Good afternoon, and welcome to Vigil Neuroscience's webinar highlighting its IGNITE Phase 2 interim data analysis. Currently, all participants are in a listen-only mode. There will be a question and answer session at the end of the prepared remarks. Please be advised this webinar is being recorded. I would now like to turn the call over to Leah Gibson, Vice President of Investor Relations and Corporate Communications. Please proceed. Good afternoon, everyone, and welcome to our webinar. Before we begin, I'd like to share a few housekeeping reminders. The webcast is scheduled to end at 5:30 P.M. Eastern Time. In addition to following along with the webinar, 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 available later today on Vigil's website in the Investors section under Events and Presentations. Quickly turning to slide four, 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 refer to the company's quarterly report on Form 10-Q for the quarter ended September 30th, 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 afternoon, everyone, and thank you for joining us. We're very excited to share with you today the interim results from our Phase 2 IGNITE clinical trial, evaluating VGL101 in people with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, or ALSP. ALSPs are rapidly progressive, fatal, rare, autosomal dominant neurological disease for which there are no currently available FDA-approved therapies. The data that we're sharing with you today not only represent the first clinical findings reported from an interventional study in patients with ALSP, but it also marks Vigil as the first company to show clinical data on TREM2 agonist as a potential therapeutic approach in patients with a neurodegenerative disease. We are also pleased to announce that we have confirmed our generic name for VGL101, which we can now refer to as iluzanebart. For the purpose of today's call, we will continue to refer to it as VGL101. As a reminder, VGL101 is a fully human monoclonal antibody TREM2 agonist, which we believe can compensate for the CSF1R deficiency underlying ALSP pathophysiology, with potential to be a disease-modifying therapy. The data that we're sharing with you today are comprised of findings from our ongoing natural history study, ILLUMINATE, in addition to data from the first six patients following six months of treatment with 20 mg/kg of VGL101 in the Phase 2 IGNITE trial. The combined look provided us the opportunity to both better understand the natural disease progression of ALSP, as well as the pharmacological activity of VGL101 in symptomatic patients. Looking at the totality of the findings from both ILLUMINATE and IGNITE, we're very encouraged by the quality and consistency of the data, which provide further support for our clinical development strategy for VGL101 as a potential novel treatment option for ALSP. In addition, our ILLUMINATE trial continues to provide critical insights into ALSP and efficacy biomarkers, MRI, and NfL, which correlate with disease progression. Importantly, VGL101 has demonstrated a favorable safety and tolerability profile with clear CNS target engagement based on soluble TREM2 levels and downstream pharmacological activity based on soluble CSF1R and osteopontin levels, and directionally supportive changes in individual patients at six months on MRI and NfL biomarkers, all key outcomes that we hoped for. I would like to take a moment to recognize the determination and expertise of our team here at Vigil, who each offer an unwavering commitment to patients every day. We extend a sincere thank you to all who have contributed to this progress, including our trial participants, their caregivers, and the clinical investigators. With these positive data, we look forward to engaging with the FDA to initiate discussions regarding a potential accelerated development path for VGL101 as a treatment for ALSP and collecting additional data from the IGNITE trial, including results from all patients in the 20 and 40 mg cohorts at six months in the third quarter of 2024. Before turning to the results, let me take a moment to highlight what makes Vigil so unique. First, we employ a precision-based approach to neurodegeneration, which we believe increases the likelihood of ultimate success.... Second, we're the only company that has two TREM2 modalities. We have both an antibody TREM2 agonist, VGL101, the focus of today's call, and also first-in-class small molecule TREM2 agonist, VG-3927, which is currently in the phase 1 healthy volunteer trial. Third, most exciting for us today, and as I mentioned previously, we're the first company to show TREM2 agonist as a potential therapeutic approach in patients with neurodegenerative disease. Our goal is to 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, beginning with the TREM2 as our first molecular target. So with that, I would like to spend a few moments introducing our featured guest. Today, we're honored to welcome Dr. David Lynch, a consulting neurologist at the National Hospital for Neurology and Neurosurgery in London. He's also an expert in adult leukodystrophies, including ALSP, and in clinical and imaging phenotypes of these rare neurodegenerative diseases. Dr. Lynch is an investigator in our ILLUMINATE and IGNITE clinical trials. I would like to take a moment to thank Dr. Lynch for joining us today from London and providing his insight and perspective on today's results. But before Dr. Lynch presents, I'm delighted to pass it along to our Chief Scientific Officer, David Gray, to showcase our interim results. Please go ahead, David. Thank you, Ivana. I am very excited to be sharing the latest data from both of our ongoing studies in ALSP. We will begin on slide 10 with the Natural History Study ILLUMINATE, because it has been invaluable both in this interim analysis as well as in our general understanding of ALSP. First and foremost, ILLUMINATE has highlighted that soluble CSF1R and NfL levels are remarkably altered in this disease, identifying them as key biomarkers for us in tracking and observing disease pathology and understanding progression. We also observed longitudinal progression on selected MRI measures, as well as on some clinical endpoints. We will make those connections as we continue through the data, and we feel we have enough to initiate engagement with regulatory authorities based on the totality of the data. Thinking about both regulatory and clinical considerations, it is great to have the quality and the consistency we are seeing, both in the data and the endpoints. We are especially excited to learn that a number of our selected endpoints not only support our biomarker strategy, but support our belief that our trial was well-designed and that there are no adjustments to be made. Specifically on MRI, the ventricular volume and gray matter volume measures are both emerging as key indicators of disease