Acumen Pharmaceuticals, Inc. (ABOS) September 2026 Capital Markets Day Transcript

Good day and thank you for standing by. Welcome to the Acumen at 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 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 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 2 readout for our product candidate for the treatment of early Alzheimer's disease, Cvernitab. 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 10Q 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 A-beta oligomer therapies to treat Alzheimer's disease. Dr. Jim Doherty, our President and Chief Development Officer, who will explain Soberna Tug's mechanism of action and why we believe it could potentially differentiate from other disease-modifying therapies. Dr. Eric Seemers, our Chief Medical Officer, who will review our ongoing Phase II study investigating Cibernatug that reads out in the late 2026, and Dr. Paul Chagru, VP, Program Lead, and Head of Research, who will explain the latest developments in our Enhanced Brain Therapy, 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, and 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. And 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 in the setup for Acumen and the value proposition 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, Lakembi and Consumla, have recently achieved an annual sales run rate exceeding a billion dollars. Sales are projected to reach two billion dollars in 2028 and reach upwards of three to four billion dollars 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 RIS. 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, and 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 we'll 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. So 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 Lakembi for treatment induction is another way to establish convenience and growth within the marketplace. And then 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 that the combination strategies using essentially anti-A beta approaches as a cornerstone of treatment are expected to be the future state of care. So it's an exciting time in the field and one that is poised for continued growth. So 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 A-beta 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's a path towards differentiation for distinctly within our pipeline. So 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 the disease. So 2026 is a pivotal year for our innovative anti-A-beta oligomer pipeline. We have Soberna Tug. 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 A-beta hypothesis and usher in a new mechanism within the amyloid space. We also have our EBD program, which is enhanced brain delivery. We've reported positive non-clinical data earlier this year and have two candidates that we're progressing towards an IND in mid-2027. So, 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-A beta oligomer approach is differentiated within the clinically validated amyloid space, an exciting possibility to differentiate on a benefit-risk basis. basis. So, Bernatug has already produced compelling phase one results in Alzheimer's patients, increasing the probability of success for it and future anti-A beta-oligomer therapies. Our Altitude AD phase two 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 two results, expedite the development of Sobernatug with a partner and seek to advance an EBD candidate through a clinical value inflection point quite rapidly. And with that, I'll 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 Soberna-Tug represents a differentiated opportunity for anti-A-beta disease-modifying therapies for the treatment of Alzheimer's disease. I'm going to touch on three related topics today. First, the soluble oligomar hypothesis. Soberna-Cup-Tug is the first monoclonal antibody targeting a beta therapy to rigorously test the oligomar 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 Soberna-Tug on clinical measures and activities of daily living, as well as safety and a variety of biomarkers. I'll talk about IgG2. Like many other potential therapeutic agents, Sabernotug 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, and 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. So, thinking about Sobernatug, how does Sobernatug differentiate from other approved antibody-based anti-A-beta disease-modifying therapies? Well, like other approved anti-A-beta disease-modifying therapies, Sobernatug is an amyloid protein-targeting monoclonal antibody. However, unlike the approved anti-A-beta DMTs, Sobernatug targets soluble A-beta oligomers. potential 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 so with the potential for less interaction with caa plaques that could adjust the risk for safety effects like aria also unlike approved uh anti-a beta DMT's, Ciburnatug, 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. So, 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 lacanumab and then more recently in dananumab. 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. What you can see on the cartoon is that as you get larger and larger components of A-beta, 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 amyloin protein. Next slide, please. So, 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. And I'm not going to go through all of the elements here on the slide today, but really what I'm hoping people can see is that, A, there's 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, this has led to the oligomer hypothesis, a refinement of the original amyloid hypothesis that posits that these small soluble clusters of A-beta molecules called oligomers are the main cause of neuronal dysfunction and memory loss in Alzheimer's disease. Okay, let's talk a little bit more about these A-beta oligomers. Can you go to the next slide? Thank you. So why are these A-beta oligomers of particular interest? In addition, as we were just looking on the last slide, there's a diverse set of pathophysiological signals that these small soluble protein fragments cause. They also show up very early in the course of disease. So 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're also a persistent component of disease. So 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. So next slide, please. All this leads to this refined A-beta oligomer hypothesis where, you know, plaques may be the visible pathology and the original thinking around amyloid biology, but these small, harder-to-tect oligomers are the most synoptic toxic species and may therefore be highly relevant for disease. Next slide, please. So 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. And the point of this mutation is a mutation in the amyloid precursor protein that leads to the production of SIBO ligomers, but no production of plaque. What you can see in this small number of families is that despite the fact that you don't 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. So 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 SIBO-oligomer hypothesis. Next slide, please. So, all this biology leads to coming up with Sobernatug to target the SIBO-oligomers. And so, Sobernatug represents the first oligomer-selective immunotherapy approach to treating Alzheimer's disease. And it's also the first oligomer-selective antibody that is being tested in the late-phase clinical trial. So as you'll hear later from Eric, Soberna Tug is currently in a phase two trial where we're focused on measures of cognitive performance in addition to the biomarkers that have been characterized to date. All right. So why then would you expect to see a difference between Soberna Tug 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 Cibernatug, which is targeting the soluble oligomers, and in this case, Lacanumab and Adacanumab, 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 adacanumab, lakanumab, and sabernatug on two different protein constructs of amyloid. So at the top, the A-beta-1 to 40 monomer, the so-called normal protein. And as you can see, sabernatug 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're comparing the affinity for SIBO oligomers. What you can see is that sabernotug has a higher affinity for soluble oligomers than either adicanumab or lakanumab. And 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. And so we see Sabernotug 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 Sabernotug 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 subernotug antibody to pull intact naturally occurring soluble oligomers directly from human tissue. His team reported that subernotug preferentially bound to soluble oligomers, whereas RMAP-148, which is the mirroring precursor for lacanumab, bound preferentially to proto-fibular A-beta. So again, additional data from the human brain showing that these antibodies are both recognizing amyloid protein, but recognizing different forms of amyloid protein. And as we saw earlier, those different forms of amyloid protein can have very different physiological effects. And these are not small differences. As you can see from the summary on the slide, Armab-158 bound approximately 64% of the fibular form of A-beta taken from the human brain extracts, and only 36% of the globular or soluble A-beta, whereas Sobernatug, in contrast, was binding about 99% of the globular or soluble form of A-beta, and only 1% of the fibular A-beta. So, a definite biologically relevant difference between the two antibodies. Next slide, please. Sort of furthering the comparison, this is now looking at the relative binding to vascular A-beta in a murine model of vascular CAA, or cerebral amyloid angiopathy. So this is recent work from Martine Grenin in Cindy Lemieux's lab at Harvard, comparing the binding profile for Sobernatug with the binding profile for Lacanumab in a head-to-head in a mouse transgenic model of CAA. So, in that study, lacanumab exhibited greater plaque and vascular labeling than did sabernatug, 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 sabernatug binds A-beta species less closely associated with vasculature than does lacanumab. 