeper, being sort of going up faster. And these are the carriers. So these are patients who have the TREM2 R47H variant, and their cognition becomes impaired faster than patients who are non-carriers, where they have the blue line that's sort of closer to being level. On the right, you see elders who are still cognitively intact. That is, they have some impairment which maybe is at the MCI level, but have not yet progressed to the point of having the diagnosis of Alzheimer's. Yet they have the R47H TREM2 mutation, and they already have impairment that can be detected with neuropsychological exam. So again, the carriers are at the top, the red line, where over time their cognitive impairment is greater, and the non-carriers are the blue line below. So clinical data here point again to the fact that stimulating TREM2 to compensate for this this loss of function or partial loss of function mutation is a viable therapeutic approach. Next slide. So you've already heard from the Vigil team on the VG-3927 profile. On this slide, I'll just like to say that I'm really excited about the strong preclinical data package, where they've demonstrated robust target engagement and pharmacological activity that can act on not only wild type TREM2, normal TREM2, either, and this sort of potentiates the effect of these variant TREM2 on clearing its normal ligands. And I think this may offer some spatial specificity of the action of this drug. That then localizes this action to the exact microenvironment in pathological tissue, making it extremely attractive as a way of attacking Alzheimer's. I'm also excited by the data presented by Christian, demonstrating that VG-3927 pharmacology strikes a great balance and basically is in every way that we can see beneficial. So these data, I believe, position VG-3927 very nicely for its clinical development in Alzheimer's disease. Next slide, please. So just to recap the unmet needs. In terms of efficacy, we're targeting microglia, an immune cell type that's involved in amyloid clearance and in neuroprotection. And we are offering the potential to impact the broader pathophysiology of Alzheimer's. VG-3927 is administered orally, so this is gonna be more convenient and will be more accessible to patients. It doesn't have to be infused by antibodies, so that has a potential to reduce the burden on the healthcare system and also offer the possibility of combination therapy. In terms of safety, unlike monoclonal antibodies, which have these Fc-mediated interactions that are responsible for ARIA, VG-3927 is a small molecule and doesn't have this liability. And since it's more spatially attuned to the disease microenvironment, this may also offer an advantage in terms of safety. So given the multifactorial nature of Alzheimer's and the goal to halt disease progression and ultimately prevent it, one must always already be thinking of these combination approaches. So a small molecule, an oral therapeutic, is ideally positioned both for combination approaches and for prevention paradigms for the future. I hope this has given you an idea of how I think, as a clinician, VG-3927 is well positioned for development in Alzheimer's disease in the context of today's landscape. With that, I'll pass the presentation back over to David Gray, who will share the near-term clinical development strategy. Thank you. Thank you very much, Dr. Gandy, for all of that overview. Very helpful. I will provide an overview of our upcoming phase I trial of VG-3927 in healthy volunteers, as well as our genetically guided precision-based strategy for early development in Alzheimer's disease. In October, we will commence dosing of our placebo-controlled phase 1, single and multiple ascending dose trial in healthy volunteers for VG-3927. As shown here on this slide, many elements of this design are familiar for small molecule development. The primary objective of this study is to examine safety and tolerability, as well as pharmacokinetics of VG-3927 in single and multiple dose settings. We also expect to conduct safety and tolerability assessment in an elderly cohort to position VG-3927 for further development. We are able to leverage our expertise and experience with gathering target engagement data via CSF biomarkers. Namely, we plan to collect soluble TREM2, soluble CSF1R, and osteopontin as markers of target engagement in this study. As we showed earlier, we have strong translational anchors from preclinical studies for soluble TREM2 as a target engagement biomarker to inform the progression of our phase one program. This slide shows an overview of our early-stage clinical development plan for VG-3927 and highlights our precision-based strategy for reducing downstream clinical risk in Alzheimer's drug development. In our phase one trial in healthy volunteers, which we just reviewed in the previous slide, we will look to establish safety and tolerability and to inform dosing via target engagement environment biomarkers, both proximal and downstream of TREM2. We project to have interim data on the SAD and MAD cohorts from this study around the middle of next year. We're also in advanced planning for clinical trial in individuals with early-stage Alzheimer's disease in a phase IB setting. The focus of this trial will be on safety and also on proof of pharmacology in symptomatic Alzheimer's patients. As