progression, where we are seeing changes at six months, which is not only helpful for our understanding of the disease, but incredibly relevant to our phase II data. Based on our understanding of the disease, the thinning of the corpus callosum and increasing white matter lesions are hallmarks of ALSP, and we would expect those to be good measures for disease progression longitudinally over time. A key learning from this interim analysis is that there is methodology and algorithm-related variability in these measurements in ALSP, which reduce their sensitivity to change over the shorter six-month time period. From both a cognitive and clinical standpoint, the Montreal Cognitive Assessment, or MoCA, and the Cortical Basal ganglia Functional Scale, or CBFS, both have data that support their use as clinical endpoints in ALSP. ILLUMINATE has demonstrated that they are both good clinical measurements for tracking progression, specifically at the 12-month time point, where we are able to see clinically meaningful progression. This timeframe is consistent with our expectations for measuring clinical progression. Slide 11 summarizes the study design for ILLUMINATE, the first ever natural history study in ALSP patients. The study is a global, multi-center, 24-month observational study of individuals living with ALSP, enrolling up to 50 participants. Key assessments include MRI and clinical assessments at baseline and every six months. Also, collection of blood biomarkers for analysis every six months for the first year and then one annually thereafter. Optionally, collection of CSF for biomarker analysis is also offered. The study also incorporates clinical scales that assess cognition, motor function, psychiatric status, severity of illness, activities of daily living, and caregiver burden. Notably, the MRI biomarker and clinical measures are the same for our Phase 2 IGNITE trial. For eligibility, participants need to be greater than 18 years of age, positive for CSF1R gene mutation, and demonstrate radiographic evidence consistent with ALSP. ILLUMINATE enrolled both symptomatic participants who fulfilled the clinical diagnostic criteria for ALSP, and prodromal participants who demonstrated radiographic evidence of disease but did not fulfill the clinical diagnostic criteria for ALSP, with greater than two clinical symptoms being that key criteria. Slide 13 shows the baseline demographics of ILLUMINATE participants evaluated in this analysis, and it reflects what I have described in the enrollment criteria previously. Notably, I want to share that we are analyzing the ILLUMINATE data in the context of a natural history study population that is relevant to the population in the phase II trial. We made these selections to ensure that learnings from ILLUMINATE would be informative when we're thinking about the phase II endpoints. Now, diving into the data, we'll start with the fluid biomarkers, which have been updated from previous data that we've shared on ILLUMINATE on slide 15. Starting with soluble CSF1R on the left, in both prodromal and symptomatic patients, we continue to see a marked loss in soluble CSF1R concentrations. This, of course, is the protein that's affected by the ALSP mutations, and soluble CSF1R levels can be viewed as a marker of microglial activity. On the right, there is a huge increase in NfL levels between prodromal and symptomatic patients in both serum and CSF, which is also consistent with previous data. The correlation remains very strong between serum and CSF NfL levels within an individual. This correlation provides two key learnings for us. First, that we can make use of serum NfL as an excellent surrogate for CSF, which is helpful given the physical burden of the lumbar puncture required for CSF collection. Second, and even more importantly, NfL is emerging as an excellent biomarker of ALSP disease state. All right, so we'll use these ILLUMINATE data to further illustrate a few of the learnings about MRI measures that I mentioned earlier. The next couple of slides are all set up the same as slide 17 here. The graph on the left is showing baseline levels of the symptomatic and prodromal groups, and the right graph shows the change between baseline and 6 months for each group. As we've shown before, even at baseline, individuals who are symptomatic for ALSP show elevated ventricular volume, which can be viewed as an indicator that some progression has already occurred. After following those patients for six months, we see further increase in the size of those ventricles, which brings us to my earlier comment that ventricular volume is emerging as a good endpoint for following disease progression. Slide 18 shows ILLUMINATE data on gray matter volume, and we're seeing similar relationship between volume changes and disease progression. We have observed a decline in volume as the disease progresses, and while the direction denoting disease progression is flipped between ventricles and gray matter, we also continue to see a marked difference between prodromal and symptomatic patients, as well as between baseline and at six months. In that same vein, loss of gray matter is a very clear demonstration of progression that is easy for people to understand as part of an overall disease state. Additionally, we have looked at changes in white matter lesion volume and corpus callosum for evidence of progression. These are radiographic hallmarks of ALSP, and we would expect to see evidence of progression on these endpoints. A learning emerging from ILLUMINATE is that precisely defining white matter lesion borders is challenging, especially, specifically in ALSP. This is due to less clear definition of the boundaries of these lesions in ALSP versus what is often seen in other diseases. For corpus callosum, the thinness and movement of the structure and its border with advancing ALSP introduces analysis variability. In both cases, these sources of measurement variability are large enough to obscure evidence of progression in the symptomatic group over a short period of time. So while we are not sharing white matter lesion and corpus callosum changes at six months, we have not changed our perspective on either as hallmarks of the disease or potential biomarkers for tracking disease progression at longer time intervals. Switching over to clinical endpoints, slide 20 shows assessment on MoCA, which is widely used as an established assessment of cognition. It is known to have variability within subject from measurement to measurement, but over time can be used to assess cognitive ability, including changes. When we look at the symptomatic group in ILLUMINATE over 12 months, we're able to see evidence of progression on the MoCA. Again, this is a well-accepted endpoint with established psychometrics and understanding of what a clinically meaningful change is. We're seeing that magnitude of progression in 12 months, which means we can