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 and Dementia. Next slide. As I mentioned, Sobernatug uses an IgG2 backbone, so that means that both lacanumab and denanumab, being IgG1 antibodies, signal to the immune system in a slightly different way than does Sobernatug as an IgG2 monoclonal antibody. That antibody subclass influences how strongly antibodies engage immune effector functions through FC receptors and complement activation. So why is IgG2 different? Well, compared to IgG1 antibodies, IgG2 has substantially weaker FC-alpha receptor binding. IgG2 gamma activates complement less efficiently. And IgG2 generally induces less antibody-dependent cellular cytosoxicity 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. So this is now looking at the current incidence of infusion-related reactions with the approved anti-amyloid A-beta therapies, lacanumab and dananumab. And 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. And so, 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-A-beta DNTs. 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. And, of course, there are changes in practice that have been occurring, most notably with Nanamab, where the company was able to show that a change in the protocol for dosing had a reduction in ARIA rates. But 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-E events specifically, are something that needs to be actively managed for patients. Next slide, please. So 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. So specifically, we're seeing changes from going from originally an autopsy based approach to diagnosis to be 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's 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. So, over the last 15 months, there have been multiple approvals in the diagnostic market for new diagnostic tests around phosphatel 217 to diagnose Alzheimer's disease, mostly in the U.S., although this is moving forward in the rest of the world as well. So, 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. So how are we using these fluid biomarkers in our own studies? And the answer is in multiple different ways. So 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. So 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're measuring amyloid-related pathophysiology, looking at A-beta 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're looking at P-tau-181 and P-tau-217, which, although are tau markers, they are associated with the pace of amyloid change. And then a little farther downstream, we're looking at GFAP for measures of astrocyte activation, and we're looking at a number of markers of synaptic injury because if our hypothesis holds for how Cibernatug is impacting the pathophysiology of Alzheimer's disease, we should be able to see effects on downstream markers like neurogranin and VAM2 that the antibody does not directly interact with. Next slide, please. So here are some of the results from our Phase I Intercept AD study in Alzheimer's patients who have been treated with Sobernatug once-monthly IV. And you can see these are data from the MAD cohorts. So these subjects, by this point in time, had received three consecutive injections of Sobernatug, 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 A-beta-4042, consistent with what you might expect to see if you are able to normalize amyloid function. And also, we see similarly dose-associated changes in P-tau-181. 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. So these data taken together are supportive of the profile of the oligomer-targeting Soberna Tug as having a meaningful effect on the fluid biomarkers in Alzheimer's patients. So next slide, please. We can also look at these biomarkers in a relative sense. So this is a comparison of results from multiple different existing antibody trials. So these are not cross-study comparisons. And so one always has to be careful with interpreting the results. But what you can see is that if you look at Sobernatug in red, what we're seeing is a fairly rapid change in PTAL 181 and also in neurobranin, consistent with the hypothesis that we're seeing a marker of early and significant impact on changes associated with Alzheimer's disease with subernotone. Next slide, please. So I hope I've convinced you of a couple of things. Sobernatug preferentially binds to soluble oligomers, which is a low-abundance, highly toxic form of A-beta that appears during the early phases of disease. This profile offers the opportunity to differentiate from the currently approved DMTs that target other forms of A-beta. In addition, that IgG2 backbone of Sobernatug really offers a different opportunity to interact with the immune system and therefore impact both the efficacy and tolerability profiles for subernitone. And finally, subernitone 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. So 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. And what I'd like to do now is talk a little bit about our altitude AD study. It's a well-powered phase two study that we believe is the first study to actually test the oligomer hypothesis with any rigor. So if you want to go to the next slide, we'll come back and talk about the slide in more detail, but what we're going to get out of this study, which is 542 people in a phase two study, so it's a large phase two study, we'll look at clinical endpoints, of course we'll look at safety, and then we have a number of interesting biomarkers that we looked at in our phase one study, and of course, now we'll look at it in our phase two altitude study. So if you want to go to the next slide. So you might ask yourself, well, how are they going to get all this data? Well, here's how we're going to do it. It's a three-arm study. So we have two different doses of Soberna Tug and one arm that's placebo. It's 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's available to people. And we've 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. So if you want to go to the next slide. So in our phase one study, we actually obtained a lot of data that were very good in terms of designing and planning this phase two altitude study. So if you look at the lower left on this slide, that's what we call a target engagement assay. So what you see on the y-axis is how much suburnitug there is that's bound to an oligomer. The x-axis is just the concentration of drug in the spinal fluid. So 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 one study was 60 milligrams per kilogram. But we would get the question, well, what if you get up to 60 and you don't see anything, you don't have any safety problems, you know, could you go higher? Well, what this graph shows you on the lower left is that when you get to the upper doses in the phase one study, you're already getting to the point of diminishing returns. In other words, that curve flattens. It doesn't just continue to go up. And so that tells us that there's really no reason to go above certainly 60 milligrams per kilogram and really there's probably no reason to go above 50 milligrams per kilogram. Now on the lower right you can see some model data so 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 and so we think the altitude is well designed in terms of having the right target engagement information. If you look carefully at that at 35 milligrams per kilogram. We actually have quite good target engagement at both peak and trough. But we also wanted to include a 50 milligram per kilogram dose group because we do think that based on our phase one results, there's more of a chance to see some reduction in plaque with the 50 milligrams per kilogram dose. Whether or not plaque reduction is important, for a drug like cibernatog that targets oligomers isn't really clear but just in case that was necessary we wanted to include that higher 50 milligram per kilogram dose in the study so if you want to go to the next slide now this is a bit small and there's a lot of information on here and I'll 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. But the important thing is on the