part of this study, and consistent with our precision-based genetic strategy, we plan to characterize pharmacology in genetically defined subpopulations of Alzheimer's patients, which include those with the disease-associated TREM2 variant. This trial will be designed to inform on patient population and on other elements for future clinical development. Looking further ahead, we anticipate conducting a phase II proof of concept clinical trial in the patient subpopulations that are informed by the phase IB data. With this, I will hand it back to Ivana for closing remarks. Thank you very much, David. Before we move to Q&A, on Slide 68, I would like to recap some of the key points regarding VG-3927 discussed today. It is the first and only small molecule TREM2 agonist entering clinical development. It harnesses the neuroprotective activity of microglia as a potential therapeutic for Alzheimer's disease. It is a highly potent and specific agonist of TREM2 with a differentiated profile, which can, can address the unmet medical needs in AD. Its unique mechanism of action through potentiation of TREM2 response to natural damage ligands can improve efficacy and safety. It activates microglia with a broad, non-inflammatory profile. It lacks an Fc effector domain, which helps with ARIA mitigation and has a favorable PK profile with a short washout period, enabling dose management of any potential ARIA observed. As a small molecule, it's manageable to being a component of combination treatment regimens for AD in the future. Lastly, has a convenient and patient-friendly oral dosing. On the next slide, Slide 69, it lists the key upcoming VG-3927 milestones. Our R&D is now open, and our phase one trial in healthy volunteers will commence dosing in October. We expect to have interim data from the phase one trial, as David mentioned, in the middle of next year. So just in closing, on Slide 70, we believe that microglia biology and neuroimmunology is the new frontier of CNS drug discovery, and that with our approach and our assets, we're extremely well-positioned to open the door to this new frontier and develop life-changing therapies for patients. Most importantly, we have a team that can execute. With that, I thank you all for joining us for our event today. I will hand it back to operator for Q&A. Thank you. Thank you, Ivana. At this time, we'll be conducting the question and answer session. Please hold for a brief moment while we poll for questions. Our first question comes from Paul Matteis at Stifel. Please go ahead, Paul. Hey, thanks so much for taking my questions. I had one specifically on the small molecule, and then I had a couple for the KOL on the call, just on TREM2 science. So on the small molecule, can you just kinda walk through why you think that a small molecule can recapitulate the selectivity and the therapeutic index of your antibody candidate? And then as it relates to just TREM2 in general in Alzheimer's, I had two specific questions. One is, so I thought that data you were showing on the slope of cognitive decline was super, super interesting. One thing we've tried to make sense of is: Why are these TREM2 mutations fairly weakly penetrant in Alzheimer's? Do you have a view on that? I think the data out there suggests they're less penetrant than one APOE4 allele. And then, and then second, do you have a view on some of the severe ARIA cases we've seen with the Alector antibody, and whether or not the ARIA there clinically, in some of those cases, looks similar to what we're seeing with Aβ antibody antibodies or looks like it's a distinct phenomenon? Thanks so much. Great. Now, Paul, thank you so much for your questions. So I'll pass it on to David first to address your first question around the VG-3927. David? Yeah. Thank you, Paul. Yeah, so in terms of understanding that comparison with antibodies, we're in a great position to be able to do that. Christian mentioned some of the data looking at, for example, gene expression and, of course, just primary potency. We have, you know, a lot of confidence that the functional profiles of both the small molecule and the antibody recapitulate all of the changes we want to see with disease-associated microglia. I think I can go a step further and just talk about, obviously, the difference with a small molecule is that you can get very, very high brain penetration. And so, we are very confident from all of the preclinical work that we've done, that we can, you know, fully match and, you know, actually have a lot of advantages when it comes to the kinds of engagement, target engagement, types of modulation that we can see with a, with VG-3927 specifically. And, you know, ultimately, we're also really enthusiastic about this specific mechanism of action that we highlighted here. So that specificity and that working in conjunction with, with, these natural damage ligands, we think is ultimately really important for enhanced activity and, enhanced therapeutic index and those, those other things. So thank you for that question. And, in terms of your other questions, Ivana, who would you like to answer that one? Yeah, why don't we start with you on the penetrant, and we can pass it on also with respect to ARIA, or I don't know, Dr. Colonna or Dr. Gandy, if you wanna kick us off on the penetrance of TREM2? Yes. Well, first of all, you know, let