track clinical progression at 12 months with the MoCA. On slide 21 is the endpoint that the FDA recommended we use, CBFS. This is a newer endpoint, which combines cognitive and functional elements. We see baseline impairment in individuals and also see clinical progression over that 12-month period on this endpoint. CBFS incorporates activities of daily living, behavioral and language components, as well as cognition, and is a nice complement to the MoCA, and we'll be looking at both of these at 12 months in the phase II. I'll briefly mention another endpoint that we looked at, which is the CDR-NACC FTLD. We are not seeing progression on this particular endpoint at 12 months. We have included it in ILLUMINATE, and we'll continue to track it, but thus far, we are not seeing that it is as sensitive to change in ALSP as compared to the MoCA or CBFS. The ILLUMINATE data I just presented provides the context for our interim data from the IGNITE phase 2 trial, and I'm really excited to walk you through them on slide 23. I want to mention a lot of these points in our high-level summary, and I'll review the favorable safety and tolerability, with the key points being that the majority of the patients did not report any serious adverse events. There were no serious or severe adverse events, and no, we had no discontinuations due to adverse events. From a PK perspective, we're seeing an exposure profile consistent with what we saw in healthy volunteers. We're also seeing good brain penetration as measured in CSF, and I'll talk a little bit more about that when we get to the PK slide. Moving on to CNS target engagement and PK biomarkers, we're seeing a reduction in soluble TREM2, similar to what we saw in healthy volunteers, indicating direct target engagement in CNS. We're also seeing increases in the CSF on osteopontin, which is a biomarker of microglial activity in the brain. Notably, the data on Soluble CSF1R increase looks very interesting. Given that this is the protein affected in the disease and a biomarker of disease pathology, the fact that we're seeing potentially larger increases in patients relative to healthy volunteers is extremely interesting. Looking at the biomarker measurements, we see directionally supportive changes at six months for individual subjects on MRI and NfL biomarkers of progression based on looking at rates of change. We will show these data at an individual patient level. As with ILLUMINATE, it is important that we are seeing good quality and consistency of data, and have confirmed our ability to collect it in this patient population. Based on what we're seeing, we have determined that we don't need to make changes to the trial design, which positions us well for being able to draw conclusions from the trial as we progress. Slide 24 summarizes the trial design for IGNITE, which is a multicenter, 12-month, open label trial of VGL101, evaluating safety, tolerability, pharmacodynamics, and pharmacokinetics of VGL101. Reminder that all the data we will look at here is from six subjects, which are all at the 20 mg/kg dose level. We do have a 40 mg/kg dose level on the study, but the data on those subjects will come at our next interim analysis. Key eligibility criteria are shown here on slide 25 and are in line with ILLUMINATE, with the addition of the requirement for patients to be able to complete the trial. The baseline demographics are summarized on slide 26, including two female and four male participants. There is nothing else of note to highlight here. Slide 27 presents our biomarkers on a spectrum that goes from soluble TREM2 as a direct measure of target engagement, and then to soluble CSF1R and osteopontin, which are markers of microglial activity. The NfL and MRI biomarkers inform on disease pathophysiology, and as per our trial design, this interim analysis will include target engagement biomarkers and microglial activity biomarkers at the six-month time point, and NfL and MRI measures being discussed here are also collected at the six-month time point. We also have serum NfL at nine months on two participants. Our clinical endpoints will only be shared at 12 months, as I mentioned before. In terms of our assessments of safety and tolerability, VGL101 remains generally well tolerated on slide 28. Only two patients out of the six we have reported treatment-related adverse events. We have seen no discontinuations due to adverse events and no treatment-related serious or severe adverse events. The one SAE was from one patient who was briefly hospitalized due to a gastrointestinal infection, which was deemed unrelated to treatment. We also want to note that we have not seen any hematological adverse events, nor have we seen any imaging-related adverse, nor blue shaded areas on the graph. The IGNITE data were in line with what we expected based on healthy volunteer pharmacokinetics. At the later time point, you'll notice that we are seeing a stable exposure level, which is very encouraging. I also want to bring your attention to the bullet at the bottom of the slide. We are measuring around an average of 0.5% CSF to plasma ratio in the patients. Another key learning from both ILLUMINATE and IGNITE trials is that we have a nice correlation within individual subjects between CSF and serum levels, as shown here on slide 30. When both measurements are taken at the same time point, you can see that correlation between the two is very high, which will allow us to look at serum measures as an excellent surrogate for what's happening within the brain on NfL. Serum collection is less burdensome for patients, and we can sample it more frequently than CSF. So having more data allows us to get more confidence in our measurements. Each of the six patients in the analysis have pre-dose data coming from ILLUMINATE. Before I get into the data, we have modeled the ILLUMINATE pre-VGL101 dosing natural history data, and one of the reasons is to avoid sharing specific visit intervals and other patient identifying information. I'll start by orienting you to how we've laid out each patient's data. Looking at patient A on slide 31, and starting from the left, there is a fluid biomarker scorecard that shows all of the CSF biomarker measurements: soluble TREM2, soluble CSF1R, and osteopontin. On the right, we have a graph demonstrating serum neurofilament light levels, starting from ILLUMINATE, and that is also modeled based on a regression of all the available pre-dose data to create a predictive slope on how they were progressing on that measure. This gives a pre-dose trajectory from each person's own ILLUMINATE data. We then have their IGNITE Phase 2 data measured at the 6-month visit. For most patients, this will be the only point at the month six visit, but for this one and one other patient, we have an additional data point for serum NfL at month nine. For reference, we've included the baseline serum NfL below each graph on