left, you're seeing changes in CSF biomarkers, including things like neurobranin, VAMP2, PTAL181. And it's a very consistent effect in terms of lowering those things. They're not all statistically significant, but directionally it's very consistent. On the far right is the A-beta 42 to 40 ratio that tends to go up, which is what you would want to see. So this is after just three administrations of Sobernatug in a phase one study. So these data, at least in my view, were surprisingly good. And obviously we've taken these types of assays and incorporated them into our Phase II altitude 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 field, exploding topic for the field. And we've continued to look at those, obviously, in our phase two altitude study. But these were all from just our phase one study. So if you could go to the next slide. And then the last thing to think about is that we are in IgG2 with the other amyloid-related antibodies being in IgG1. Now, IgG2s have less of what's called effector function than IgG1s, that conceivably could provide you with better safety. Again, in our phase one study, those are small studies, but the safety appeared to be quite good. We did have five cases of RAE, or about 10% of the patients. But importantly, Only one of those was symptomatic, and that person's symptoms were very, 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 went away. So, being an IgG2, we think has the potential for improved safety compared to the other monoclonal antibodies that have been approved or being studied. So, if you want to go to the next slide. Well, let's talk a little bit then about the Idris as our primary endpoint. Some of you may be more or less familiar with the IDRIS 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. But if you just want to go ahead and go to the next slide. So let's talk a little bit more about the IDRIS 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 IDRIS 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. So in the IDRIS, 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. So 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 IDRIS, 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. So the net result of some of these differences, I think, is that if you look at the signal-to-noise ratio for the IDRIS, 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 IDRIS and the CDR sum of boxes in them to compare head-to-head, but the expedition studies, which looked at a drug called solanazumab, actually contained both of the scales, and so you can compare them directly. And so in the Expedition study, the effect size was much greater for the Idris. It was 0.193 compared to the CDR sum of boxes, which was 0.006. For the Expedition 2 study, the effect size was about twice that of the CDR sum of boxes. In Expedition 3, it was higher, but not by as much for reasons which aren't clear. But very consistently, you see a higher effect size for the Idris when you can compare it head-to-head with the CDR sum of boxes. And then finally, the last line there is looking at denanomab phase 2 studies, and I think this is a good illustration, actually, that in the phase 2 study of denanomab that had 245 people, the IVRS did reach statistical significance at 0.04, but the CDR sum of boxes did not at 0.14. Now, when they went on to phase three with much larger studies, both of those were statistically significant. So it's like a lot of things, if you're underpowered, you just need more patience. But I think it's a good illustration of the fact that you can be positive on the Idris and negative on the CDR sum of boxes. And we just feel that overall, the IDRIS is a more sensitive scale and accurate scale. And that's why we chose it as our primary. But again, the CDR sum of boxes is one of our key secondary outcomes. So 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 study was we used a blood test, PTAL217, to screen people for the study. So 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 study. And what you can see is that the primary reason for screen failures in our Phase I study, which did not use this PTAL-217 blood test screener, was amyloid PET scans. If you look at altitude, the largest reason for screen failures was the blood test, the PTAL-217. The overall screen failure rate for both the Phase I and the Phase II is about the same. But the question is, why do you screen fail? And 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. So at the time we did this, 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. but it cuts down considerably the number of PET scans or spinal fluids that you need to obtain. So if you want to go to the next slide. So this is a graph of our enrollment for the study, which was very rapid. We enrolled the study in 10 months, and that was well beyond anybody's expectations at the time. And 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 and they like this PTAL-217 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 like 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 UK sites and that always takes a little bit of time but if if we would have just let the US keep running with this and we probably would have even enrolled it a little bit faster so we were very pleased with this And what we've heard from the sites is they were very pleased with the protocol, too. So if you want to go to the next slide. And so here's the net result of this. So we, again, we were doing some very novel things. And at the end of the day, what we want to see is how we compare it with clarity. The clarity study of Lakanumab has a patient population most similar to ours. For those of you who are familiar with the trailblazer studies of denanomab, they had a requirement for tau, which we did not have. Clarity did not have. So they have a little bit different patient population. But again, Clarity did not have the PTAL-217 screening because when they designed the study, it wasn't available. And so, and we did have that PTAL-217 screening. But the net result, when you look at the baseline data for altitude and clarity, is they are very, very similar. So, in other words, we were able to implement this, at the time, novel screening technique with PTAL-217, but we ended up with essentially exactly the same patient population as was obtained with the clarity study where they did not have the screen with PTAL217. So 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. So again, we're very pleased with these results. So if you want to go to the next slide. So let me talk then in a little bit more detail about what we are looking at in the study. So I talked already about our primary outcome variable for clinical endpoints is the IDRA scale. But again, the CDR sum of boxes, of course, will be a key secondary. the ADCS-IADL and the ADOS-COG that you see there are actually components that make up the ibris. So we'll look at those things individually. And of course, as I mentioned, and as you heard, we did see some plaque reduction in our phase one study. And so we'll look at that in altitude, 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. And obviously, we're going to look very carefully at RAE rates, RAH 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 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. And then finally for biomarkers again we were very pleased to see these change in in our phase one study and we'll be looking at these again in in the phase two study one one of these which is particularly i think important for us is neuro granin because it's a synaptic biomarker it's a post-synaptic biomarker and uh these oligomers are toxic to synapses and so we're looking at the usual suspects in terms of csf biomarkers but the neurogranin is something that we want to demonstrate that and expand on our phase one results and show an effect in our much larger phase two study. For plasma biomarkers, GFAP is an interesting one. It actually reflects astrocytes, which are a different type of nerve cell um and it's sort of an inflammatory marker so we saw again some phase one data that looked um very promising for gfap we'll be excited to see the results from a much larger phase two and of course we're going to look at ptau 217 uh not you know we used it as a screener but then we'll also be looking at that as a measure of at least biochemical efficacy so if you want to go to the next slide so these are the takeaway messages and i i'm not going to read all these these to you we just talked about those but i think the thing to keep in mind is that we had as you heard we had some very good phase one results which led to a phase two study 542 two people so not a small phase two that enrolled very very quickly very smoothly we have a high percentage of patients who elect to roll over into the open label extension so they they like being in the study they like being on the drug and and certainly the sites have told us the same thing so we're just very much looking forward to seeing the results from altitude when those unblinded results are available. So thank you very much. And with that, I'll turn it over to Paul.