me tell you that it's true that the penetrance is limited. On the other hand, you know, these are heterozygous mutations. So homozygous mutations have an incredible strong penetrance that cause dementia in 100% of cases. So, the low limited penetrance because we're looking at heterozygous mutation. The other point I'd like to make is that it's true that the mutation it has a limited penetrance. If you look at the overall genetic association, you can see that many of the genetic associations being identified for Alzheimer's disease they all point to this TREM2 signaling pathway. And indeed, you know, so far, TREM2 has been really the major molecule involved in microglial response to A β plaque. Of course, in immunity, as you would imagine, the response is always very robust. There's some redundancy, and of course, there's additional mechanisms that can compensate for the lack of TREM2 or for the reduced functional TREM2. But regardless, you can see that all the genetics, many of the genetic factors always point to or towards TREM2. So I think, you know, in general, small effects are more frequent when you have more, small effects are more evident when you have a higher frequency in a population, whereas there are more penetrance with very rare mutations. But nevertheless, as I said, rare mutation, homozygous mutation, causes a very strong mutation. Thank you, Dr. Colonna, for that. Then on the ARIA, I guess what I would just like to highlight, and then we can go to Dr. Gandy or Dr. Colonna again, is that we believe that, you know, no ARIA, no efficacy. We've seen ARIA now, it's a known risk in Alzheimer's disease. It's been accepted because obviously we have approved therapies. We do not believe that there is anything different with what Alector is seeing versus what's observed with approved therapies. But I think what's really important to differentiate here is our small molecule. We believe that our smaller molecule, which does not have an Fc region, has been mentioned, that has a different PK profile, and obviously, with this increased specificity and potency in the area of active disease, we believe can be really a true differentiator when it comes to safety. But, Dr. Gandy, I don't know if you wanna add anything to that. Yeah, I can just make two points about the complexity of ARIA. I think that our understanding is still evolving. First is, it looks somewhat like a phenomenon that's been known for a long time in cancer immunotherapy called Posterior Reversible Encephalopathy Syndrome. And that may be complicating the picture of what we're seeing clinically with ARIA in Alzheimer's disease. The second thing is that we think the real, the amyloid that's most important in ARIA is the amyloid that's deposited around blood vessels. And that's where the leakage is allowing the edema, the water and salt to leak out, and eventually those vessels can rupture. And we can't really resolve that very well with our current efforts at imaging. So we haven't really gotten down to to understanding the entire spectrum of ARIA and exactly which molecules and which sort of loci inside the brain are the most important. So I think it's- Thank you. still early days. Yeah. Thank you, Dr. Gandy. Let's, we should probably move on to the next question. Thank you. Our next question comes from Andrew Tsai with Jefferies. Your line is open. Thanks, good morning. Appreciate all the updates, very helpful. So maybe two quick ones. So you've shared a lot of great data today on VG-3927. So can you just maybe summarize how your oral compares specifically to the TREM2 antibodies or even the Aβ drugs? For example, how does your brain penetration compare, potency, and so forth? And well, you know, how do you think the eventual therapeutic window will compare in terms of efficacy and safety? And then secondly, as we think about your eventual proof of concept study in actual Alzheimer's patients, I understand you're looking at genetically defined Alzheimer's population first, but what would be your plans for the non-genetically defined broader population? What would you need to see to move forward into this broader population? Thank you. Yeah, great. Thank you, Andrew. So I'll pass it on to David. David, around brain, brain penetration and differentiation from antibody. Yeah. No, thank you for the question, Andrew. Starting with brain penetration, antibodies typically have about 0.1%-0.2% of what's in the plasma, that is what you see in the brain. And with the small molecule, and specifically with VG-3927, what we see is essentially, you know, equal concentrations or near equal concentrations between what's free in the brain and then what's free in peripheral tissues. So that's a, that's a tremendous difference and a tremendous opportunity to, you know, engage that target at a much higher level, or engage, you know, engage the TREM2 target at a much higher level with the small molecule, with VG-3927. In addition, there are other key differentiators, some of which we've highlighted. So the oral bioavailability, and we project once daily dosing, that's a really nice advantage, the ability to combine with other therapies. And then, you know, getting back to this unique biology, which I just mentioned before, that increased specificity in and around areas where there's active disease, we think could be really important for