the right. This will become important because as we go through the patients, there is a clear distinction that will emerge.... In ILLUMINATE, we have observed that there were people with very high NfL levels that remain high across multiple time points, and also another smaller group that have low NfL levels upon entering the study. Therefore, we have identified a high NfL baseline group and a low NfL baseline group, where the serum NfL levels correlate with progression on cognitive and MRI measures. Those with higher NfL levels tend to present with a higher level of cognitive impairment, and while we've seen little to no cognitive impairment in those with age-normal NfL levels. So this first subject had a biomarker response in the same direction as phase I for all of the CSF measurements. I'll just note that the soluble CSF1R change at 34% is a very large one compared to what we observed in healthy volunteers in phase I, which was typically less than 10%. This will be a theme across the other responders as well. At the six-month time point, the serum NfL levels went up, and then it started coming down between six months and nine months, moving in the right direction. We are highlighting this because there are different NfL profiles that are observed in different diseases and with different treatments. For example, in a treatment being explored for Hunter's syndrome, NfL changes were just slightly elevated at six months, and at later time points, they began to come down and actually come down quite substantially. We don't know the time course for NfL and ALSP or how much of an insoluble NfL reservoir may be present in the brain. However, it's very encouraging to see this downward trend at the later time point for this subject. Notably, the NfL levels were reduced in the CSF between the phase II baseline and the six-month time point. Lastly, I want to bring your attention to this individual's baseline, which at 80 pg/ ml, is very high and way above the normal range. Slide 32 shows the key MRI measures that are sensitive to change that we saw in ILLUMINATE, and we're showing this for the same patient that we just looked at. We have applied the same regression-based approach to show the rate of progression prior to treatment. We've taken all of their ILLUMINATE MRI measurements and used them to model a slope for the natural history portion of the graphs and then projected that slope with the dotted line, which estimates the trajectory of what continued progression at the same rate would have looked like. The solid line in the phase II portion shows the measurement from the IGNITE Phase 2, highlighting the difference in this case between the observed and projected value, which we show in milliliters of volume. In this case, there is a change in the progression trajectory that appears directionally favorable for both ventricular and gray matter volume measures. Moving on to patient B on slide 33. This is a patient who had a very nice soluble CSF1R response of +32%. Now, that +60% soluble TREM2 change will probably stand out to you, as it also stands out to us. That level of increase is well beyond anything we've seen before in our other studies, and we don't know exactly what is causing that. After looking into the subject's history, we found an unrelated medical event that was proximal in time to the measurement. It is known that this type of an event is associated with a transient increase in soluble TREM2 levels. Unfortunately, sharing more details than that would risk identifying the patient. Looking at patient B's NfL levels, we're seeing an increase in NfL between the natural history baseline and the phase II baseline. This person with a very high baseline NfL level is at almost 160%. So at that six-month time point, we see a very nice decrease relative to baseline, which is in the direction that we would hope to see following treatment. Going into slide 34, we can see patient B's MRI measures, which are both what you would want to see. On the left are the MRI measures that appear to be stabilizing based on their pre-Phase II trajectory for gray matter volume. On the right, we see very, very little change on the ventricular volume, and so this is favorable for patient B. Looking at patient C on slide 35, we also have nine months of serum NfL data. Baseline NfL levels were elevated and rising prior to entry into the phase II study. The measurement that we have for soluble CSF1R at -5% corresponds to the six-month time point. At six months, we are also seeing an increase in NfL over baseline. But at nine months, we don't have a soluble CSF1R measurement, but we do have a serum NfL measurement, and we're seeing a decrease between the six-month and the nine-month time point in that serum NfL level. Looking at patient C's MRI measures on slide 36, we see a decrease in gray matter volume at 6 months and a modest relative increase on ventricular volume over that timeframe. Moving on to patient D on slide 37. This is one of two people in the study who have very low baseline NfL levels at entry that are in the normal healthy range. Although they meet the criteria for entry to the study and for being symptomatic, their NfL levels and cognition are normal. We see a response on the CSF biomarkers in the table on the left, and the serum NfL level at six months is increased, albeit with a low absolute magnitude. Going to slide 38 for patient D, we see stability on MRI measurements during the pre-study assessments and also modest to minimal changes at the 6-month visit. This contrasts with the first three patients, A, B, and C, and highlights an important emerging trend wherein there's a positive correlation between biomarker levels and disease progression. More specifically, for patients that have lower levels of NfL, we are seeing slower or less progression on MRI. In the case of this patient D, what we are seeing at month 6 is an encouraging progression trajectory. For these patients with low or near normal NfL baseline levels and low rates of progression on MRI measures, we hope to see and continue this kind of stabilization on both NfL and MRI biomarkers, and that that continues beyond the six-month time point that we have here. Patient E on slide 39 is similar in that they also have low NfL levels of 12 pg/ ml at baseline. On the biomarker table on the left, there is a response on two of the three CSF biomarkers. On the right, this patient's NfL levels are similar to patient D, and they are not changing, in the ILLUMINATE, the natural history study portion prior to phase II. During phase II, serum NfL levels at six months increased, albeit, with a low absolute magnitude. Looking at the MRI measures on slide 40 for this patient, for which there was limited pre-study progression, we're seeing relatively no change for gray matter volume and a reduced rate of ventricular expansion. This data shows a similar trajectory to the previous patient