Thank you, Eric. So 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. So 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 barbain barrier with only about 0.1 to 0.2 percent of dosed antibody actually reaching the target in the brain. One way to get around this of course is to give higher doses of antibodies so companies have increased the dose and by increasing the dose you get more antibody that trickles across the barbain barrier to get to the brain. Another way is to engineer or develop antibodies that have longer half-lives. So 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 A-beta antibody space, ARIA-E and ARIA-H are the main concerns. that we see when we increase drug levels. So, 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. So, in areas close to large blood vessels and to the ventricles of the brain, we see higher concentrations of antibody. And 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. So one way that companies have tried to get more drug into the brain is the use of the receptor-mediated transcytosis system. So 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. So 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 and 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. So what I'd like to describe to you is our effort to develop bispecific antibodies for the treatment of Alzheimer's disease. So 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 a beta species of interest and 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 a beta you bind to as we know there are antibodies that target large portions of A-beta plaque, protofibrils, fibrils. Some target monomer, and our company is unique in developing antibodies that target A-beta 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 the 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. So 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 A-beta oligomers are the toxic species in Alzheimer's disease. So we've selected two antibodies from our portfolio of antibodies to take into this program. ACU-193 or Sobernatug, which is currently in phase two clinical studies that read out later this year, and a novel antibody called ACU-234, which we developed and has new and unique properties. So at the other end of the molecule is the transporter. So 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 antitransferrin receptor molecule approved in the world for the treatment of a rare brain disease. And they have a platform of transferrin, single chain, and BHH transporters that we could use to screen for molecules that work best with our cargo. So, this is the approach that we took. So, we really were agnostic in how we viewed molecules of interest. So, we kept in mind transferrin receptor affinity, the architecture of the molecule, the valency of the molecule, and selectivity for A-beta oligomers. But we did not go in predetermining that any one of these should be of a certain form. So, we looked at a range of transferrin receptor affinity, a variety of architectures, both monivalent and bivalent, and a range of A-beta binders. So, 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 transparent receptor in the single-digit nanomolar range. And 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 into the brain after sub-Q dosing, and that antibodies are released into the brain and are able to engage A-beta species of interest. As you can see at the bottom, we also look to make sure that the antibodies still bound A-beta in Alzheimer's brain. So this is a histological study that we did showing that both ACU-301 and ACU-401 are still able to bind the A-beta species of interest and that this wasn't altered in the construction of these bispecific molecules so this is just one slide showing some of the in vivo work we did in mice um as you can see after sub-q dosing acu401 you can see that there's rapid uptake uh the red line into the blood after sub-q dosing um you can see that it becomes comparable to the ib 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. And then the sub-Q dose, you can see kind of lags a little bit behind the IV dose. both have a high C-max, both have a very nice T1 half-life, and suggest that these antibodies are worth taking forward into additional studies. So our next step was to look at these antibodies and how they perform in primates. So we use cinemologous monkeys for these studies. And as you can see, we designed a two-phase study. So in the first phase, animals were dosed sub-Q with 5 mg 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. And 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. So animals were then dosed IV with two mg per kg of antibody, the same antibody they received before. And then 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. So when we look at the PK, you can see that both ACU401 and 234 are rapidly taken up after sub-Q dosing. On the left, you can see kind of a blow up of the first 24 hours. You can see that very rapidly, within 8 to 12 hours, the antibody is getting close to a C max, 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, and what you can see is that after sub-dosing, ACU401 at the end of two weeks still has a very good half-life and suggest that as we go forward in 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. So when we look at three regions of the brain, the prefrontal cortex, the potamen, and the hippocampus, we noticed that the trends with ACU-401 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 ACU-234. At 24 hours, this increases further to a 40-fold difference between ACU401 and 234. And this is a pattern, again, that we see in all brain regions, including the potamen, 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. So we're thinking that this elevated level in the hippocampus is likely due to either a contamination or sampling error. And 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, but what we saw was that if you look at drug levels in the CSF, there's no difference between ACU-234 and ACU-401, again highlighting that the transfer 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 sub-Q dosing. We looked at red blood cells, hemoglobin, hematocrit, and reticulocyte count, and you can see that either dosing with the monoclonal antibody 234 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. So to summarize the key takeaways from this study, we've shown that when we dose with ACU 401, 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. And after sub-Q 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 So when we started this program, we had a lead candidate profile in mind. So 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 uh at least 40-fold increased 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 a beta 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. And this is important because we can dose at much lower levels with this high affinity binding. And 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 four degrees for an extended period of time. And finally, we saw that there was a very good uptake of drug after sub-Q dosing. and that this should allow us to move into the clinic with a subcute product. So what are our 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. And then, finally, we're developing bioanalytical assays that we'll need for the clinic, PD, PK, ADA, and other assays. And, of course, throughout this process, we've been interacting with the agency for their guidance. So, our next goal is to file an IND next summer, mid-2027. And 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 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile our Q&A roster. Our first question is going to come from the line of Pete Storofilos with Cantor. Your line is open. Please go ahead.

Hi, Dan. Thanks for hosting the event, and thank you for taking our questions. You know, when you look at the baseline characteristics of those enrolled in altitude, how do they sort of compare to the enrolled in the registrational studies for lacanumab and denanumab? And, you know, when you look at the baseline CDR sum of the boxes for altitude, it's 2.91. You know, clarity 3.17. I believe for denanumab, it was 3.9. Sort of help us understand if these are similar populations or there's some type of meaningful difference on the CDR sum of the boxes.

Yeah, well, thanks for that question. this is eric i'm happy to to take that one so if if you look at um we'll just start off with the cr sum of boxes uh there's a numeric difference uh there are small numeric difference but um especially and i know the print's a little small but if you compare it to the standard deviation those now these aren't head-to-head comparisons obviously so you have to be careful but those differences certainly aren't clinically meaningful, and I don't think statistically they're significant either. I mean, 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. And if you look across the board at all the baseline characteristics, they're very, very similar. And to my mind, I don't see anything in there that's a meaningful difference in the two patient populations. For denanomab, as I mentioned, those patient populations are a little different. And I think that's because they had this requirement for a certain amount of tau positivity. So if you look across all the various measures. The denanomab studies, the patients are a little bit more advanced or a little bit worse. So that is a little bit different patient population. But for us, for altitude and for clarity, that's about as close as you're ever going to see in terms of baseline characteristics in two different studies, I would say.