therapeutic index and ultimately, obviously, for efficacy. So, you know, there's a number of axes upon which we see differentiation. We also mentioned a lack of an Fc domain, which could be very important as we understand more about, you know, things that might drive ARIA and so on. So I, you know, I think we're looking at three, four, five different important axes for differentiation on that front. Thank you, David. Then to your question about clinical development plan. Obviously, as we said, you know, we have a precision-based approach. We believe it makes sense to start with following genetics, and that is why we wanna start with genetically defined subpopulations, meaning the TREM2 variants and also some other variants that obviously fit into this mechanism of action. But we do believe, and as you heard from Dr. Colonna and Dr. Gandy, is that microglia are very, very important and are the key control of neuroinflammation in the brain, and they are associated not just with beta amyloid, but also with tau processing much more broadly. So obviously, as we learn, we plan to expand into the larger AD population. But starting with these TREM2 variants, I think will provide us with insights to really think about how best to design our clinical program going forward. We can move to the next question. Thank you. Our next question comes from Laura Chico with Wedbush. Your line is open. Hey, good morning, guys. Thanks very much for taking the question. I've got one for Dr. Gandy and then one for Vigil. So for Dr. Gandy, could you just talk a little bit from your clinical perspective about AD genotyping efforts right now? I guess I'm trying to understand challenges in terms of identifying patients with TREM2 or related variants. Could you just speak to kind of current efforts at present? Thank you. Yeah. Well, so currently, you know, there's a research genotyping that's that goes on as much as is very broad. But clinically, I guess the, you know, APOE4 genotyping is the most common, and though it's recommended by CMS for the new anti-amyloid antibodies, it's not required. So it's possible for, you know, for patients to decline APOE genotyping and accept the fact that if they harbor an E4 allele, they may be at a higher risk for ARIA. And if a physician is willing to, you know, this is all sort of at the discretionary level. If the physician is willing to go forward and the patient is willing to accept the risk and that can be documented, then genotyping can be avoided. Obviously, genotyping is, it sort of opens up a Pandora's box of issues for the entire family, and often I find patients prefer to avoid that if possible. And maybe what I can add, Laura, before your other question is, we obviously are working with large, you know, genetic banks to genotype Alzheimer's patients and to be ready for our trials. And we do believe that the future is in genotyping because it's becoming clearer and clearer that there are, you know, subgenetic populations that we might better serve if we really understand what their underlying genetic defect is. But please, what is your next question? Sure, yeah. So, just two on the development plan. So first, as you're moving towards a phase I or phase II study in, symptomatic AD patients, would the plan be to exclude patients that are on an anti-amyloid regimen? So that's the first question. And then second, could you just speak at all with VG-3927, with respect to any effects on peripheral inflammation markers that you've seen in the animal models to date? Thank you. Yeah. So why don't I take the first question, and then we'll go to the next question. So the plan for us is to establish the VG-3927 as a monotherapy. So obviously, first we'll do the phase I healthy volunteer study, and then the plan is for that one phase IB study for TREM2 to be a monotherapy. And then obviously, as you heard from everybody on the call today, there's a lot of excitement about ability to combine small molecule with the existing therapies. But I think it's gonna be important for us to establish the monotherapy first. And David, you want to take the other question? Yeah, yeah. I mean, we have been very thoughtful and very careful, even since the very beginning of the program, to do extensive profiling of cytokines and chemokines in all of our safety assessments. We have looked, you know, very carefully at the question that you're asking about, and we have not seen any effects that are, you know, really no effects on cytokines or chemokines in any of our preclinical studies across multiple different studies, and, you know, really also across two different modalities. So that applies to both our antibody program as well as our small molecule program. So from the perspective of looking at any kind of markers of inflammation, we have been, you know, very, very pleased with what we're seeing, which is basically nothing. Thank you. Our next question comes from Yatin Suneja with Guggenheim. Your line is open. Hey, team, this is Divan on for Yatin. Thanks for taking my questions. Two more pharmacological questions for me. I'll start with the first one. Are there differences in TREM2 ligand concentrations in the brains of patients versus healthy volunteers? And if so, how are you thinking of, you know, translating your healthy volunteer data kind of into the optimal dose for patients, given what