Good day, and thank you for standing by. Welcome to the Acumen Pharmaceuticals Investor Day conference call. At this time, all participants are in a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Alex. Ma'am, please go ahead. Thanks, Michelle. I'm Alex Braun, Head of Investor Relations, and on behalf of the Acumen team, I'd like to welcome everyone to our virtual Investor Day. Today, we intend to take you on a deeper dive into Acumen's value proposition as we near the phase II readout for our product candidate for the treatment of early Alzheimer's disease, sabirnetug. As a reminder, we will be making forward-looking statements. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of those risks can be found in our most recent 10-Q filing with the SEC. Any forward-looking statements are only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. Today's speakers will include Dan O'Connell, our Chief Executive Officer, who will briefly touch on the Alzheimer's landscape and potential of Aβ oligomer therapies to treat Alzheimer's disease. Dr. Jim Doherty, our President and Chief Development Officer, who will explain sabirnetug's mechanism of action and why we believe it could potentially differentiate from other disease-modifying therapies. Dr. Eric Siemers, our Chief Medical Officer, who will review our ongoing phase II study investigating sabirnetug that reads out in late 2026. Dr. Paul Shughrue, VP, Program Lead, and Head of Research, who will explain the latest developments in our Enhanced Brain Delivery or EBD program, which we believe to be a promising next generation addition to our pipeline. Following their presentations, there will be a live Q&A discussion. In addition, there is a question submission box on your screen that will be open throughout the presentations this morning and during the Q&A session to submit written questions. We'll collect those questions throughout the hour and take as many as time allows. With that, I'll hand this over to Dan. Good morning. I'm Dan O'Connell, CEO of Acumen. Thank you for joining us today. I'm pleased to provide you with an overview of our opportunity and the setup for Acumen and the value proposition and strategy as we seek to bring better treatment options forward for people impacted by Alzheimer's disease. Let's start with the magnitude of the opportunity and unmet need. Today, an estimated 7.2 million Americans are living with early Alzheimer's disease, a stage characterized by symptoms and confirmed amyloid pathology. Absent a cure or effective preventative treatment, that population is expected to nearly double by 2060 to roughly 13.8 million Americans. For the current treatment landscape, two FDA-approved disease-modifying agents are now available and have been shown in clinical studies to slow disease progression. These have ushered in a new era for treatment in Alzheimer's disease. Global sales of the approved anti-amyloid agents are growing and poised to accelerate. The approved agents, Leqembi and Kisunla, have recently achieved an annual sales run rate exceeding $1 billion. Sales are projected to reach $2 billion in 2028 and reach upwards of $3 billion-$4 billion by 2030. The early market adoption for these amyloid plaque-directed agents has occurred despite systemic infrastructure challenges and debates about the overall efficacy and safety of these agents, including amyloid-related imaging abnormalities, otherwise referred to as ARIAs. Nevertheless, we see this market is poised for continued growth and large enough to support multiple multi-billion dollar products, given the magnitude of the population. One of the primary drivers of market expansion and continued growth and development is the proliferation of blood-based biomarkers. Essentially, a blood test to confirm or inform a diagnosis of Alzheimer's disease. The use of blood-based biomarkers has already transformed Alzheimer's drug development. As an example, we were early adopters of a phospho-tau blood test, plasma test in our ongoing phase II study. The use of that measure streamlined our screening and enrollment, reduced patient burden and site burden, and reduced the overall cost. It was a real way to innovate within the space and achieve efficiencies in our program. Today, we have four approved blood tests for Alzheimer's disease. These are all being commercially deployed and will continue to, I think, establish and confirm Alzheimer's cases more broadly. Triaging patients in the primary care setting with blood-based biomarkers is expected to allow specialists to really focus their time and attention on treatment options. We see this as really contributing to the growth overall in the space. As we look at the Alzheimer's market today, we see this as a market that is essentially underdeveloped and poised for continued and significant growth over the next decade. That growth will fundamentally be accelerated through the continued deployment and establishment of the clinical infrastructure to offer treatment options to patients. The adoption of blood-based biomarkers to characterize and potentially confirm more cases in the population. Additionally, other formats of drugs, such as the recently approved subcutaneous version of Leqembi for treatment induction is another way to establish convenience and growth within the marketplace. I think experienced physicians just becoming more familiar with treatment options, risk assessments in terms of ARIA, managing safety considerations for patients will continue to expand the adoption and growth of these agents. Another concept that will continue to fuel the growth going forward is the combination strategies. Using essentially the anti-Aβ approaches as a cornerstone of treatment are expected to be the future state of care. It is an exciting time in the field and one that is poised for continued growth. In this early phase of AD market development, we see a massive opportunity to improve on the safety and efficacy of current amyloid-targeting approaches. Our goal at Acumen is to develop products with improved benefit to risk profiles, with either increased efficacy or increased safety or potentially both. We see a path to better efficacy and safety and a risk-benefit profile improvement based on our approach, which is to target soluble toxic Aβ oligomers. Oligomers are early instigators and persistent drivers of Alzheimer's pathology. Jim will talk more about this mechanism in his talk, but we think it is a path towards differentiation distinctly within our pipeline. Suffice to say, there is room for improvement here, and we at Acumen are laser-focused on that opportunity and seeking to have an outsized impact on that disease. 2026 is a pivotal year for our innovative anti-Aβ oligomer pipeline. We have sabirnetug. Our lead program is positioned to read out clinical proof of concept data late this year, really data that we believe will provide the clinical validation of the Aβ hypothesis and usher in a new mechanism within the amyloid space. We also have our EBD program, which is Enhanced Brain Delivery. We have reported positive non-clinical data earlier this year and have two candidates that we are progressing towards an IND in mid-2027. To summarize our value proposition and strategy, we are still in the early days of effective treatment approaches for what is a very large, growing, and diverse Alzheimer's population in need of better options. Our novel anti-Aβ oligomer approach is differentiated within the clinically validated amyloid space, an exciting possibility to differentiate on a benefit-risk basis. Sabirnetug has already produced compelling phase I results in Alzheimer's patients, increasing the probability of success for it and future anti-Aβ oligomer therapies. Our ALTITUDE-AD phase II trial will read out later this year, which is a hugely exciting milestone for us as a company, and our EBD program gives us future optionality well into the future. Our strategy to expand stakeholder value is based on successful phase II results, expedite the development of sabirnetug with a partner, and seek to advance an EBD candidate through a clinical value inflection point quite rapidly. With that, I will turn the call over to Jim. Thanks, Dan. Good morning, everyone, and thank you for joining us today. As we approach the readout of the ALTITUDE-AD trial, I'm pleased to take this opportunity to talk about some of the key reasons why we believe sabirnetug represents a differentiated opportunity for anti-Aβ disease-modifying therapies for the treatment of Alzheimer's disease. I'm going to touch on three related topics today. First, the soluble oligomer hypothesis. Sabirnetug is the first monoclonal antibody targeting Aβ therapy to rigorously test the oligomer hypothesis in a late-phase clinical trial. Critically, as you'll hear later from Eric, the ALTITUDE-AD trial represents a well-powered study focused on the potential benefits of sabirnetug on clinical measures and activities of daily living, as well as safety in a variety of biomarkers. I'll talk about IgG2. Like many other potential therapeutic agents, sabirnetug is a monoclonal antibody of the IgG type. It's important to consider, though, that subtypes of IgG have different signaling properties in the immune system. Finally, as Dan mentioned in his introductory remarks, there have been a remarkable expansion on the availability and diversity of fluid-based biomarkers that will become increasingly critical in the diagnosis of AD, as well as in clinical practice. Next slide, please. Thinking about sabirnetug, how does sabirnetug differentiate from other approved antibody-based anti-Aβ disease-modifying therapies? Well, like other approved anti-Aβ disease-modifying therapies, sabirnetug is an amyloid protein targeting monoclonal antibody. However, unlike the approved anti-Aβ DMTs, sabirnetug targets soluble Aβ oligomers. Those will have potential effects on efficacy, meaning direct removal of what we believe are the most toxic agents that disrupt cortical function. We'll talk more about that as we go along. And potential effects on the safety profile. With the potential for less interaction with CAA plaques, that could adjust the risk for safety effects like ARIA. Also, unlike approved anti-Aβ DMTs, sabirnetug, as I was just mentioning, is an IgG2 antibody that has potential effects on the safety profile, potentially a reduction in inflammatory effects, and reduced ARIA risk. Next slide, please. Amyloid beta was first recognized as the major protein component in Alzheimer's disease plaques in the mid-1980s, becoming a key hallmark of Alzheimer's disease. This led to the amyloid cascade hypothesis in the 1990s, and a key framework for Alzheimer's research that has recently produced two anti-amyloid monoclonal antibody-based disease-modifying therapies for the treatment of AD in lecanemab and then more recently in donanemab. Amyloid precursor protein becomes abnormally processed, leading from amyloid beta peptides that are normally existing in a monomeric form to protein aggregates that can form larger and larger structures with different pathophysiological properties. And what you can see on the cartoon is that as you get larger and larger components of Aβ, you do get these structural differences, and it was once thought that this was a fairly linear process going from smaller to larger fragments, but it has been more recently understood that this is more of a dynamic process where you've got cycling between pools of different sized and shaped amyloid protein. Next slide, please. Why do we care about that? As you can see from this figure from an excellent recent review on the amyloid biology in Alzheimer's disease, you can see that all these different forms of amyloid have been shown to interact with the central nervous system in somewhat different ways. I am not going to go through all of the elements here on the slide today, but really what I am hoping people can see is that, A, there is a lot of diverse signaling and pathophysiology that these fragments of amyloid can produce. But more than that, if you notice that specifically the soluble oligomers have a much larger total number of interactions and are interacting with many more functional systems and actively disrupting synaptic function. When you come to all this has led to the oligomer hypothesis, a refinement of the original amyloid hypothesis that posits that these small soluble clusters of Aβ molecules, called oligomers, are the main cause of neuronal dysfunction and memory loss in Alzheimer's disease. Okay, let us talk a little bit more about these Aβ oligomers. Can you go to the next slide? Thank you. So why are these Aβ oligomers of particular interest? In addition to, as we were just looking on the last slide, there is a diverse set of pathophysiological signals that these small soluble protein fragments cause. They also show up very early in the course of disease. They are an early element of the pathophysiology of Alzheimer's disease, occurring at the very earliest days, far before the presence of larger amyloid plaques and far before the time when cognitive impairment begins to appear. But in addition to being an early component of disease, they are also a persistent component of disease. These oligomers continue to be present as the disease progresses and other forms of amyloid and tau protein are becoming dysfunctional, contributing, we believe, persistently to the pathophysiology in AD. Okay, the next slide, please. All this leads to this refined Aβ oligomer hypothesis where plaques may be the visible pathology and the original thinking around amyloid biology, but these small, harder-to-detect oligomers are the most synaptic toxic species and may therefore be highly relevant for disease. Next slide, please. There is something called the Osaka mutation, which is a rare mutation that appears in an extremely small number of Japanese families that has been characterized. The point of this mutation is a mutation in the amyloid precursor protein that leads to the production of soluble oligomers, but no production of plaque. What you can see in this small number of families is that despite the fact that you do not have plaques of amyloid in the brain, you have robust levels of soluble oligomer, and that is associated with the cognitive impairment of Alzheimer's disease. This is data that supports that soluble oligomer biology may be sufficient to produce the cognitive impairment of Alzheimer's disease. So a human experiment supporting the soluble oligomer hypothesis. Next slide, please. All this biology leads to coming up with sabirnetug to target the soluble oligomers. Sabirnetug represents the first oligomer-selective immunotherapy approach to treating Alzheimer's disease. It is also the first oligomer-selective antibody that is being tested in a late-phase clinical trial. As you will hear later from Eric, sabirnetug is currently in a phase II trial where we are focused on measures of cognitive performance in addition to the biomarkers that have been characterized to date. All right. Why then might you expect to see a difference between sabirnetug and other types of anti-amyloid therapies? Can we go to the next slide, please? These are a number of studies that show some of the profile differences between sabirnetug, which is targeting the soluble oligomers, and in this case, lecanemab and aducanumab, two other antibodies that target different sizes and shapes of oligomer. What you can see on the left-hand graph is an SPR experiment looking at relative affinity between aducanumab, lecanemab, and sabirnetug on two different protein constructs of amyloid. So at the top, the Aβ1-40 monomer, the so-called normal protein. As you can see, sabirnetug has lower affinity than either of those two agents for monomers. But then if you look at the filled symbols at the bottom, there you are comparing the affinity for soluble oligomers. What you can see is that sabirnetug has a higher affinity for soluble oligomers than either aducanumab or lecanemab. Given that monomer exists in high excess in the brain, the relative affinity between monomer and soluble oligomer also contributes to how much antibody is available to target the abnormal oligomer proteins. We see sabirnetug having a very attractive profile, both in being very potent to targeting soluble oligomers, but also being less potent at targeting monomers, giving an even greater relative affinity for sabirnetug for soluble oligomers. On the right-hand side is some recent work from Omar De Leon in the Klein Lab at Northwestern University. His team utilized advanced immunoaffinity chromatography using targeted tools like the sabirnetug antibody to pull intact naturally occurring soluble oligomers directly from human tissue. His team reported that sabirnetug preferentially bound to soluble oligomers, whereas r-mAb148, which is the murine precursor for lecanemab, bound preferentially to protofibrillar Aβ. Again, additional data from the human brain showing that these antibodies are both recognizing amyloid protein, but recognizing different forms of amyloid protein. As we saw earlier, those different forms of amyloid protein can have very different physiological effects. These are not small differences. As you can see from the summary on the slide, RmAb158 bound approximately 64% of the fibular form of Aβ taken from the human brain extracts, and only 36% of the globular or soluble Aβ. Whereas sabirnetug, in contrast, was binding about 99% of the globular or soluble form of Aβ and only 1% of the fibular Aβ. So a definite biologically relevant difference between the two antibodies. Next slide, please. Furthering the comparison, this is now looking at the relative binding to vascular Aβ in a murine model of vascular CAA or cerebral amyloid angiopathy. This is recent work from Martine Grenon in Cynthia Lemere's lab at Harvard, comparing the binding profile for sabirnetug with the binding profile for lecanemab in a head-to-head in a mouse transgenic model of CAA. In that study, lecanemab exhibited greater plaque and vascular labeling than did sabirnetug, although the authors do caution that immunohistochemistry conditions must be carefully optimized when making direct comparisons between antibodies. These results are consistent with the idea that sabirnetug binds Aβ species less closely associated with vasculature than does lecanemab. This is a careful and comprehensive analysis that we won't have time to discuss fully today, but I encourage you to check out Martine's paper in Alzheimer's & Dementia. Next slide. As I mentioned, sabirnetug uses an IgG2 backbone. That means that both lecanemab and donanemab being IgG1 antibodies signal to the immune system in a slightly different way than does sabirnetug as an IgG2 monoclonal antibody. That antibody subclass influences how strongly antibodies engage immune effector functions through Fc receptors and complement activation. Why is IgG2 different? Compared to IgG1 antibodies, IgG2 has substantially weaker Fc gamma receptor binding. IgG2 activates complement less efficiently, and IgG2 generally induces less antibody-dependent cellular cytotoxicity and less microglial activation. In Alzheimer's disease, that's important because some investigators believe that a portion of ARIA and infusion reactions may be related not only to amyloid removal itself, but also to the inflammatory responses generated when antibodies engage microglia and vascular amyloid. Next slide, please. This is now looking at the current incidence of infusion-related reactions with the approved anti-amyloid Aβ therapies, lecanemab and donanemab. I think the point here is that these type of inflammatory reactions do represent a significant impact to patient populations being treated with these agents. You can see the numbers here on the screen, both for infusion-related reactions as well as hypersensitivity-related reactions associated with the clinical trials for these two programs. Next slide, please. In addition, here are the values for the incidence and severity of ARIA with approved anti-Aβ DMTs. Of course, this is a huge area of investigation in the field and an area where there's an awful lot of effort being placed for the management of patients now that these therapies have achieved the marketplace. Of course, there are changes in practice that have been occurring, most notably with lecanemab, where the company was able to show that a change in the protocol for dosing had a reduction