Thank you for that. And, you know, As you noted during the call, there was in the Alzheimer's space in terms of biomarkers to appear far in advance of symptoms, as well as, you know, some of the underlying pathology like various top species. You know, how do these updates, including newer biomarker updates, inform your approach and assumptions about disease and clinical studies? And are there any that stand out to you, especially the newer biomarkers? As you, you know, look at alpha phase three, you know, including biomarkers not listed in your presentation, like perhaps 2, 4, 3?

Well, yeah. Go ahead, Jim. No, another great question. And, yeah, the field is moving so quickly. It's a good problem to have, obviously, but especially PTL-243 is one of the ones that is newer and seems to be, you know, quite promising. But the first thing that we'll do, actually, of course, is look at our altitude results and look at the biomarkers that we do have in there. So just for instance, when we designed the altitude study, there weren't any PTALs that were FDA-approved at that point, or there weren't any diagnostic, blood-based diagnostic biomarkers approved at that point. So now we have four of them. So one of the things we'll go back and look at when we get our altitude data is when we do design our phase three, should we tweak the screening procedure that worked very well previously with the PTAL-217 assay that we use? But now that there's four different assays that are FDA approved, we'll need to rethink that for what we do in phase three. So, but anyway, there's a lot happening in the field, and it's a good problem to have in a way. I mean, we're going to look at this very carefully. Jim, did you want to add something to that?

Yeah, Eric, just to layer a couple of additional thoughts on, and 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. So, we certainly know that there are additional markers that are being evaluated now, and I think that's only going to continue. You mentioned 243 is one of them, and 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, And I think that only helps in diagnosis, but I think it'll also help in clinical trials. And 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 the clinical symptoms have appeared. And as we showed earlier, there's a ton of evidence that there's physical interaction with synaptic circuitry. So, you know, it's entirely feasible that there are measurable things happening in the brain that are occurring very early in disease. And so I think future work will be to try to understand, does that mean that there is pathophysiology triggered by oligomers that can be measured early on? So I think there will be multiple ways that biomarkers are going to be utilized moving forward. And it's just really great to see both the expansion of markers like PTAL 217. 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's going on and hopefully how individual treatments are benefiting patients. So I think all that's to come. We've 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 would 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.

Thank you. Just one last question on EBD. Let's say that altitude reads out positively. Will that impact your decision to sort of bring Sobernatug versus 234 forward? You know, positive data would just clinically de-risk the binding properties of Sobernatug. So, you know, why not stick to supernatal?

So, Jim, do you want to grab that one? Yeah, absolutely.

And I think the way we think about this is, as Paul very well said in his presentation, we've been fairly broad in our thinking around what's the best set of properties to have in a molecule. And we think that 401 and 301, having both of them, gives us optionality. Each one offers different opportunities. And it's important to note that 401 is, as Paul described, coming from 234. And although 234 is a distinct molecule from Soberna Tug, they are quite similar. So we haven't made major changes. In fact, we still like the selectivity and monomer affinity that we have with 234. And, you know, it actually even offers some opportunities different than what we get with Soberna Tug. So we think both are really robust candidates, and we'd 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's got the overall best set of properties to take forward into phase one. But I think also the good thing is that what I'd 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'll still have the other molecules sitting in late preclinical phase that we could possibly bring forward in the future. And 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 bar markers or in earlier phase of disease. And so we really want to maintain optionality. And so we're interested in profiling both molecules.