D, for whom we are seeing a relatively flat slope that started during the natural history study portion and did not change much through the phase II time points. These data offer an important possibility that for those who are earlier in their disease progression, there is a potential for VGL101 to keep these biomarkers generally stable, which we think would be very meaningful. Slide 41 shows the data on our sixth patient, patient F, and it shows supportive directional changes on two of the three CSF biomarkers, most notably, again, soluble CSF1R, which is emerging as a key biomarker of ALSP disease pathology. Moving over to patient F's NfL levels, we can see that their phase II baseline NfL level is 54 pg/ml, which is again quite elevated when compared to age-matched controls. The NfL levels appear to be decreasing in the natural history portion prior to entering into phase II and increasing between the phase II baseline and the month six time point. Again, albeit at a low absolute magnitude. Notably, CSF levels of NfL were reduced between the phase II baseline and the month six time point. Now, looking at the MRI changes for patient F on slide 42, starting with gray matter volume, the natural history study data are showing progression. The change from phase II baseline at the month six time point is what we would want to see for someone with such a progressive trajectory. Then, if we look at the ventricular volume, we're not seeing much of a change on this measure in the pre-dose period, and the ventricle size remains stable during the phase II portion out to the six-month time point. So with patient F as our sixth and final patient in this interim analysis, let's take a look at some of our key takeaways. By way of summary on slide 43, we'll be looking at the directionality of volume change in ventricles and on gray matter. Starting with ventricular volume, five of the six patients had a directional change, albeit some that were larger than others, supporting a reduced rate of ventricular expansion. If we were to look at gray matter volume, three of the six patients presented a directional change supporting a reduced rate of atrophy. Moving into our CSF and serum biomarkers on slide 44, we are focusing on soluble CSF1R and NfL because both ILLUMINATE and IGNITE data demonstrate that they are emerging with the most changes in ALSP. Starting with soluble CSF1R, four of the six patients showed an increase in soluble CSF1R. Importantly, in those patients, the magnitude of those increases were larger than the ones we saw in healthy volunteers, which we find very encouraging. Looking at NfL levels, we saw that three of the six patients showed a change in their serum trajectory. One of those patients saw a decrease at the six-month time point, and two of those patients saw a decrease between the six-month and the nine-month time point. For the two patients with low baseline levels of NfL, we saw low absolute changes. This brings us back to our earlier discussion, that when it comes to low or near normal levels of NfL in serum, stabilization would be very encouraging for any patient who is earlier or slower in their disease progression. Lastly, we saw that two of the six patients showed reduced NfL levels in their CSF at six months. At this point, we've gone through each patient individually, as well as provided an overview of how all six patients compare in terms of their biomarker levels and changes. So I'd like to take a minute to recap the points that we feel are the most important on the next slide. To sum up on slide 45, today, we spent a good amount of time sharing key learnings from ILLUMINATE, our natural history study, because it continues to be an invaluable source of information for us when it comes to better understanding ALSP. The totality of the ILLUMINATE data, including longitudinal progression on selected MRI and clinical measures, in combination with the interim IGNITE data, support our initial plan to engage with regulatory authorities. It has also given us confidence that the biomarkers and measurements we selected are sensitive to progression and validate our initial thoughts about where to measure clinical assessments, where and when to measure clinical assessments. We've gone through a lot today, but it shouldn't be overlooked that the safety and tolerability of this antibody is favorable based on what we've seen so far. We are incredibly encouraged by the target engagement biomarkers, in particular, soluble CSF1R. Our level increases, which were relatively larger than what we observed in healthy volunteers in the phase I study. We spent most of our time going through the directional changes in MRI and NfL. So obviously, we're very excited about those changes and how they tend to support our understanding of VGL101 and its potential impact on ALSP disease progression. Lastly, we are very proud of both the quality and consistency of this interim data because it supports not only a continuation of both studies, but to do so without modification. All told, we are encouraged by these results and very excited to see what happens over the next six months. We plan to engage with the FDA to initiate discussion around a potential accelerated development pathway for VGL101 in ALSP. Additionally, our next data readout is expected to be on all patients treated with 20 and 40 mg/kg at, for six months in Q3 of 2024. And now I'll hand it over to Dr. Lynch to provide a brief, brief background on ALSP and importantly, his perspective on the ILLUMINATE and IGNITE data. Great, thank you. Good afternoon. My name is David Lynch. I'm a neurologist at the National Hospital for Neurology in London and at University College London. Today I'm going to talk to you about ALSP, its symptoms, its underlying cause, and why there's such an urgent need for treatment for this devastating disease. I'm also going to share my perspectives on Vigil's interim data on ILLUMINATE and IGNITE. I'm an investigator in both trials, and I treat ALSP patients at my practice at UCL. However, I did not treat any of the patients evaluated in the interim IGNITE analysis that was presented today. ALSP is an acronym for Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. It is a rare autosomal dominant neurodegenerative disorder that's caused by mutations in the CSF1R gene. CSF1R mutations primarily cause degeneration of the brain's white matter, and as a rare disease, it's estimated to affect about 10%-25% of patients who have an adult-onset genetic leukoencephalopathy. That's certainly what I see in my practice. About 20% of our patients end up with a diagnosis of ALSP, and the number of referrals we are receiving are increasing all the time. In a recent important development, ALSP received an ICD-10 code, which should help to make the process of diagnosing the disease more uniform. Unfortunately, this disease has quite significant and rapid progression. Most