in ARIA rates. You can see that ARIA rates remain a meaningful effect for both molecules across total populations, as well across APOE carrier status. On the right-hand side, you can see that not only is it total ARIA cases, but the number of symptomatic and serious ARIA events, and in this case, ARIA events specifically, are something that needs to be actively managed for patients. Next slide, please. Turning the page a little bit to be thinking about fluid biomarkers. As Dan mentioned in his introduction, and as I'm showing you here, there has been a huge evolution of improvement in the use of biomarkers for the diagnosis and treatment of Alzheimer's disease, and this is occurring quite rapidly. Specifically, we're seeing changes from going from originally an autopsy-based approach to diagnosis, to the use of amyloid PET, as well as other PET imaging agents, to do functional measures to diagnose disease. And coupling that with CSF lumbar punctures to measure biochemical biomarkers to allow you to both identify who is suffering from Alzheimer's disease, but also where they are in their time course of disease. To finally, more recently, blood-based biomarkers. There has been a huge surge in both of the diversity and availability of blood-based biomarkers for diagnosis, as well as for understanding stage progression in disease, and hopefully in the future, to help manage both clinical trials and therapeutics. Next slide, please. Over the last 15 months, there have been multiple approvals in the diagnostic market for new diagnostic tests around phospho-tau217 to diagnose Alzheimer's disease, mostly in the U.S., although this is moving forward in the rest of the world as well. We believe that this is going to become an increased opportunity to have better ability to diagnose patients and to also substantially broaden the number of patients who will be diagnosable. Next slide, please. How are we using these fluid biomarkers in our own studies? And the answer is in multiple different ways. Because so many different proteins can be analyzed, it really can give one a broader picture of the impact and the effect of the agents being tested. This is a little bit of a cartoon showing the kinds of biomarkers that Acumen has been looking at in our own programs. And you can see we are measuring amyloid-related pathophysiology, looking at Aβ 42/40 ratios, so very proximal to the mechanism of action of the antibodies that we are delivering. But also at another level of integration, we are looking at pTau181 and pTau217, which although are tau markers, they are associated with the pace of amyloid change. And then a little farther downstream, we are looking at GFAP for measures of astrocyte activation, and we are looking at a number of markers of synaptic injury, because if our hypothesis holds for how sabirnetug is impacting the pathophysiology of Alzheimer's disease, we should be able to see effects on downstream markers like neurogranin and VAMP2 that the antibody does not directly interact with. Next slide, please. Here are some of the results from our phase I INTERCEPT-AD study in Alzheimer's patients who have been treated with sabirnetug once monthly IV. And you can see these are data from the MAD cohorts. These subjects, by this point in time, had received three consecutive injections of sabirnetug, and because it was a phase I study, at multiple doses. And what you can see is both a dose-related and persistent change in the ratio of Aβ 40/42, consistent with what you might expect to see if you were able to normalize amyloid function. And also we see similarly dose-associated changes in pTau181. And really importantly, we see similar dose-associated changes with both neurogranin, a postsynaptic marker of synaptic health, as well as VAMP2, a presynaptic marker of synaptic health. These data taken together are supportive of the profile of the oligomer targeting sabirnetug as having a meaningful effect on the fluid biomarkers in Alzheimer's patients. Next slide, please. We can also look at these biomarkers in a relative sense. This is a comparison of results from multiple different existing antibody trials. These are not cross-study comparisons, and one always has to be careful with interpreting the results. But what you can see is that if you look at sabirnetug in red, what we are seeing is a fairly rapid change in pTau181 and also in neurogranin, consistent with the hypothesis that we are seeing a marker of early and significant impact on changes associated with Alzheimer's disease with sabirnetug. Next slide, please. I hope I have convinced you of a couple of things. Sabirnetug preferentially binds to soluble oligomers, which is a low abundance, highly toxic form of Aβ that appears during the early phases of disease. This profile offers the opportunity to differentiate from currently approved DMTs that target other forms of Aβ. In addition, that IgG2 backbone of sabirnetug really offers a different opportunity to interact with the immune system and therefore impact both the efficacy and tolerability profiles for sabirnetug. And finally, sabirnetug shows rapid and robust effects on multiple fluid biomarkers that are associated with cognitive impairment, both proximally when you think about amyloid protein itself, but also downstream markers like the synaptic markers. With that, I appreciate your time, and I will turn the call over to Eric, who will talk through the profile for the ALTITUDE-AD trial. Well, thanks, Jim. What I would like to do now is talk a little bit about our ALTITUDE-AD study. It is a well-powered phase II study that we believe is the first study to actually test the oligomer hypothesis with any rigor. If you want to go to the next slide. We will come back and talk about this slide in more detail, but what we are going to get out of this study, which is 542 people in a phase II study, so it is a large phase II study. We will look at clinical endpoints, of course, we will look at safety, and then we have a number of interesting biomarkers that we looked at in our phase I study, and of course, now we will look at it in our phase II ALTITUDE-AD study. If you want to go to the next slide. You might ask yourself, "Well, how are they going to get all this data?" Well, here is how we are going to do it. It is a three-arm study. So we have two different doses of sabirnetug, and one arm that is placebo. It is an 18-month study with infusions given once every four weeks. And after the 18-month period, there is a one-year open label extension that is available to people, and we have actually been finding that a very high percentage of people want to go into that open label extension. But the real readout of the study will be the placebo-controlled portion, which is at the end of the 18 months. If you want to go to the next slide. In our phase I study, we actually obtained a lot of data that were very good in terms of designing and planning this phase II ALTITUDE-AD study. So if you look at the lower left on this slide, that's what we call a target engagement assay. What you see on the y-axis is how much sabirnetug there is that's bound to an oligomer. The x-axis is just the concentration of drug in the spinal fluid. This is a spinal fluid test. The reason why this is so important is before we did the study, the top dose in our phase I study was 60 mg per kilogram. We would get the question, "Well, what if you get up to 60 mg and you don't see anything? You do not have any safety problems. Could you go higher?" What this graph shows you on the lower left is that when you get to the upper doses in the phase I study, you are already getting to the point of diminishing returns. In other words, that curve flattens. It does not just continue to go up. That tells us that there is really no reason to go above certainly 60 mg per kilogram, and really there is probably no reason to go above 50 mg per kilogram. On the lower right, you can see some model data. We took the data from the graph in the lower left, and then we did some modeling with it to choose our doses for ALTITUDE-AD. We think ALTITUDE-AD is well designed in terms of having the right target engagement information. If you look carefully at that at 35 mg per kilogram, we actually have quite good target engagement at both peak and trough. We also wanted to include a 50 mg per kilogram dose group because we do think that based on our phase I results, there is more of a chance to see some reduction in plaque with the 50 mg per kilogram dose. Whether or not a plaque reduction is important for a drug like sabirnetug that targets oligomers is not really clear, but just in case that was necessary, we wanted to include that higher 50 mg per kilogram dose in the study. If you want to go to the next slide. This is a bit small and there is a lot of information on here, and I will just remind people that the information here is in our corporate deck slides, and you can look at it in more detail if you want. The important thing is, on the left, you are seeing changes in CSF biomarkers, including things like neurogranin, VAMP2, pTau181, and it is a very consistent effect in terms of lowering those things. They are not all statistically significant, but directionally it is very consistent. On the far right is the Aβ 42/40 ratio. That tends to go up, which is what you would want to see. This is after just three administrations of sabirnetug in a phase I study. These data, at least in my view, were surprisingly good. Obviously, we have taken these types of assays and incorporated them into our phase II ALTITUDE-AD study. On the right-hand side, you can see the plasma biomarkers, which generally move the same direction. As probably many of you know, plasma biomarkers in Alzheimer's disease has just been an exploding topic for the field, and we've continued to look at those, obviously, in our phase II ALTITUDE-AD study. These were all from just our phase I study. If you could go to the next slide. The last thing to think about is that we are an IgG2 with the other amyloid-related antibodies being an IgG1. IgG2s have less of what's called effector function than IgG1s that conceivably could provide you with better safety. Again, in our phase I study, those are small studies, but the