Thank you very much for taking our questions.

Thank you. And one moment for our next question. Our next question will come from the line of Paul Matisse with Stifel. Your line is open. Please go ahead.

Hi, this is Emily on for Paul. Just a couple quick questions for us. So on the EPD profile, we were wondering what's the TPP here? You know, so like what dosing frequency would you like to see, as well as maybe, like, how quickly do you think you can get data from inpatients following that mid-2027 IND filing? Yeah, thank you.

So, we're open to all of this at the moment. We are currently running another primate study. And in that study, we're looking at different doses and different dosing frequencies. and we're hoping that the output of that study will guide us in how we set up and run our phase one SAD-MAD study. So, certainly weekly, twice monthly, monthly are all under consideration at the moment, and we haven't made any decisions about the dosing frequency. We'll let the data guide us in how we do that. In regards to the design of our SAD-MAD study, certainly something that that we're discussing right now uh thinking about uh the best option for this molecule and uh you know based on data that we get from the altitude study uh will certainly directly impact how we think about um the studies that we run the biomarkers we use the end points of interest uh so yeah all of that is still under consideration and um as stated you know by the middle of next year, we'll be ready to move forward.

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's probably fair to say a key determinant of success and altitude will be the placebo arm. So given the use of the P-tau screening, the relatively high proportion of MCI patients and some of the similarities you've highlighted with Clarity, 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. So, you're absolutely right. The patient populations, well, first of all, the patient populations in Clarity and altitude are quite similar, and there's 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. So 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 lacanamab showed a signal in a patient population that's very similar to the patient population we have in altitude, I think bodes well for us. That seems to be the sweet spot. So even though the placebo decline may not be as great, your drug efficacy ends up being better in that earlier population. So 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. So we feel good about the patient population that we've identified, and I would expect the placebo decline will be similar to what we're seeing in Clarity. We obviously don't know that at this point, but that would be my expectation.

Makes sense. And then maybe as a quick follow-up for Jim and Dan, it'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. And so we think there's ample opportunities to differentiate on both efficacy and safety. And a clinically meaningful safety benefit we think is commercially pertinent. So that is an important underpinning of the value proposition of Sobernatug 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 homozygates, is an important aspect of sort the overall, the totality of the opportunity for Soberna Tug to differentiate.

Great. Thanks.

And one moment for our next question. Our next question is going to come from the line of Jeff Meacham with Citi. Your line is open. Please go ahead.

Hey, guys. Thanks for hosting this event. Super helpful. I have a couple of questions. The first, maybe it's just the oligomer hypothesis. I'm asking if you, what clinical result from altitude do you think would most strongly validate the attribution of the, you know, of the oligomers and the effect for Soberna And the second question is, you guys have a slide on the FDA approvals of the blood-based diagnostics market. But just want to get some perspective of when you think these should really get some momentum commercially from, you know, from neurologists. Does that, you know, help you, hurt you, neutral to you? Just wanted to kind of put that in context.

Maybe I'll lead out and then invite Jim or others to comment. I think in terms of the clinical validation of the oligrimal hypothesis, I know personally I'm looking for a pronounced efficacy signal, and that is, you know, on a clinical measure supported by downstream biomarkers. We've talked a lot about the biomarkers, and I think some of the biomarkers that are sort of on mechanism for an oligomer-directed approach are the ones that are going to be service, underpin that validation. So, that certainly would be the most robust validation and clinical evidence in support of the oligomer hypothesis. And in terms of the diagnostics, I mean, that market is, as I think Jim mentioned, we've got four agents, excuse me, four tests approved in the last 15 months. And so it, again, is sort of in the early phase of commercial deployment. But given the demographics and the population, we see that that, you know, minimally invasive, relatively low cost measure could really inform the overall population that is experiencing the early onset of amyloid pathology, presumably oligomer, potentially oligomer related pathology. And so that will open up, I think, the field more broadly and, you know, necessitate access to better treatment options.

Yeah, I think Dan said it well, but I would just echo, you know, the oligomer hypothesis, the target's been validated. Amyloid biology has been validated as meaningful for Alzheimer's disease. And so we're really at this point, and we've got the data from the altitude study that we've been talking about. So there's biomarker evidence that there are things physiologically happening. And, of course, we can show that Soberna Tug 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. So, it really does come down to, does that hypothesis then result in a meaningful effect on cognitive function? And I think for us, that's what's exciting about altitude. We're really going to be answering that key question for ourselves, but also for the field in general. And 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 that we'll see so those those are the kind of things that we're really going to be looking at none of that should be surprising to anybody but uh obviously the cognitive readouts are the most important thing and then 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 and maybe just one quick thing about the uptake of the diagnostics um in our discussions with KOLs, it's 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. So I think that now that's not necessarily our view, but you can find that opinion. But I think that's a good indication of how rapidly I would expect the use of these blood-based biomarkers to increase. Thank you.