patients accumulate significant disability and become incapacitated about three or four years from their disease onset. The average time from disease onset to death is about six years, and unfortunately, we have no approved therapies that can slow down or stop the disease. This slide summarizes how ALSP can present in a number of different ways, causing symptoms primarily affecting cognition and motor skills. The most common symptoms include personality change, inappropriate behavior, or psychiatric symptoms like new anxiety or depression. Patients then develop worsening problems with their memory, as well as difficulty with speech and word-finding. But alongside these cognitive symptoms, patients tend to have problems with their gait and their balance. They may be stiff and have slowness of movement. They can experience decreased coordination and tremor and will usually develop difficulty swallowing and speaking. And as the disease progresses, all of these symptoms multiply. Patients become increasingly immobile to the point of being bedbound and totally reliant on others for their care. This slide shows that dramatic progression in ALSP. About 50% of patients will die by five years, and very few patients will live longer than that, and that's what I see as a treating clinician. This is such an aggressive disease. For these patients, reducing that rate of decline or stabilization would be an incredible advance. ALSP is caused by mutations in the gene CSF1R, and the CSF1R gene encodes a microglial surface receptor, which is responsible for this survival, proliferation, and various other functions of microglia, shown here on the left panel. It functions in a parallel pathway to TREM2, another microglial surface receptor, which has a similar function. The CSF1R mutations in ALSP result in loss of function of the receptor and lead to microglial loss and dysfunction, as seen in the right panel, which shows a reduction in microglia, which are stained brown with the microglial marker in both white and gray matter. Abnormally pigmented microglia are also typical of ALSP. In addition to microglial pathology, there are pathological changes in axons, including these abnormal axonal spheroids, which are a cellular hallmark of ALSP. They are typically filled with cellular debris, including NfL, and they're caused by impairments in axonal trafficking and transport. ALSP does have well-defined imaging changes. One of the most important is brain atrophy, which we can measure by looking at the size of the ventricles. The ventricles enlarge as the disease progresses, and we know from the ILLUMINATE study that this is apparent even over a six-month period. Here we see the same patient imaged at baseline and again at six and nine months. The patient has both cognitive symptoms and significantly elevated NfL levels. You can see by looking at the pink arrows, that the ventricles are enlarging at each time point.... Importantly, this ventricular expansion can be measured and quantified, and it can be used as a biomarker of disease progression and treatment response, as demonstrated in the ILLUMINATE and IGNITE data you just saw from VGL. As you saw earlier, NfL levels are significantly elevated in symptomatic ALSP patients, particularly those who have cognitive impairment at baseline. Shown here again on the left are the data on CSF neurofilament levels at baseline from the ILLUMINATE study. The ILLUMINATE and IGNITE studies have also shown that serum and CSF neurofilament levels are highly correlated. Of course, increased neurofilament levels have also been demonstrated in other neurodegenerative diseases. However, in ALSP, we see significantly higher levels than in those other neurodegenerative diseases. We see this figure from Delaby et al., which includes Alzheimer's disease, Down syndrome, ALS, frontotemporal and Lewy body dementia, corticobasal syndrome, and progressive supranuclear palsy. The significantly elevated NfL levels make it a robust fluid biomarker in ALSP, given its relationship to axonal integrity. Elevated NfL levels in ALSP correlate with cognitive decline and progression on MRI measures, and therefore, NfL can serve as a biomarker to monitor treatment response, as you have seen in the IGNITE data. So I'd like to offer my key takes on the interim data from Vigil's ILLUMINATE and IGNITE trials, which were presented earlier. So these are the first-ever natural history study and interventional trial in ALSP, respectively. And overall, they serve to increase our understanding of disease pathophysiology and how imaging and fluid biomarkers can be used to follow disease progression and to evaluate response from a potential treatment. Regarding the data from the first interim analysis of six patients treated with six months of VGL101 at 20 mg/kg in IGNITE, I believe that the data, while early, are very positive. As a reminder, ALSP is a devastating disease which is progressive and fatal and does not have any approved therapy. VGL101 has a favorable safety and tolerability profile, with the advantage of an accessible once-monthly intravenously dosed drug. VGL101 increased soluble CSF1R levels, which are believed to be a key biomarker of disease pathology, to levels higher than previously seen in healthy volunteers in the phase I study. This suggests rescue of microglial activity, which is compromised in ALSP. Most notably, we're seeing changes in two key biomarkers of ALSP pathology, MRI and NfL, within six months in a small patient set, which I find extremely encouraging, as it suggests VGL101 may be able to impact disease progression early on. In particular, the reduction in ventricular volume expansion is very relevant clinically in real-world practice, as this is a measure that we physicians use to track disease progression. Five of the six patients treated with VGL101 for six months showed a reduction in their rate of ventricular expansion. For context, it takes at least one year to see any change in MRI in patients treated with HSCT, even for the patients who respond to this highly risky therapy. Additionally, four out of the six patients also showed reduction in their NfL trajectory, either in the serum or the CSF, suggesting an impact on neuronal degeneration. So what we saw today represents the first-ever interventional data set in ALSP patients, and it supports VGL101's potential as a therapeutic, which is very encouraging to me as a clinician treating patients with ALSP. These are also the first-ever data on TREM2 agonist as a treatment approach in patients with a neurodegenerative disease. I'm very excited to continue as an investigator in ILLUMINATE and IGNITE and generate more data and more patients over a longer duration, so that we can continue evaluating VGL101 and these positive trends on imaging and fluid biomarkers. Thank you, and I can now hand you back to Ivana. Thank you very much, Dr. Lynch. Before we move to