safety appeared to be quite good. We did have five cases of ARIA-E, or about 10% of the patients. Importantly, only one of those was symptomatic, and that person's symptoms were very subtle. In fact, they were more subjective. You really couldn't pick up anything on exam, and they resolved as we held the drug, and the ARIA-E went away. Being an IgG2 we think has the potential for improved safety compared to the other monoclonal antibodies that have been approved or are being studied. If you want to go to the next slide. Let's talk a little bit then about the iADRS as our primary endpoint. Some of you may be more or less familiar with the iADRS as an endpoint. The CDR Sum of Boxes is the other scale that's used commonly in Alzheimer's trials as a primary endpoint. We have it as a secondary endpoint. If you just want to go ahead and go to the next slide. Let's talk a little bit more about the iADRS scale and the CDR Sum of Boxes, just to compare and contrast a bit. Both scales conceptually are similar in that they combine cognitive items and functional items, with the functional items being activities of daily living, that sort of thing. There are more items in the iADRS than the CDR Sum of Boxes, but still conceptually, it's a composite scale that combines the two domains. There are some technical differences in how the scales are administered. In the iADRS, the cognitive measures are strictly performance-based. In the CDR, it's performance-based, but it's also based on a structured interview and also rater judgment. It actually takes a minimum of six hours of training to be a CDR rater, and there's a certain amount of subjectivity based on people's experience that goes into the rating. There's a bit of difference in how they're done. For the functional measures, that's a structured interview with the study partner for the iADRS, and it's what's called a semi-structured interview with the study partner, plus this added rater judgment piece for the CDR Sum of Boxes. The net result of some of these differences, I think, is that if you look at the signal-to-noise ratio for the iADRS, it's better than the signal-to-noise ratio for the CDR Sum of Boxes. There aren't a lot of studies that have both the iADRS and the CDR Sum of Boxes in them to compare head-to-head. The EXPEDITION studies, which looked at a drug called solanezumab, actually contained both of the scales, and so you can compare them directly. In the EXPEDITION study, the effect size was much greater for the iADRS. It was 0.193 compared to the CDR Sum of Boxes, which was 0.006. For the EXPEDITION2 study, the effect size was about twice that of the CDR Sum of Boxes. In EXPEDITION3, it was higher, but not by as much, for reasons which aren't clear. Very consistently, you see a higher effect size for the iADRS when you can compare it head-to-head with the CDR Sum of Boxes. Finally, the last line there is looking at donanemab phase II studies. I think this is a good illustration actually, that in the phase II study of donanemab that had 245 people, the iADRS did reach statistical significance at 0.04, but the CDR Sum of Boxes did not at 0.14. When they went on to phase III with much larger studies, both of those were statistically significant. It's like a lot of things, if you're underpowered, you just need more patients. I think it's a good illustration of the fact that you can be positive on the iADRS and negative on the CDR Sum of Boxes. We just feel that overall, the iADRS is a more sensitive scale and accurate scale, and that's why we chose it as our primary. Again, the CDR Sum of Boxes is one of our key secondary outcomes. If you want to go to the next slide. One of the things that we did that was really novel at the time in the ALTITUDE-AD study was we used a blood test, pTau217, to screen people for the study. In this slide, on the left-hand side is data from our phase I study. On the right-hand side is the data from our phase II ALTITUDE-AD study. What you can see is that the primary reason for screen failures in our phase I study, which did not use this pTau217 blood test screener, was amyloid PET scans. If you look at ALTITUDE-AD, the largest reason for screen failures was the blood test, the pTau217. The overall screen failure rate for both the phase I and the phase II is about the same. The question is, why do you screen fail? I think everybody agrees that you're much better off screen failing from a blood test than to get all the way to a PET scan and have a PET scan. At the time we did this was really very novel, and we think it actually worked very well. We also think it's something that could be used in clinical practice. In other words, screen with a blood test and then confirm if you think that's necessary with either a PET scan or spinal fluid. It cuts down considerably the number of PET scans or spinal fluids that you need to obtain. If you want to go to the next slide. This is a graph of our enrollment for the study, which was very rapid. We enrolled the study in 10 months. That was well beyond anybody's expectations at the time. Part of the reason why we think that was the case was that people, the sites and the site PIs have told us that they really like the study design, and they like the drug. They like this pTau217 screening because, again, if you're going to screen fail, it's a lot better to do it with a blood test than with a PET scan. The other thing I might just point out on this graph is that if you notice September, October 2024, the rate was a little faster before that, maybe not quite as fast after that, but that's because we were sort of transitioning to our European and U.K. sites, and that always takes a little bit of time. If we would've just let the U.S. keep running with this, we probably would've even enrolled it a little bit faster. We were very pleased with this, and what we've heard from the sites is they were very pleased with the protocol too. If you want to go to the next slide. Here's the net result of this. Again, we were doing some very novel things. At the end of the day, what we want to see is how we compare with Clarity AD. The Clarity AD study of lecanemab has a patient population most similar to ours. For those of you who are familiar with the TRAILBLAZER-ALZ studies of donanemab, they had a requirement for tau, which we did not have, Clarity AD did not have. They have a little bit different patient population. Again, Clarity AD did not have the pTau217 screening because when they designed the study, it wasn't available. We did have that pTau217 screening. But the net result when you look at the baseline data for ALTITUDE-AD and Clarity AD is they are very similar. In other words, we were able to implement this, at the time, novel screening technique with pTau217, but we ended up with essentially exactly the same patient population as was obtained with the Clarity AD study where they did not have the screening with pTau217. We feel like we really accomplished our screening process overall in a way that was very, very good. But we did it in a way that was much easier for patients in the site. Again, we're very pleased with these results. If you want to go to the next slide. Let me talk then in a little bit more detail about what we are looking at in the study. I talked already about our primary outcome variable for clinical endpoints is the iADRS scale. Again, the CDR Sum of Boxes, of course, will be a key secondary. The ADCS-iADL and the ADAS-Cog that you see there are actually components that make up the iADRS. We'll look at those things individually. Of course, as I mentioned and as you heard, we did see some plaque reduction in our phase I study, and so we'll look at that in ALTITUDE-AD. But whether plaque reduction is really important for efficacy when your drug targets oligomers rather than plaque, it's not really clear whether that's necessary. From a safety standpoint, again, we have an IgG2 rather than an IgG1. We think that has the potential for better safety. Obviously, we're going to look very carefully at our ARIA-E rates, ARIA-H rates, and just adverse events in general as you would in any study. Infusion-related reactions, I think could be an important thing when we do see our data from ALTITUDE-AD, because again, potentially with an IgG2, this could be less of an issue than it is with some of the other antibodies being studied currently. Finally, for biomarkers, again, we were very pleased to see these change in our phase I study. We will be looking at these again in the phase II study. One of these, which is particularly, I think, important for us, is neurogranin, because it is a synaptic biomarker. It is a postsynaptic biomarker. These oligomers are toxic to synapses. We are looking at the usual suspects in terms of CSF biomarkers. The neurogranin is something that we want to demonstrate that and expand on our phase I results and show an effect in our much larger phase II study. For plasma biomarkers, GFAP is an interesting one. It actually reflects astrocytes, which are a different type of nerve cell, and it is sort of an inflammatory marker. We saw, again, some phase I data that looked very promising for GFAP. We will be excited to see the results from our much larger phase II. Of course, we are going to look at pTau217. We used it as a screener, but then we will also be looking at that as a measure of at least biochemical efficacy. If you want to go to the next slide. These are the takeaway messages. I am not going to read all these to you. We just talked about those. I think the thing to keep in mind is that we had, as you heard, we had some very good phase I results, which led to a phase II study, 542 people, so not a small phase II, that enrolled very, very quickly, very smoothly. We have a high percentage of patients who elect to roll over into the open label extension. They like being in the study, they like being on the drug, and certainly the sites have told us the same thing. We are just very much looking forward to seeing the results from ALTITUDE-AD when those unblinded results are available. Thank you very much. With that, I will turn it over to Paul. Thank you, Eric. In this last segment, I would like to describe our new drug discovery effort, developing next-generation