Thank you. And one moment for our next question. Our next question comes from the line of Tom Schrader with USB slash BTIG. Your line is open. Please go ahead.

Thank you for taking the questions. terrific event uh very related questions but eric is the best we're all going to be looking for comparative signals it's the most likely best comparator cdr sum of boxes versus clarity and then on the oligomer line of questioning you know because you're 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? And then I have a follow-up for Paul.

Yeah, well, as far as the CDR sum of boxes, as I mentioned before, there aren't a lot of studies that have the Idris and the CDR sum of boxes. But if you want to compare to clarity, you pretty much are going to have to use the CDR sum of boxes. Again, you always have to be little careful about making comparisons between studies because they're not head-to-head comparisons really so you know we'll see what we get and that'll be the scale that can translate best i would say um so hopefully that 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 i I mean, 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.

And that's certainly something that we'll be looking for. So 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, we certainly noted, is the rate of effect is quite rapid in the Sobernotog intercept data. So that is at least consistent with the idea that you've made that we might be able to see rapid effects.

So that's certainly something we'll be looking for in the much more complete and the much larger data set from Altitude. and a follow-up for paul and i'm not sure what you can say here but 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 uh and i guess uh you're obviously very close to the field are other people that are i mean there's a huge number of programs there were other people finding what you are finding that highest entity tfr binding by valent does make sense just any sense of because what

you're finding is so different than what we've been reading about for three or four years i'm curious if you give us any help right so so again we went into this you know with with eyes wide open not um not relying too heavily on the dogma so again we we went through a library of molecules and let the data drive the selection of leads and, you know, progress from there. I think the early work was done, you know, Genentech and Denali are similar platforms. You know, both came from Roche, Genentech. And in their hands, you know, monobalant looked better than bivalent. antibodies that had a lower affinity seemed to perform better than high affinity. And I think from there, everybody assumed that that was, you know, how all molecules worked. I know that, you know, at the ADPD meeting, and again, at AIC 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. and 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, you know, all molecules need to be at a certain affinity to work. So, you know, 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 didn't release from the receptor from the blood-brain barrier wall to get into the brain. So, you know, we were able to confirm that if the affinity is too high, that the antibody doesn't release to get to target. But in the low nanomolar range where our leads are, they do seem to release, get into the periculum of the brain and engage A-Beta as we would like. So I think it's still early days.

Thank you. And 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. And one is the slide 10 frame that phase three is partner enabled. So, is this a base case rather than self-funding? And another is on sub-Q. How are you thinking about the role of sub-Q in late-stage development? And then I have one question on EBD.

So, thanks, Deb. I'll address the partner question if I understood it correctly. So we think that on a successful phase two result, there will be tremendous interest and desire to expedite the development of Soberna Tug. And doing that with a partner makes a tremendous amount of sense. Precisely how that comes about, I think, is to be determined. But I think in terms of the scale of the phase three 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 SobernaTug playing into a phase three strategy and haven't specified precisely how that has how that will be incorporated. There's prior precedent. I think if you look at Lakembi, you know, their first use of subcutaneous Lakembi was in a maintenance mode as part of the open label extension in their Clarity AD study. So there are a couple of things for us to look at, a couple of things that we're thinking about. But, you know, we see a partnership for phase three as an attractive way to unlock more value for stakeholders interested in seeing Sabarnatag move forward.

Great. Thank you. And 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?

So, 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 and anemia is another concern. So, this molecule, as we've seen thus far, no evidence of anemia. So, we believe it should have a better safety profile. You know, again, you're not going to know for certain until you go to the clinic and do those studies. But, you know, the optionality with the EBD program is, you know, if we have a molecule that's getting in 40 times better than a monoclonal antibody, you can either dose the same to get the same, you know, efficacy. So dose 40 times less than SuburnaTug to get the same efficacy. Or if there's, you know, an opportunity for more efficacy, you can dose more drug safely. So 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. And it's not, and as Paul and I've 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. But I think additionally, in the case of an A-beta-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.

And 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 um we did have a few come in um one was are you using ai to assist in analyzing the trial data more quickly for altitude so i'll turn that over to uh i think jim yeah happy to take one that one so that's a really interesting question uh the short answer is we are like i think everyone we are trying to best understand understand how we can use AI tools for a lot of the things that we do.

So 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. But 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 end points, a lot of time points, and a couple of different concentrations of Soprano Tug 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. But 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. So, the open label extension, which was initiated in 2025, should we expect any OLE data in the readout?

Just clarify that. yeah no thanks thanks for the question we will not include ole data in our top line results and the reason is because um obviously some of those patients will have only rolled over into the ole for a very short period of time and it uh 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. But 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.

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. So I'll 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 just connect. Everyone, have a great day.