Q&A, I would like to close by reiterating our excitement around the results we shared with you today. We're incredibly proud to be the first company to show clinical data on TREM2 agonist as a potential therapeutic approach in patients with neurodegenerative disease. As you have heard today, these interim results also reaffirm our belief in the potential of VGL101 as a novel treatment option, and we look forward to providing additional Phase 2 IGNITE data from all patients in 20 mg and 40 mg cohorts at six months in the third quarter of 2024. I want to again thank our trial participants, their caregivers, and the clinical investigators for making this study possible. It is a testament to this community of patients and caregivers that have progressed from identifying the CSF1R gene in 2012 to the first promising clinical data readout of VGL101 in ALSP patients in just over 10 years. We extend a sincere thank you to all who have contributed to this progress. We look forward to our continued engagement with the ALSP community and further advancing VGL101's clinical development. With that, I will hand it back to our operator for Q&A. 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 Andrew Tsai at Jefferies. Please go ahead, Andrew. Hey, this is AJ for Andrew. Thanks so much for sharing these encouraging data and for taking our questions. So firstly, in terms of your meeting with the FDA, are there precedents where MRI has served as the basis of an accelerated approval? And my second question is: What's your confidence that you'll continue to show durability of these markers going into 12 months across these patients? Like, what kind of continuation should we expect to see in month-over-month trajectory, or, I guess, like, why do you think patient B responded so strongly to treatment? Why don't I start, and then I will, you know, pass it on to David to comment as well. First of all, thank you for the question. We really appreciate it. The MRI has not been established as a surrogate endpoint to date. However, in our discussions with the agency, they have left the door open for that to happen, and we feel now, you know, very encouraged with the data we're seeing from the natural history study as well from IGNITE, that we'll be able to make those correlations, which will be necessary for, MRI to be established as surrogate endpoint. And what I mean by that is the correlation between the changes in MRI and the clinical, outcomes for these, you know, clinical progression for these patients. In terms of, you know, what we expect to see, we certainly are encouraged by what we're seeing, and we certainly expect to continue to see, you know, the movement in the, in the right direction as we progress, because as we all know, six months is very early, and as Dr. Lynch mentioned, for example, with hematopoietic stem cell transplant in patients where that actually works, it takes, you know, at least a year to see some kind of changes, and the fact that we're seeing changes here are extremely encouraging. But, David, anything else you would like to add? So, I mean, we designed the study to be 12 months for a couple reasons. One of the main ones, as we saw borne out in ILLUMINATE, was that we understood that it would probably take 12 months to see clinical changes, which was confirmed in that natural history study. But also, we don't fully understand the time course of NfL and how that could be cleared. As I mentioned before, given our mechanism and the location of where NfL comes from in terms of axons, we certainly were open to the possibility that it could take a little while to fully see those trajectories change. Those two individuals that have the nine-month time point, the reason we wanted to show that all the data that we have is because that is something that we were open to the possibility that it could take a little bit longer. So I'm really excited to see the next data, given that directionality and the way that those longer time points are headed. And ultimately, you know, in terms of your question about individual patients, there's still some learnings there. That was one of the, you know, it was the highest serum NfL that we had in terms of patient B. And you know, I think we're still learning what that might mean with a steep rate of progression, being able to see a response like we saw there was really encouraging. But, ultimately, there's still some pieces of that that we need to fill in, and we'll certainly be thinking about, you know, potentially analyzing the dataset, taking into account baseline NfL levels as part of the analysis going forward. Got it. Thanks so much, and, congratulations. Thank you. Our next question comes from Paul Matteis at Stifel. Hey, thanks so much for taking the question, and thanks for the transparent data set and showing every individual patient's data point. It's appreciated. I had two questions. One is, on your upcoming meeting with the FDA, can you clarify the question or questions that you're going to be posing, at least at, like, a high level? Are you going to be asking whether a phase I or II study like this, at a certain number of patients could be fileable, or is it more about a reaffirmation, kind of like you said, Ivana, related to a biomarker path to approval? And then second, we totally appreciate that six months is super early to really see anything in a neurodegenerative disease. I was just curious if you've seen any of the clinical endpoint data at six months, and how often you've been kind of taking these clinical measures, and just sort of qualitatively there, if there's anything that you can share. Thanks so much. Sure. No, Paul, thank you for the questions. Let me start, and then I'll pass it on to David as well. So in terms of the meeting with the FDA, so obviously there's no meeting scheduled. Yeah, we, we wanted to make sure that we received the data, we're able to analyze it, and then obviously, now that we have the data, we're very encouraged and want to start that conversation. So the conversation is really to start educating the agency, right? Because the agency really doesn't know this disease, and certainly doesn't know it like we do. And so the plan is to start that education process, really start educating them about the biomarkers, showing them that there is a correlation between these biomarkers and the disease progression. Then that will take us, obviously, into a subsequent conversation of: Yes, if these are the biomarkers, and we agree that those are biomarkers, what does that biomarker strategy look like? So that's what I can share now in terms of, you know, the approach with the agency. And then in terms of, you know, clinical data, as David pointed out from the natural history study, we're not seeing anything at six months. So the data is too noisy at six months, right? There is nothing to see, and that's the same as what we saw now at six months. So it's gonna