antibodies for the treatment of Alzheimer's disease. As we all know, there are inherent challenges with therapeutic monoclonal antibodies for the treatment of neurodegenerative diseases, including Alzheimer's disease. These antibodies have a very poor penetration across the blood-brain barrier, with only about 0.1% - 0.2% of dosed antibody actually reaching the target in the brain. One way to get around this, of course, is to give higher doses of antibody. Companies have increased the dose, and by increasing the dose, you get more antibody that trickles across the blood-brain barrier to get to the brain. Another way is to engineer or develop antibodies that have longer half-lives. If the antibody is around longer in the system, then of course, there's more antibody that eventually gets into the brain. One issue with increasing the amount of drug that you give is that there are safety and tolerability concerns. In the Aβ antibody space, ARIA-E and ARIA-H are the main concerns that we see when we increase drug levels. What happens is we end up with a dose tolerability safety limit so that we can only give the patient so much drug before we start to see an increase in these safety signals. Another concern with monoclonal antibodies is that they don't distribute throughout the brain equally. In areas close to large blood vessels and to the ventricles of the brain, we see higher concentrations of antibody. In other brain regions that are called the deep brain regions that are more isolated, we see certainly lower concentrations of antibody, this potentially causing a differential treatment outcome in these brain regions. One way that companies have tried to get more drug into the brain is the use of the receptor-mediated transcytosis system. This is a system that the brain uses to selectively shuttle large molecules of interest into the brain, molecules like insulin and transferrin and other things that the brain needs that are normally kept out by the blood-brain barrier. A number of decades ago, researchers realized that if you raise antibodies to these receptors on the blood-brain barrier, that you can use these receptors to carry large molecules, such as antibodies, into the brain. The most advanced of these is the transferrin receptor. As we've seen, you can use antibodies or antibodies fragments, attach them to large molecules of interest, and use these to shuttle into the brain. This greatly increases the amount of drug that you get to the brain and associated efficacy, while at the same time reducing side effects, since you can reduce the drug that you're delivering to the patients. What I'd like to describe to you is our effort to develop bispecific antibodies for the treatment of Alzheimer's disease. When thinking about developing molecules, we started from scratch. It was a whiteboard exercise for us. We thought about this as two major pieces. On the one side, the business end of the molecule is the cargo. This is the part that's actually binding to the Aβ species of interest. On the other end, linked by a linker, is the transporter, and this is the portion of the molecule that's binding to the transferrin receptor to facilitate the entry of the molecule into the brain. Both sides of these molecules are very important. The cargo determines what species of Aβ you bind to. As we know, there are antibodies that target large portions of Aβ plaque protofibrils, fibrils, some target monomer, and our company is unique in developing antibodies that target Aβ oligomers. This part of the molecule determines the efficacy. The other end of the molecule, the transporter part, as I mentioned before, can be based on a number of different receptors that are at the blood-brain barrier. CD98, insulin receptor, transferrin receptor are just a few. This part determines the PK of a molecule, how long the molecule is around in the blood and in the brain, and also has associated safety risks that need to be kept in mind. If we focus in and look at these a little bit more carefully, what sets us apart in our view of developing these bispecific antibodies is we believe that Aβ oligomers are the toxic species in Alzheimer's disease. We've selected two antibodies from our portfolio of antibodies to take into this program. ACU193, or sabirnetug, which is currently in phase II clinical studies that read out later this year, and a novel antibody called ACU234, which we developed and has new and unique properties. At the other end of the molecule is the transporter. This is the portion of the molecule that helps facilitate entry into the brain. We looked at a number of different companies that had different transporters and different platforms and decided to partner with JCR. JCR is the first company to have an anti-transferrin receptor molecule approved in the world for the treatment of a rare brain disease, and they have a platform of transferrin single-chain VHH transporters that we could use to screen for molecules that work best with our cargo. This is the approach that we took. We really were agnostic in how we viewed molecules of interest. We kept in mind transferrin receptor affinity, the architecture of the molecule, the valency of the molecule, and selectivity for Aβ oligomers. But we did not go in predetermining that any one of these should be of a certain form. We looked at a range of transferrin receptor affinity, a variety of architectures, both monovalent and bivalent, and a range of Aβ binders. This slide summarizes about a year and a half worth of drug discovery work, and the leads that emanated from this work, ACU301 and ACU401. As you can see, these are both bivalent antibodies with a relatively high affinity to the transferrin receptor in the single-digit nanomolar range. These antibodies we took through a variety of in vitro and in vivo assays to characterize to end up selecting these two molecules. You'll notice that these antibodies are at odds with a number of dogmas that are in this field, one being that bivalent antibodies bind too strongly and don't release into the brain, that antibodies with high affinity also don't release, and that using a linker will result in clipping of the transporter off of the antibody. In our studies, we've noticed that none of these events happen, that we see very good penetration of the blood-brain barrier and into the brain after subQ dosing, and that antibodies are released into the parenchyma of the brain and are able to engage Aβ species of interest. As you can see at the bottom, we also look to make sure that the antibody still bound Aβ in Alzheimer's brain. So this is a histological study that we did showing that both ACU301 and ACU401 are still able to bind the Aβ species of interest, and that this wasn't altered in the construction of these bispecific molecules. This is just one slide showing some of the in vivo work we did in mice. As you can see, after subQ dosing ACU401, you can see that there's rapid uptake, the red line, into the blood after subQ dosing. You can see that it becomes comparable to the IV dose shown in blue, and that both of these have a good half-life out to a week. When we looked in brain, we see an expected difference in the peaks that we see in the brain. The IV, of course, peaking quicker because it's available immediately to get into the brain. The subQ dose, you can see, kind of lags a little bit behind the IV dose. Both have a high Cmax, both have a very nice t1/2, half-life, and suggest that these antibodies are worth taking forward into additional studies. Our next step was to look at these antibodies and how they perform in primates, so we used cynomolgus monkeys for these studies. As you can see, we designed a two-phase study. In the first phase, animals were dosed subQ with 5 mgs per kg of antibody, and they were dosed with either ACU401 or the monoclonal antibody ACU234. The little blood samples that you see in red were collected over time, over a 35-day period of time. We also looked at hematology endpoints in a sample that was collected pre-dose, and then 24 hours after dosing. Once the blood collections were completed at day 35, all of these animals then rolled into the next phase of the study. Animals were then dosed IV with 2 mgs per kg of antibody, the same antibody they received before. Half of the animals, three animals, were euthanized three hours after dosing, and then the remaining three, 24 hours after dosing. At the point of euthanasia, we collected the brain and the CSF, as well as the blood samples that you can see in the slide. When we look at the PK, you can see that both ACU401 and ACU234 are rapidly taken up after subQ dosing. On the left, you can see kind of a blow-up of the first 24 hours. You can see that very rapidly, within eight to 12 hours, the antibody is getting close to a Cmax, and then it's maintained thereafter for a period of time. On the right, you can see where we've tracked the antibody levels out to two weeks. What you can see is that after subQ dosing ACU401 at the end of two weeks still has a very good half-life and suggests that as we go forward into clinical studies, we'll have optionality on how we want to dose patients with this drug. The other thing worth pointing out is because these antibodies are getting in so rapidly, taken up so rapidly, that there's less of a concern about half-life with these antibodies as we were with the monoclonals that get in poorly because these antibodies seem to be getting in so well. We're less concerned about half-life. When we looked at three regions of the brain, the prefrontal cortex, the putamen, and the hippocampus, we noticed that the trends with ACU401 were very similar in all three brain regions. As you can see in the prefrontal cortex, within three hours, you see a pretty remarkable uptake of drug into the brain, about 22-fold higher than what you see with ACU234. At 24 hours, this increases further to a 40-fold difference between ACU401 and ACU234. This is a pattern, again, that we see in all brain regions, including the putamen, which is one of those deep brain regions that's very hard to get drug to. You'll notice in the hippocampus that the ACU234 levels were higher than expected and higher than what other companies have reported after dosing a monoclonal