you've seen so far in terms of synergistic signaling? Great. David, you want to take that? Yeah. So I mean, there certainly are differences accompanying, you know, plaque deposition and multiple of these different pathologies are a lot of the ligands that are the TREM2 ligands. So, you know, we talk about TREM2 as its natural ligands being damage-associated or disease-associated ligands for a reason. That's because the, you know, many of those ligands for TREM2 are, in fact, the markers of neurodegeneration. You know, things like we talked about ApoE, we talked about sulfatide. Really, all of the things that TREM2 is sensing and then converting into its more active microglial state are these damage-associated ligands. So yes, there are expected to be increases both in patients and also in specifically the plaque microenvironments. And so, you know, to your second point, what we expect is that the biomarkers that we're looking at in healthy volunteers will help us understand target engagement and other aspects of microglia activity. But whatever we're seeing there, we would expect enhancement in the patient population. Got it. Thank you. It's very helpful. And then my second question is, essentially, given what you've seen so far, you know, how long would you expect to need to cover that EC 50 level that you showed on the graph, for clinical benefit, with the synergistic signaling effects? You know, would you need to kind of cover, TREM2 for a larger fraction of the 24 hours between doses? And maybe can you comment on how the dynamic nature of TREM2, recycling kind of plays into that? David, I'll pass it on to you again. Yeah. So I mean, it's great that you appreciate that dynamic nature of TREM2. It's very important. We're in a great position here with VG-3927. First of all, because we robustly project a once daily oral dosing from a half-life and target coverage perspective. And then second, with a small molecule, we have dosing flexibility. So we have the ability to you know, look at clinical data and, you know, really kind of finely tune that to make sure that we're optimizing you know, overall the response profile that we're seeing. So in combination with the actual properties of VG-3927, which are excellent for once-a-day dosing and good target coverage, we also have this flexibility with a small molecule that is unique to that modality. Got it. Thanks so much. Thank you. Our next question comes from Graig Suvannavejh with Mizuho. Your line is open. Hey, thanks so much for taking my questions, and for doing the webinar. Maybe two questions for the KOLs, maybe Dr. Gandy. I know that your comments around 6.7 million in the U.S. with Alzheimer's, and just trying to get a sense from you around perhaps what percent of patients ultimately might be, you know, appropriate for this type of therapy. I don't know if it's 5% or 25%, as it relates to the genetically defined subpopulations. And then my second question, I think is bigger picture just on the mechanism, and obviously, we're all aware of some of the safety signals that have been seen with other programs. But I just want to get your comfort with what's known right now around VG-3927 and the therapeutic window with respect to the candidate. Thanks. Yeah, well, I mean, the genetically defined population of Alzheimer's patients who have TREM2 mutations is rather a small population. But the expectation is that that will predict or provide information that will guide interaction with the wild-type, with molecules or with patients who have the wild-type TREM2 molecules. So I think that, you know, the mutant population really gives us a window into the larger population. I think, you know, all the signs so far are the VG-3927 is very promising, and I would be, you know, comfortable with seeing it, you know, move forward. Certainly, the population of patients that are going to be candidates for anti-amyloid antibodies is going to be rather small. A recent paper from Mayo Clinic showed that only about 10% of patients that they expected to qualify for antibodies actually did qualify because the side effects and there are multiple morbidities and that sort of thing. So I think we have a, you know, a long way to go from the antibodies, and I think this provides a way forward. Can I just get your opinion as my follow-up on your comfort with kind of the safety with VG-3927, in light of I believe it was hematology signals that we're seeing with the Denali program? Yeah. So that seems to be due to the-- That's, so that's a hybrid molecule with an anti-TREM2 antibody bound to the transferrin receptor. And my understanding is that the interpretation of all the data so far is that those side effects and what led to the cancellation of that program is due to the transferrin receptor part of that chimeric molecule, not to the anti-TREM2, not to the TREM2 activation side. Yeah, and maybe, Graig, to just highlight to that point, we actually now have data in patients, right? Over 300 that are ePRO reported, and then obviously from our healthy volunteer studies of more than 400 individuals, much more than 400 individuals who have been exposed to some kind of a TREM2 agonist, and there's been no hematologic safety signals in any of those populations. Thank you. At this time, the call has concluded. You may disconnect. Thank you. Thank you. You're welcome.