take 12 months, and we kind of knew that from our conversation with the KOLs before we started the study, and that's why, you know, our real look at the clinical data will be at that 12-month point. David, anything else? I mean, just to add to that data, yeah, the data at this point is genuinely noisy, and it is, you know, we'll have to see what happens as we go out to the 12-month time point. But, there's overall nothing to be gleaned from the clinical data so far, given what we know from the natural history study on the clinical endpoints. You know- Yeah. I'll just say, like, you know, a key part of being able to execute a program like this and think about accelerated approval pathways is having the right endpoints and being able to correlate them with clinical progression. And so a really big advancement for us here is to actually be able to have that data, to go to the agency and you know, bring that to them and start to have that conversation, which is, you know, just I feel really grateful that we have that data, and we're going to be able to initiate that dialogue. All right. Makes sense. Thank you so much. Thank you. Our next question will come from the line of Jason Butler at JMP Securities. Hi. Thanks for taking the questions, and let me add my congrats on the results. I guess just in terms of the ILLUMINATE data, have you looked in the symptomatic patients to see, you know, whether you're also seeing high and low NfL baseline or subpopulations? And is there any, you know, kind of correlations that you're seeing there, that could inform patient selection in the future in terms of other... any other biomarker or baseline characteristics? Thank you. Yeah. Hi, Jason. Thank you so much for the question. So, yes, we see that in NfL in the ILLUMINATE study as well, that there are some patients that have these low NfL levels, and those patients are not cognitively impaired. And so, yes, we're definitely seeing that. And we, though, ultimately think those patients will convert, so the idea in that patient population is to keep them, right, at those levels and make sure that you're not, that they're not ultimately converting from that low NfL level to high NfL level. Because remember, what we tried to do in our phase ii study is to really select for that early patient population, right? So those mild to mildly moderate, and this is probably why we ended up with the two patients that have, you know, these very age-normal ranges of NfL. But, David, anything else? We heard from Dr. Lynch how aggressive and progressive this disease is. So while, you know, the majority of the symptomatic patients in our dataset do have high baseline NfLs, there, as Ivana mentioned, there are a couple that are low, and that's, you know, and again, a really important learning from the study. And I think as I mentioned before, certainly thinking about how we would analyze the data, knowing that now, and pre-specifying some analysis that might be different, is probably how we're approaching it, as opposed to thinking about enrichment. I think both groups are important, and for that lower group, preventing progression would be fantastic. Okay, great. Thanks again, and, and congrats again on the results. Thank you. Our next question comes from the line of Laura Chico with Wedbush. Hi, good afternoon, and thanks very much for taking the question. I, I guess I wanted to ask about the next update, and I believe you will have both the 20 and 40 mg / kg dosing. Just a question around expectations on the higher dose and how that might change your plans. And I guess secondarily, is it more important to get a greater number at 6 months, or is 12 months perhaps more informative to discern what's going on in the NfL trends? Thanks. Sure. So why don't I... I'll let, David take that. David, why don't you take that question? You know, I think we're really eager to see both more individuals at 6 months as well as people at 12, and I mean, this is maybe trite, but to get to 12, you have to start with six. So I think, you know, both of those time points are obviously important. We want to see these trends continue and be maintained and really be able to continue to learn about the time course of NfL, for example, and those changes. You know, speaking about the 40 mg/kg dose, as you probably remember, we did not see differences on the biomarker, the CSF biomarkers that were meaningful in the healthy volunteer population. We clearly see that 20 mg/kg is a pharmacologically active dose based on the biomarkers that we've measured in the IGNITE Phase 2. However, we are also seeing some differences, specifically on soluble CSF1R, with those changes looking to be, you know, bigger than what we saw in the healthy group. So, while I think we don't have a expectation based on healthy volunteer level that we would need to go higher, the reason we're, we're testing dose, both doses is to have dose, that dose ranging and to be open to the possibility that they may have a different response. I think that's probably what we can say right now, is that it's an important piece of the dataset, but we don't have a specific expectation of more response. Thanks very much. Thank you. Our next question will come from Jeff Hung at Morgan Stanley. Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions, and congrats on the progress. Since the ventricular expansion points to progressive atrophy, which is hard, if not impossible, to reverse, how are you thinking about positioning VGL101 as it relates to disease progression? Is the value greatest here in the prodromal or low NfL baseline patients who have yet to have that deterioration, or do you think VGL101 is best positioned to help patients once they start going through that ventricular expansion? Thanks so much. Yeah, look, as we said before, and I think as Dr. Lynch very nicely pointed out, this is an extremely progressive, devastating disease, right? So any you know, movement in a positive direction in something like this is gonna be extremely important. So we think that in both patient populations, you know, and the ones that have high NfL levels, are cognitively impaired, and where, you know, these MRI measurements are moving very rapidly, slowing that progression is gonna be huge. And then in the patients that haven't converted, that have low NfL levels and are not cognitively impaired and are not progressing, maintaining them and not allowing them to convert is also gonna be incredibly important. So I think what we are saying is that VGL101 is could be really important, across the board. David, anything? No, I agree with that. I agree with that 100%. Thanks so much. That's really helpful. I think that was our last question. So, thank you so much all for joining us tonight. We really appreciate all the questions, and I will turn it to the operator to close out the call. At this time, the call has concluded. You may disconnect. Thank you.