antibody. They, of course, see similar differences in all brain regions. We're thinking that this elevated level in the hippocampus is likely due to either a contamination or sampling error. We're repeating animal studies right now in monkeys, and we'll have a chance to look to see if in fact this was some sort of a sampling error. We also looked at CSF levels in this study. I'm not showing that data. What we saw was that if you look at drug levels in the CSF, there's no difference between ACU234 and ACU401. Again, highlighting that the transferrin receptor system is increasing drug levels in the brain, but not in the CSF. As I mentioned, we also looked at a panel of hematology endpoints in this study 24 hours after the subQ dosing. We looked at red blood cells, hemoglobin, hematocrit, and reticulocyte count. You can see that either dosing with the monoclonal antibody ACU234 or with our bispecific antibody, that there was no difference observed in any of these endpoints. This certainly is a positive indicator and suggests that there might be a low risk for anemia in patients. To summarize the key takeaways from this study, we've shown that when we dose with ACU401, we see a robust uptake in the brain, with levels as high as 40 times higher than a conventional monoclonal antibody. Looking at a panel of hematology endpoints, we see that there's a relatively low risk of anemia based on the markers that we looked at. After subQ dosing, we see that the antibody is rapidly taken up into the plasma and that there's a very nice PK profile that's amenable to a variety of dosing options going into the clinic. When we started this program, we had a lead candidate profile in mind. What we saw is that the antibody gets in much better than we had hoped for. We were hoping for around a 20-fold increase in antibody levels with our bispecific antibodies. As you can see, we've got at least 40-fold increase in antibody levels. We wanted to make sure that when we combine the transferrin receptor with our antibody, that it wasn't compromising binding to the oligomer, and we see that we've maintained high Aβ oligomer specificity versus monomer. We also noticed that we've maintained the ability to bind the transferrin receptor at high affinity in the low nanomolar range. This is important because we can dose at much lower levels with this high-affinity binding. We also showed that the high-affinity binding doesn't mean that the antibody is stuck to the vessel wall, that it actually does release into the parenchyma of the brain. We saw no signals that would suggest that there are going to be issues with anemia. We also looked at the stability of these antibodies and found that these antibodies have good stability and should be able to be maintained in an auto-injector at 4 degrees for an extended period of time. Finally, we saw that there was a very good uptake of drug after subQ dosing, and that this should allow us to move into the clinic with a subQ product. What are next steps? Next steps are, of course, we're doing a second monkey study. This will help us determine the dose and the treatment paradigm that we take into the clinic. We're doing additional IND-enabling studies, including supportive CMC work, safety tox work, and an in vivo tox study. Then finally, we're developing bioanalytical assays that we'll need for the clinic, PK, ADA, and other assays. Of course, throughout this process, we've been interacting with the agency for their guidance. Our next goal is to file an IND next summer, mid-2027. I'm going to stop here and hand it back over to the operator for questions. Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile our Q&A roster. Our first question is going to come from the line of Pete Stavropoulos with Cantor. Your line is open. Please go ahead. Hi, Dan and Jim. Thanks for hosting the event, and thank you for taking our questions. First question, when you look at the baseline characteristics of those enrolled in ALTITUDE-AD, how do they sort of compare to the enrolled in the registrational studies for lecanemab and donanemab? When you look at the baseline CDR Sum of Boxes for ALTITUDE-AD, it's 2.91, Clarity AD, 3.17. I believe for donanemab it was 3.9. So sort of help us understand if these are similar populations or there's some type of meaningful difference on CDR Sum of Boxes. Yeah. Well, thanks for that question. This is Eric. I am happy to take that one. If you look at, we will just start off with the CDR Sum of Boxes. There is a numeric difference there, a small numeric difference. But especially, and I know the print is a little small, but if you compare it to the standard deviation, these are not head-to-head comparisons, obviously, so you have to be careful. But those differences certainly are not clinically meaningful, and I do not think statistically they are significant either. You get a certain amount of variability in these studies just due to patient or study variability from one study to the next. If you look at the Mini-Mental score, that actually is exactly the same in both studies. If you look across the board at all the baseline characteristics, they are very similar. To my mind, I do not see anything in there that is a meaningful difference in the two patient populations. For donanemab, as I mentioned, those patient populations are a little different, and I think that is because they had this requirement for a certain amount of tau positivity. If you look across all the various measures, the donanemab studies, the patients are a little bit more advanced or a little bit worse. That is a little bit different patient population. But for us, for ALTITUDE-AD and for Clarity AD, that is about as close as you are ever going to see in terms of baseline characteristics in two different studies, I would say. Thank you for that. As you noted during the call, there has been a lot of progress in the Alzheimer's space in terms of biomarkers, some of which show changes that start to appear far in advance of symptoms, as well as some of the underlying pathology, like various tau species. How do these updates, including newer biomarker updates, inform your approach and assumptions about disease and clinical studies? Are there any that stand out to you, especially the newer biomarkers as you look at ALTITUDE-AD or incorporate into the phase III, including biomarkers not listed in your presentation, like perhaps pTau243? Well- Yeah. Go ahead, Jim. No, another great question. The field is moving so quickly. It's a good problem to have, obviously, but especially pTau243 is one of the ones that is newer and seems to be quite promising. The first thing that we'll do, actually, of course, is look at our ALTITUDE-AD results and look at the biomarkers that we do have in there. Just for instance, when we designed the ALTITUDE-AD study, there weren't any p-taus that were FDA approved at that point, or there weren't any blood-based diagnostic biomarkers approved at that point. Now we have four of them. One of the things we'll go back and look at when we get our ALTITUDE-AD data is when we do design our phase III, should we tweak the screening procedure that worked very well previously with the pTau217 assay that we used? Now that there's four different assays that are FDA approved, we'll need to rethink that for what we do in phase III. Anyway, there's a lot happening in the field, and it's a good problem to have, in a way. We're going to look at this very carefully. I don't know, Jim, did you want to add something to that? Yeah, Eric. Just to layer a couple of additional thoughts on. I think first, taking a step back, what we see, and I think what a lot of people see, is that there's just been a continuous development in both the precision of especially fluid-based biomarker analysis, but also the diversity. We certainly know that there are additional markers that are being evaluated now, and I think that's only going to continue. You mentioned pTau243 is one of them. I think you'll see that as time goes forward, we're going to have a better ability to both understand where individuals are in their journey in this progressive disorder. I think that only helps in diagnosis, but I think it'll also help in clinical trials. When you sort of zoom into the oligomer hypothesis, as we talked about today, oligomers are an early element of disease. They start showing up fairly early during the time course of disease, well before clinical symptoms have appeared. As we showed earlier, there's a ton of evidence that there's physical interaction with synaptic circuitry. Yeah, it's entirely feasible that there are measurable things happening in the brain that are occurring very early in disease. I think future work will be to try to understand, does that mean that there is pathophysiology triggered by oligomers that could be measured early on? I think there will be multiple ways that biomarkers are going to be utilized moving forward. It's just really great to see both the expansion of markers like pTau217. As Eric said, there are now four approved tests out there, and that's only going to help, both in terms of trials, but probably more importantly for clinical practice. But then also the diversity of the markers coming forward, being able to understand in more detail what is going on and hopefully how individual treatments are benefiting patients. I think all that is to come. We have done a fair amount of work analyzing the data from the INTERCEPT study. So there are individual publications out there kind of laying out the data that we talked about today in much more detail. But we certainly think about this in multiple levels. And really we want to look beyond the proximal amyloid and tau and start incorporating some downstream biomarkers, which we think are going to be really interesting and important for assessing synaptic health and synaptic function. Great. Thank you. Just one last question on EBD. Let us say that ALTITUDE-AD reads out positively. Will that impact your decision to sort of bring sabirnetug versus ACU234 forward? Positive data would just clinically de-risk the binding properties of sabirnetug. Why not stick to sabirnetug rather than introduce risk? So Jim, do you want to grab that one? Yeah. Absolutely. I think the way we think about this is, as Paul very well said in his presentation, we have Been fairly broad in our thinking around what is the best set of properties to have in a molecule. We think that ACU401 and ACU301, having both of them gives us optionality. Each one offers different opportunities. It is important to note that ACU401 is, as Paul described, coming from ACU234, and although ACU234 is a distinct molecule from sabirnetug, they are quite similar, so we have not made major changes. In fact, we still like the selectivity and monomer affinity that we have with ACU234, and it actually even offers some opportunities different than what we get with sabirnetug. So we think both are really robust candidates, and we would be comfortable taking either of them forward into the clinic. The work that Paul's team is doing now is going to lay out what has got the overall best set of properties to take forward into phase I. I think also the good thing is that what I would love to see is that both molecules actually do well in that analysis. Then we have a tough decision on which one to take forward, and we will still have the other molecule sitting in late pre-clinical phase that we could possibly bring forward in the future. Again, thinking back to what I was just saying a couple of minutes ago, maybe there are different opportunities in either slightly different populations of patients that are identified by biomarkers or in earlier phase of disease. So we really want to maintain optionality, and so we are interested in profiling both molecules. Thank you very much for taking our questions. Thank you. One moment for our next question. Our next question will come from the line of Paul Matteis with Stifel. Your line is open. Please go ahead. Hi, this is Emily on for Paul. Just a couple quick questions for us. On the EBD profile, we were wondering what is the TPP here? What dosing frequency would you like to see? As well as maybe how quickly do you think you can get data from in-patients following that mid-2027 IND filing? Thank you. We are open to all of this at the moment. We are currently running another primate study, and in that study we are looking at different doses and different dosing frequencies, and we are hoping that the output of that study will guide us in how we set up and run our phase I SAD/MAD study. Certainly weekly, twice monthly are all under consideration at the moment, and we have not made any decisions about the dosing frequency. We will let the data guide us in how we do that. In regards to the design of our SAD/MAD study, certainly something that we are discussing right now, thinking about the best option for this molecule, and based on data that we get from the ALTITUDE-AD study, will certainly directly impact how we think about the studies that we run, the biomarkers we use, the endpoints of interest. Yeah, all of that is still under consideration, and as stated, by the middle of next year, we will be ready to move forward. Great. Thank you. Thank you, and one moment for our next question. Our next question comes from the line of Jason Zemansky with Bank of America. Your line is open. Please go ahead. Good morning. Congrats on the great progress, and thanks for taking our questions. Maybe to start, it is probably fair to say a key determinant of success and ALTITUDE-AD will be the placebo arm. Given the use of the p-tau screening, the relatively high proportion of MCI patients, and some of the similarities you have highlighted with Clarity AD, how should investors think about placebo decline? Is it going to be broadly comparable to prior amyloid studies, or are there characteristics that could make it meaningfully different? Well, yeah, maybe I can address that. You are absolutely right. First of all, the patient populations in Clarity AD and ALTITUDE-AD are quite similar, and there are more patients who would be classified as MCI than have mild dementia. It's roughly 80% have MCI. As the disease progresses, actually, the rate of decline, and we'll say in a placebo group, actually gets greater. As you go to earlier stages, you might see a little bit smaller rate of decline. But as it turns out, for your drug to have efficacy, it appears to be that the sweet spot is this patient population that's now being called early AD, which is either MCI or mild dementia due to Alzheimer's pathology. The fact that lecanemab showed a signal in a patient population that is very similar to the patient population we have in ALTITUDE-AD, I think bodes well for us. That seems to be the sweet spot. Even though the placebo decline may not be as great, your drug efficacy ends up being better in that earlier population. You have to be very careful about comparing studies with different patient populations because you will see different rates of decline in the placebo group. But at the end of the day, what you really want to show is the difference between active treatment and placebo. In other words, the efficacy. We feel good about the patient population that we've identified. I would expect the placebo decline will be similar to what was seen in Clarity AD. We obviously don't know that at this point, but that would be my expectation. Yeah, makes sense. Then maybe as a quick follow-up for Jim and Dan, there's been a lot of focus on the potential for differentiation through efficacy. But based on your market research and physician work, do you have a sense of how much commercial value could be specifically created through safety differentiation, particularly around ARIA and, I guess, overall tolerability? Thanks, Jason. We think there's ample opportunities to differentiate on both efficacy and safety, and a clinically meaningful safety benefit we think is commercially pertinent. That is an important underpinning of the value proposition of sabirnetug and really why we think the risk-benefit profile in totality and presumably across maybe a more diverse set of patients, including E4 carriers and homozygotes, is an important aspect of the overall, the totality of the opportunity for sabirnetug to differentiate. Great. Thanks. One moment for our next question. Our next question is going to come from the line of Geoff Meacham with Citi. Your line is open. Please go ahead. Hey, guys. Thanks for hosting this event. Super helpful. I have a couple questions. The first, maybe it is just the oligomer hypothesis. I am asking you, what clinical result from ALTITUDE-AD do you think would most strongly validate the attribution of the oligomers and the effect for sabirnetug? The second question is, you guys have a slide on the FDA approvals of the blood-based diagnostics market. Just want to get some perspective of when you think these should really get some momentum commercially from neurologists. Does that help you, hurt you, neutral to you? Just wanted to put that in context. Thank you. Sure. Maybe I will lead out and then invite Jim or others to come in. I think in terms of the clinical validation of the oligomer hypothesis, I know personally I am looking for a pronounced efficacy signal, and that is on a clinical measure supported by downstream biomarkers. We have talked a lot about the biomarkers, and I think some of the biomarkers that are on mechanism for an oligomer-directed approach are the ones that are going to underpin that validation. That certainly would be the most robust validation and clinical evidence in support of the oligomer hypothesis. In terms of the diagnostics, that market is, as I think Jim mentioned, we have got four tests approved in the last 15 months. It again is in the early phase of commercial deployment. But given the demographics in the population, we see that minimally invasive, relatively low-cost measure could really inform the overall population that is experiencing the early onset of amyloid pathology, presumably potentially oligomer-related pathology. That will open up, I think, the field more broadly and necessitate access to better treatment options. Yeah. I think Dan. Thank you very much. Said it well, but I would just echo. The oligomer hypothesis, the target's been validated. Amyloid biology has been validated as meaningful for Alzheimer's disease. What we're really at this point, and we've got the data from the ALTITUDE-AD study that we've been talking about, so there's biomarker evidence that there are things physiologically happening. Of course, we can show that sabirnetug is recognizing aberrant protein from the brains of Alzheimer's patients, both from our own work with INTERCEPT, but then also from some of the collaboration work I showed you earlier. It really does come down to does that hypothesis then result in a meaningful effect on cognitive function? I think for us, that's what's exciting about ALTITUDE-AD. We're really going to be answering that key question for ourselves, but also for the field in general. I think by teeing up a lot of biomarkers in addition to the study, we can address the next level question about which of the available biomarkers best correlate with any of those signals that we'll see. Those are the kind of things that we're really going to be looking at. None of that should be surprising to anybody, but obviously the cognitive readouts are the most important thing. For us, really trying to understand the relationship of some of the individual markers to any potential cognitive signals is really going to be the exciting part. Yeah. And maybe just one quick thing about the uptake of the diagnostics. In our discussions with KOLs, it is really coming along. In fact, the discussion is not whether or not you want to use one of these blood-based biomarkers, but whether you really need to do a PET scan or spinal fluid afterwards to confirm amyloid pathology. There are some KOLs out there that say that the blood test may just be good enough. That is not necessarily our view, but you can find that opinion. But I think that is a good indication of how rapidly I would expect the use of these blood-based biomarkers to increase. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Tom Shrader with USB/BTIG. Your line is open. Please go ahead. Thank you for taking the questions. Terrific event. Very related questions, but Eric, we are all going to be looking for comparative signals. Is the most likely best comparator CDR Sum of Boxes versus Clarity AD? On the oligomer line of questioning, because you are maybe hitting the toxic particle directly rather than through equilibrium, I think one of the differentiators could be speed of action. Is there a way you might likely capture that in this first readout? Then I have a follow-up for Paul. Yeah. As far as the CDR Sum of Boxes, as I mentioned before, there aren't a lot of studies that have the iADRS and the CDR Sum of Boxes. Right. But if you want to compare to Clarity AD, you pretty much are going to have to use the CDR Sum of Boxes. Again, you always have to be a little careful about making comparisons between studies because they're not head-to-head comparisons, really. We'll see what we get, and that'll be the scale that can translate best, I would say. Hopefully that answers your question. I don't know if Jim or Dan want to take your second one. Yeah, just to comment on the second question. I think it's a really good point, Tom. Based on the biology, you might expect that if these toxic oligomers are really disrupting a lot of ongoing synaptic function, you might be able to see a rapid response. That's certainly something that we'll be looking for. Yeah, at this point, I don't think there's much more to say beyond that. Other than I will point out, and if you go back to the slides that we were showing earlier, and using Eric's very appropriate caveat to be careful about comparing across studies. But when we look at the effects on various biomarkers across multiple antibodies, I think one thing you can see is, that we certainly noted, is the rate of effect is quite rapid in the sabirnetug INTERCEPT data. That is at least consistent with the idea that you've made that we might be able to see rapid effects. That's certainly something we'll be looking for in the much more complete and the much larger data set from ALTITUDE-AD. And a follow-up for Paul, I am not sure what you can say here. Do you understand or have any glimmer of sense of why your results are so different than the other players who have detailed their results? I guess you are obviously very close to the field. Are other people that are There is a huge number of programs now. Are other people finding what you are finding, that high affinity TfR binding bivalent does make sense? Just any sense of, because what you are finding is so different than what we have been reading about for three or four years. I am curious if you give us any help. Right. So again, we went into this with eyes wide open, not relying too heavily on the dogma. Again, we went through a library of molecules and let the data drive the selection of leads and progress from there. I think the early work was done, Genentech and Denali are similar platforms. Both came from Roche, Genentech. In their hands, monovalent looked better than bivalent. Antibodies that had a lower affinity seemed to perform better than high affinity. I think from there, everybody assumed that that was how all molecules worked. I know that at the AD/PD meeting, and again at AAIC this year, there are a number of other labs that are showing that bivalent antibodies work as good as monovalent, maybe even a little bit better. Companies now are really starting to dig into exactly how high affinity does a molecule need to be. It seems to be molecule dependent rather than all molecules need to be at a certain affinity to work. Just to be fair, in our hands, we have seen, we did have a molecule that had very high affinity in the mid-picomolar range, and that antibody we showed did not release from the receptor from the blood-brain barrier wall to get into the brain. We were able to confirm that if the affinity is too high, that the antibody does not release to get to target. In the low nanomolar range where our leads are, they do seem to release, get into the parenchyma of the brain and engage Aβ as we would like. I think it is still early days to- Thanks for the detail. Yep. Yep. Thank you. One moment for our next question. Our next question comes from the line of Dev Prasad with Lucid Capital Markets. Your line is open. Please go ahead. Hi. Thank you for taking our question. I have a couple of questions. One is the slide timeframe that phase III is partner enabled. Is this a base case rather than self-funding? Another is on sub-Q. How are you thinking about the role of sub-Q in late-stage development? Then, I have one question on EBD. Thanks, Dev. I will address the partner question if I understood it correctly. We think that on a successful phase II result, there will be tremendous interest and desire to expedite the development of sabirnetug, and doing that with a partner makes a tremendous amount of sense. Precisely how that comes about, I think, is to be determined. I think in terms of the scale of the phase III and ultimately moving all the way to BLA is an attractive opportunity for Acumen to enter into a partnership. I think the second question was on the sub-Q, and I think as it stands, we would envision the sub-Q formulation for sabirnetug playing into a phase III strategy and have not specified precisely how that will be incorporated. There is prior precedent, I think, if you look at Leqembi, their first use of subcutaneous Leqembi was in a maintenance mode as part of the open label extension in their Clarity AD study. There are a couple things for us to look at, a couple things that we are thinking about, but we see a partnership for phase III as an attractive way to unlock more value for stakeholders interested in seeing sabirnetug move forward. Great. Thank you. On EBD program, just wondering, could the lower systemic dose enabled by the brain delivery, can it itself reduce ARIA or other systemic liability, independent of the oligomer selectivity? That remains to be seen, of course, but in theory, you would imagine that since you're giving less drug, you would see less ARIA. Anemia is another concern. This molecule, as we've seen thus far, no evidence of anemia. We believe it should have a better safety profile. Again, you're not going to know for certain until you go to the clinic and do those studies. But the optionality with the EBD program is if we have a molecule that's getting in 40 times better than a monoclonal antibody, you could either dose the same to get the same efficacy, so dose 40 times less than sabirnetug to get the same efficacy, or if there's an opportunity for more efficacy, you can dose more drug safely. It certainly gives you optionality in dosing and allows you to treat patients the way that you think best for efficacy. I think it's an interesting example where, as Paul was saying in his talk, obviously anything that you can do to increase your brain exposure relative to plasma exposure is going to be beneficial for a brain-targeting approach. As Paul and I have talked about a lot of times, it's not just the absolute amount that you're getting in, but because the transferrin receptors are scattered throughout the capillary bed network into the brain, you're also getting a much more broad distribution of antibody into the brain. But those are benefits for any brain-targeting large molecule. I think additionally, in the case of an Aβ-targeting molecule, because ARIA, as one of the key safety risks, is likely associated with CAA plaque that's actually found in the vasculature, if you're able to reduce the circulating level of antibody that you need to deliver the appropriate therapeutic amount to target, it would, in theory at least, have the benefit of lowering the absolute concentration that's seen at those CAA plaques. So you do get an additional benefit for this specific mechanism of action, even beyond just the general benefits of a TfR-targeted approach. Got it. Thank you. Thank you. I would like to hand the conference back over to Alex so she can read any web questions we may have. Awesome. Thank you, Michelle. We did have a few come in. One was, "Are you using AI to assist in analyzing the trial data more quickly for ALTITUDE-AD?" So I'll turn that over to, I think, Jim. Yeah, happy to take that one. That's a really interesting question. The short answer is we are, like I think everyone, we are trying to best understand how we can use AI tools for a lot of the things that we do. There's quite a bit of work going on inside of Acumen to sort of best understand how to use AI tools. I would say at this point, we are not directly intending to do that for primary analysis of the study. At this point, we've got our primary analysis locked in. I do expect that there will be, as we've been talking about today, quite a bit of what I would call secondary analysis. We've got a lot of endpoints, a lot of time points, and a couple of different concentrations of sabirnetug in the study, and so we will be doing a fair amount of analysis, and it may well be that AI tools could be useful in facilitating that process. I do believe that AI tools are pretty clearly going to be impacting the way we do what we do. It's just a matter of finding the best ways to apply that. Awesome. One other question that came in is regarding the OLE. The open-label extension, which was initiated in 2025, should we expect any OLE data in the readout? Just clarify that. Yeah. No, thanks for the question. We will not include OLE data in our top-line results, and the reason is because, obviously, some of those patients will have only rolled over into the OLE for a very short period of time, and there just wouldn't be enough data to really do it justice. Now, at some future time point, I think those OLE data will be very valuable. Even though obviously there's no placebo group, but we are discussing ways to address that. As time goes on, those OLE results will be quite valuable. But we're not going to include any of them in our top-line results from the placebo-controlled portion of ALTITUDE-AD. Great. All right. We have no more questions. I want to thank everyone for tuning in today. We very much appreciate your interest in the company, and we are always available for follow-up questions. I will turn it back over to Michelle to close out the call. This will now conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.